sr | NON MTT 3 9002 06679 0123 PRESSOR RESPONSIVENESS TO ANGIOTENSIN AND NOREPIN EPHRINE IN THE HYPOTHYROID RAT A POSSIBLE MECHANISM FOR THE REVERSAL OF EXPERIMENTAL HYPERTENSION IN THE RAT BY HYPOTHYROIDISM RAR IMA TARZANA RAGNAROS, PATS T IRL NENA PEALE NCATE ITE a DUAN F. JOHN GENNARI 1203 MUDD . LIBRARY . Medical MEDICAL LIBRARY Digitized by the Internet Archive in 2017 with funding from Arcadia Fund httos://archive.org/details/pressorresponsivOOgenn Pressor Responsiveness to Angiotensin and Norepinephrine in the Hypothyroid Rat: A possible Mechanism for the Reversal of Experimental Hypertension in the Rat by Hypothyroidism F. dohn Gennari Submitted to the Faculty of Yale University School of Medicine as partial fulfillment of the requirements for the degree of Yoctor of Medicine. From the Department of Internal Medicine wet me P JUN 1963 LiBRARN Acknowledgment I want to express my deepest thanks to Dr. FP. d. Mulrow for his guidence throughout the course of this study. His constant insistence on maintaining the prin- ciples of scientific technique in animal experimentation was an invaluable course of instruction for the novice who wishes to enter the field of medical research. His day to day enthusiasm and willingness to sit down and discuss problems were an added gift, and a continuing source of inspiration. I also wish to thank Pat Rice, who always expedited the delivery of equipment and rats, Nancy lowell, who helped me with laboratory technique, and Victor Faisano, a Notre Dame High School student who worked with me during the summer. My thanks also go to Voctors Gerende and Anderson in the biostatistics department for their assistance in the statisticel analysis of my results. .b ..4 .1@ of erltadt t2eqesd ym aaetgxe od daew L.. atds to gatueo ot tueadgiuctdd gone 5 bag aid tot worluM -~qizq edd aninistaiem mo soqsdahent tastemoo aiH ~Vbsdc noi¢ednemitegdxe Lemina ni ¢vpiadeed oftitnetoa To aelqie soiven ais tot noidoutsantl To Setuoo oldewtayat sass 638 2ffi ,Sovseaet [soibom to bisit edd t6tns of BE oly bos mvob tie.ot ezacngatifiw ong misteudiag Yeb oF me goivaidaoo s bas itis babbs 18 Stew emaddorg eauoe ib ‘ ,moitariqest to sawo0e hoy ibsqxe ayswia odw ,soit dst xual od datw of le ae odw ,ifswol yous ,aist bas tasm@giups to: Rtotaen ead ,onsaiei yodokY bas , eupkadoed yiotaarods ft dd iw oor beqiosi ax déiw Seidrow ody: Saobyte foodse dg tl ema€.ertoh 2 -1smmse ond griiud roe tebeAd Bas ebuetad 2 ardthelt od cg ocala axasad yl peng 10% toedPtsgoh goitariadeoid. adi mi .atigeaest yor to eltayians fsoitetteta edt af Introduction Method Results Discussion Summary Figures Tables References Table of Contents 19. 20. 26. 31.6 “Fi i 2 ee _s : oe - tagtno) Introduction A relationship between thyroid function and the production and maintenance of experimental hypertension in the rat has been demonstrated by many investigators. braun-Menendez (1) first showed that thyroidectomy or thiouracil administration in the rat reversed or pre- vented renal ischemic hypertension. ‘ince that time, Salgado (2) has shown that experimental hypothyroidism prevented the hypertension produced by desoxycorticos- terone (DOC) administration, and Chappell et. al. (3) reversed or prevented adrenal regeneration hypertension by propylthiouracil (PIU) administration. Recently, Fregly (4,5,6) has shown that PTU administration or 1?) treatment also prevents or reverses renal ischemic hyper- tension, and that PTU administration has the same effect on the hypertension produced by a high salt diet. The question that naturally arises is what is the mechanism of this phenomenon. In seeking a common de- nominator for the effect of thyroid suppression on so many forms of experimental hypertension, one wonders whether vascular reactivity to pressor hormones and its relation to thyroid function plays a role. Hyperthyroid- ism in man and in the dog has been shown to increase cardiovasculer responsiveness to norepinephrine and epin- ephrine (7,8,9). Conversely, Page and McCubbin demon- strated a decreased pressor responsiveness in hypothyroid degs to norepineprine, epinephrine, and angiotonin (10). However, they were unable to reverse renal ischemic hyper- tension in the dog by thyroid ablation ‘Chor The purpose of this study, then, is to investigate the pressor response to angiotensin and norepinephrine in the hypothyroid rat, a model which has been demonstrated to reverse experimental hypertension. eit Das meitunee btoryas agowsed. dtneagindaiter’ as nolened rogyel {stuemiteqxe to sonsnstnian bas nottouboug etodsgidcevnt YA yd botstiamomed aged ash tat pdt oe 10 Yaotsebiorydd tadd bewods, sarit At) sobmenan- posse i ~sig 10 beatever tat ont ci soiiatieinimbs Lioesuoasds emis teds eect? spereset oioeaive i Sehied harsy sbi encgheah vd hapa noida Caine ONS | (¢) .f8 .do [isqget® bas moitartetainbs (900) oporag ‘ofamedteqyud noitstameget Laneths beimeverq x0. 9at3 UitnaeeH .nolttetts inimbs (urd) Lioaxmoind Iyqotg z 10 nottsttainiads UTE tadd nworde aed (BeSeh) » race “requ. otmentoe ts iene agSeLavet To aieevetg cals tem | Sootts sues oft eet moidetdeinimbs UTE tadt bas atotéaot hae tab tisa dy tad s yd beouborg pe senate am a0 —p oft ai dsdw ak eeetita ylisisten sant goiteeup. od? . ie -9b somuco § saitese al sfonsmongdg aids to we ineioem oa NO volecetqqua: bioryald to soothe, eid 10% rotaninon, ie ? 2tebaow eno , mors Ketteqgyl Isicomfiteqxe ei amo? Yas sdi bas esnom1od teeeetg of ytivisoges raieomev aontodw -hiowgditeqyH .alot s ayeiq sotsonat bioryds of fotisies _ gansuoni o¢ mwode need asd gob odd ni bap supe Rt mat “Wyo Sis euitdgenigeton of ssenpvienogeen isisoaavoibtas | ~fomeb aiddyvoll bins egst ,yleatevaod (28 eT) oni rigs blorygdidogys! mt seehevienoges1 toReesq beesetaeb s betetta -(Of) ninosofgns bas ,satidgenige ,smitqoeniqeton od jagab € “Toit Qimedtoer ieaet sarevet ot sidsny etew yedt _tevewoH (ff) soistelds bionydt yd gob edd ai aotenot sisgitgevar od at ,uodt ,vybudea atdt to saequsg adT anixtdqenteerton bas itenetoigns ot senoqzet toaaeny end, hbotettadomeh ased esd doidw fobom s ,tax biotytoqym: ond nb oO Lane t tagqyal Lei nominague 96 TOVe't Ct Method A colony of 30 male Sprague Dawley rats was main- taanea on regular Purina laboratory chow in a temperature controlled environment Cri mee The rats were weighed twice weekly, and blood pressure determinations were made at least once weekly throughout the course of the study. Blood pressure measurements were done in the unanesthe- tized rat according to the technique of Friedman and Freed (12), modified by Fregly (15). The figure obtained for the systolic pressure in each rat is the mid-point of 4 consecutive blood pressure recordings within a 10 mm. Hg range, after stabilization of the rat in the re- straining cage. 4fter three weeks of baseline blood pressure and weight determinations, 12 rats were chosen for y131 treatment. This group included 4 rats in which angio- tensin response measurements had been carried out, ac- cording to the method described below, prior to treat- ment. The other 8 were randomly chosen from the colony. Each of these 12 rats was given 850 microcuries (uc.) Nar?! intraperitoneally. the rats were then isolated for 83 deys, after which time they were returned to the same environment as the control animals for the remainder of the experiment. Norepinephrine and synthetic angiotensin II were used for the pressor assays and were diluted to the de- sired concentration in a normal saline solution, to which 100 units of heparin per cc. had been added. With angio- tensin only, polyvinylpyrrolidone, 1 mg. per cc., was @lso added to the injection solution to minimize losses due to adsorption. The pressor agents were injected intravenously through a #24 needle in the tail vein of the unanesthetized rat, according to the technique of : | : ey 7 © ae, a, " ; -ien eau sier yolwued oe ofa 0€ to gaotos A- ni 7 suitstequed 2 ai vedo yrodutod sh sulwL telegen we sensed berigiow stew atat edt .(.4°SP) J MOMmAOTL VAS Secchi) absm o1sw acottentansteb etwecste boold bas), MOew eoiwh) .yYouta odd te saxyoo outd inodgsotde yiusew sone teaol sa, ~ordeenasie od. at en0d gtaw attemetvesem stveastg pool’ bas aawbotxd to supintiges oft of gatbr0eosa ter Sesid iy benissido eiwgi? eft .(&L) ylaeil yd bettibem (81) bee% inieg-bim odv~ai dst dose mi ot#kestq obLodeya: odd 10% OL s aidtiw egnivbtoos,r sxwaestq boold oviduodenoo it a: -ot sid mi tert oft to mottexifidsda rstts ,ogaet gil a + 9B HI" ouinberse a eit 4 Drs guyeaety boo fd enitf{eersd to antgaw sotdt ila | Cla act mosode etew ater Sf atocteaisieseb: aioe -oigus Moidw ct eter * bebelont quong etal taomtaerd | 98 ,ivo Set11e0 heed bed atnemervesem senoqast miaasd -tsexid oF totrq ,woled bediteseh bomtem orid) ot Bokbr09 | — sitd mort mseorio ylaobust s1ew!8 teddo SAT inom .on) eeitootota O88 sevig asw atex SJ seeds to dogd, bsteloek neds stew avery eA! .yileemetixrsqartar, Pei tay, edd oft beniuset stew vert outs ciotdwiretie y~ageb es 10% qahitcwey edt 19% siamins floréneo ont ee tdompotiviee same , tgembisgxe 9i5 to) etew Il aianesotgns oliediaye bus eniadqeniqetell. » Sh ot od peda lib Stew bis aysers ToReetq oAs TOT peas tokdw ot ,moLrtefow onilse lagioa s nat Nok tate wbomes beta ~cigns Ati” .ao5be nosed bed .09 19q niteqed to atgamO0i 28w ,..99 tey .ae f ,snobiLorayg i ynivylog 4 vino mianes ageaol esiminka ot moisuloa uoitos (iat ang og bubbe cz2ls botoeta: Yew cénsga teseetg ofl .meitqvoabs/ ot exb to wiev (ket ant oi elboon PS*t e dgwotde yLe -yomewerbat to supindesd edt of yoistovos ,dat bexidentazensay ont Cotlove (14). Figure 1 is a photograph of a rat in the restraining holder, with the tail pressure cuff, micro- phone, and intravenous needle in place. Pressor response measurements were always carried out in both e control and an y151 treated rat on the same day. Pressor response to a control solution of heparin-saline was also measured in each rat. The pressor response to angiotensin was measured from 43 to 5 weeks after pial treatment in the following manner. Two doses, 30 mug. (millimicrograms) and 60 mug., were tested in each rat. After stabilization of the rat in the restraining holder, and following 2 iden- tical blood pressure determinations at 30 second intervals, the test dose was injected rapidly intravenously, and the blood pressure measured at 20 second intervals until it returned to pre-injection levels. The difference between the pre-injection blood pressure and the peak systolic pressure following injection was defined as the pressor response. At least two injections of each dose level of angiotensin were carried out in each rat, except for rat #13. Pressor response to norepinephrine was measured at 6 weeks after y131 treatment in the same manner as angio- tensin except that the first blood pressure measurement was taken at 10 seconds after injection. ‘wo dose levels, 120 mug. and 240 mug. were tested, and at least 3 inject- ions of each dose were carried out in each rat. Thyroid function in the 1'°1 treated rats was assessed only incidentslly during the course of the experiment, by means of bi-weekly weight determinations. oid mi TH1 & TO ‘igs tgotonq 8 ei r stegiit (OL) svestod — orgie , Vise eineasetqg List eld dtgw. 19h Lock gaintatdect | ~m Sip ni sibess ap onerenapy tne node ve Cidela A betiTe9o caeaka 2 TSW. I MOMS TRG OR abstiiens canneTS.. e oh) 1, “4 eid oo tea pataow, '*'3 LB, baw foxdpoo 8 tod at JNO) to noitulor io1jnoo 8 of 9emogeet nossext., Web. omar a, ster nose mi berwesem oe ls 2a oni baanath beiwesen asw stanetoigas of satipaaat ronagigy of. aniwoflo? ait ni taemigets ety tt ts ansow ae od e a oy Oa bes (ametg oro tmet Lim). gun OF ,29aob uk sien to noldesiirdsde rettA tat dose, mi detagt -etow ,- Aum, «1ebi S gotwollot bos ,teblod grintattess ant ai det ond elevisint Bropse OF te enoitagimie: ab, ervanetg, bool igo-tt bar Ulewenevettal yibigst besoappi 2aw, gach .taas. edd, fisou eleviedni Dbroasee OS fa Dotveaem, stuaagtg boots sot, eonetettis edt .atlevel noitoo,aisetg od heatytet th aseg add bas s1Muae STG boold noiso@pat-s1g edt noewiad ogd eS beantich sew noijoe¢as gniwoLlfer owaaetg 9 bhoi aye ach doso to agoitoegar owd sanol oA . 920OGAat toecatg tgsoxe test Noans ai tuo beliies ga 19W tienetcigaa to Level | Sh det tod, te So %npssom asw exitdgenice ton oF 92 noGaet. _xovaett. -Ofgn6 as Tengen omee edt at tnemtsord rery tot te 2usew 2 tmanotwersm sinensig Dookd geait sat ded tqeoxe alaned ,elevsf agob owl sHoisoeagat tetis =beooge, Ot ds s5ls3 as i ds bas .boetest e1isw .gum O68 bas «gue OSt ~toopor € tess Jot dose ai dwo bebaiso stow ge0b deco To, aged bsaceass asw gixi batlsett yd ,dcomitegxe st to eetv0eo aft aaitud yYldeinobtagi yino eaotionintigb, tdgicew Yisxoov~id te sasem 4. At the termination of the experiment, 8 weeks after gl3! treatment, all of the treated rats were sacrificed, blood was collected for plasma PBI (protein bound iodine) determination, and the thyroid remnants were removed for microscopic examination. Five control animals were sacri- ficed and treated in the same manner for comparison. Plasma. PBI's were done according to the dialysis tech- nique of Seligson (15). Hematoxylin and eosin stains of sections of thyroid tissues were prepared. Statistical analysis of all results for significance was carried out by means of the unpaired 't' test. ab. euiliccs etew abst eteant. ond te ide “hie 133 s (ongbot haved gistotg) 18d eancelg 103 bate slieg: aaw boodd a). qiéasoitingie s bewode etst saitecototigas Io .gum 0@ bae Of sod of senogeet -28%q tot beteet? edsa € to ativaet oft eworle + aldsTt tette asvisow © basa groted aiemetotigns of aasrevienogeat Toe 1o229tq etotod beib ,éFk , sey dirvet sit) .tnomfasit Pihg to owl (.bodaed ed biuoo-tnembsens rely godts samogeet 2eonev temoqeet mi a2ne toe jonidaib es wede edst ae tdd ont sasotosh & ewode bain? atid brs s2tevel n20h deed $a). sift .lavel mienetotsas «Rum 0d orld ‘$8 gSanoqeo% 4On257q edt tud ,ylieotdatiste ditw Lseb od ifema oot ef quor stentt e8 betos atat edt doidw mi »youte aint af at [yest eee Pi own control, are in agreement with the results of the larger study discussed above. Norepinephrine Pressor responsiveness to norepinephrine was measured in 8 control and 7 hypothyroid rats. Figure 5 illustrates a typical response to 120 and 240 mug. in a control and a hypothyroid rat. The peak response occurred at the measurement taken 10 seconds after injection, and the duration of response was 30-50 seconds in all the rats tested. There was no measurable alteration in duration of response in the hypothyroid rats, but again, a decreased pressor response to both dose levels of norepinephrine was observed. The average pressor response and the number of injections carried out at each dose level in every rat tested are shown in Table 5. The data were handled in the same manner as the data for angiotensin. The mean pressor responses of the 8 control and the 7 hypo- thyroid rats to 120 and 240 mug. of norepinephrine are shown in Table 6 and in Figure 6. The decrease in pressor responsiveness in the hypothyroid rats was significant at both dose levels (p<.03, p< .001). 5. Pressor Response as % Change in Blood Pressure Because of the significantly lower basal blood pres- sure in the hypothyroid rats, the pressor responses to both angiotensin and norepinephrine were also calculated as the percentage of the pre-injection blood pressure in each rat. The mean pressor responses of the control and hypothyroid rats to both angiotensin and norepineph- rine .calculated by this method, are shown in Table 7. As can be seen, the hypothyroid rats still show a signif- icantly decreased (p<.001) pressor response to both doses of angiotensin and to the higher dose of norepinephrine. The mean hypothyroid response to 120 mug. of norepinephrine, though still lower than the mean control response, is only borderline significant (p<.06). eit to etinaset oft atiw tnemestgs al. ors ovods betawontD: outs regiel ‘ bes, bersesow esw emtutgeniqeson ot seensviagogest aststiantizt ¢@ exweri .steat Bioryddeoayn Y one ToseetT 9° foginos" 6 at boe forteos & mi sgum OAS bas OS ct sehoqeet fsorqyd £ oid $8 beviys0:6 senoqaet Aseq ‘SH? itat biowydtogyd 8 oft bas ,motdoeiet tetta eboovee OF neitsd SHeMsTHLSOM eter edd Lis mr abmogse Oe=0E 28W ganoqeot 10 mordetsb sottatywh ni notésist fe sidaiweasem 6h eaw etsdT .betact | hezestosb s ,tisas ded pater Broryisoqymd edt of senoqaet To oniadgqentqston to elevel seob Asod ot semoqaet Toees1g | todmun sdt base senogesy teaasig #gastove ‘edt .bavisedo asw yieve oi [svefl sa0b dose #8 tuo Debrtss anotdeotat to. Bbelbusna stew stebh edT .2@ sidsT ni mvonde ors bateotd tar ofl watanetotans vet steb sri ss eansa aman end ok -cqaya Y ent Sos Lowlaco 8 eft to ssameqast tdceast¢g nsom ats enitnqentqeton to «Bent OLS bos OSf of ated broryad “Gessiq7 Mi gasatseb ofT 1.0 Stygit ci bas 0 sidsT ai mwoda tnsaliingte aaAw etsy b totyitogyel edy ai sasnesvianoge st .(700, S@ ,€0.>q) aleve edob dtod Js oiveeet boolt at ogaad® & as sanogaeh qoaee tt .2 ~zeatq boold feand tewel Ciineotiing ic eit to geausoed ot aoanhogaet toaasttg ett ,2¢s8% b toryttoqyel edd mi omse ad Oo betelwoiss oafs stew eniidgeniqeton Ons alanedoizns diod esivgaeoig boold motioespini-eiag sit te Sesineorsg ant 38 fottmos sit to asenyqast toeaetg asem ea 38% Nose. ‘ai wih snigeaton bas nianedoigns Adod ot eter bioryldoqyal bas -¥ ofdsT mt mvors ots ,boddem cidt yd bets fue Dwo ; ont ~tingte s wothe IfLite asar bioryddoqyd ent ,m990 9d. 89. ad e.0b Adjod of samogeet toezetg (100. >q) bszsstosb yivasoi -onitigentqsion To scob tefzid eft of bas atansdoigns to ,aaivdqsatqeion to .gum OST of samogast bioryddoqyd neem ont ak ,sanoges: fottnoo naom edt neds towol {{ite dass .(d0.>q) tmsoittingie oni Lisbtoed yine Discussion Radioactive iodine induced hypothyroidism in the rat has been demonstrated to result in a decreased basal blood pressure and a decreased pressor responsiveness to both norepinephrine and angiotensin II. Hypothyroidism was demonstrated in all the irradiated rats tested for pressor responsiveness by means of plasma PBI and thyroid histology at the time of sacrifice. Feller et al. (17) measured plasma PBI and iodine content of the thyroid gland, and studied thyroid his- tology in 200 to 300 gram rats, at selected intervals after the intraperitoneal injection of 875 uc. cae In all the rats so treated, the PBI fell to less than 1.0 ug. %, thyroid gland iodine content fell to 0.36 ug-, and thyroid histology revealed only rare thyroid epithelial cells still intact, at eight deys after treat- ment. Thus, complete histological and functional destruc- tion of the thyroid gland was demonstrated to occur one week after treatment. Fregly (6), again irradiating 200-300 gram rats with 875 uc. I'?', showed them all to be hypothyroid by meens of colonic cooling rate, radio- active iodine uptake, and thyroid histology, at intervals up to six months after treatment. On the basis of these two studies, it was sefe to assume that thyroid function 191 treatment, had been disrupted within two weeks after I since hypothyroidism was demonstrated at the time of sacri- fice, eight weeks after irradiation. The growth pattern of the 12 rats treated with ztot (Figure 2) was characterized by a three week period of normal weight gain followed by a complete cessation of weight gain for the remainder of the study. This resulted in a final mean weight of 310 grams for the hypothyroid rats as opposed to 390 grams for the control rats. Lom— plete absence of weight gain has been repeatedly observed ig baayo2 itt anid mi me btoreddoged booubat emibo: pelselbeanl® pike {seed bessstosh s at tivest ot b3ie13 anomed mood 2en Yer aesnsvianogest iosee tg beeset9eb s bus etwaagetq boold mathftorvdtogyH .1i1l alanestofgas DRS, enitigenigetem ited of Tot botasd etat bodaibsrti and iis ak beds7d anomob BBW hioravyds bas Tat smeely “to anmeom ed eeonevienocaet joaeetg .99LTi10K82 + emis ond os Ville * of bus 197 smasig beruecon (Th) .f8 ge retiet S155 ezid brorydd heibute ons ,pna ls bioryd? end to duadadd. %S 5 ora * 3 oa sadd agel of [let Idd end ,botestd oe asad oft (fs st ) of Lfet taedmoo entbot bnelg biexytt .X “Be | storyit star yino beleevet ygolodetd biorydd bre ,-BY -teeidi asits eysb dodates ts ,sostai (lite elleo {sifediigqes ~syugesb [envitoast bas isotgoloteain ateiqmos ,eutl “tren B90 Lupe o¢ botertanemeb asw basls broryads aig To nokd anidstbetri siags .(d) yfgert ,foomisets tet is “As ow od Ife gent bewotes fety ,o8 G76 Adiw ats msig O08 OOS -—otbsi ,etsit aniloos staofoo to ensem yd bs toryddedyd od afaytedat J6 ,ypolotain Browgtt Sas ,eaat gy antbor svitos z en) ke od to atasd od a0 ,tmomisets nedts adinom xia ot qu notions? brorgds tedd smyees od otes epw di .asibpsa owl rer . . tremics1g ~'I tedte exoow awd aisiiw bedquieib: ssed bed _iyose te smid edd ta Soedatienomeb Baw netbirorgltoaya soafe soissibsiai tests avlvow Jrigbe sort ‘ 'o woiw badesad atet St eft to sretiaq Asworg od to betrsq xooew setdd « yd pall adi-iaadele asw (S. otugrT) to neligeaeo atefamoo s yd bewetfel aise, dSdptew Lasrien bodiiuest atAl .ybuda ont Lo weharenst sid 16% nisg dufeiow biotvdtogyl ea¢ t3ot zeus Of€ To Jidgiew aged ientt os ne GM - sadat Lo ~stnoo end tot ems7gy ORC od beaogge as eset beyreado yibeisedet nosed esd nisy srigiow to eorvesde ei sig 4h (avrsini potdelea te ,edet mtg OOF of OOS mi Wotod > rel to mottoetar is emenereqe td el odd testis 10. following the onset of propylthiouracil treatment in the growing rat (4,5,18). This occurs immediately, without any time interval of normal growth. Thyroidectomy has also been shown to lead to a decrease in weight gain in growing rats (2,19), but not as striking as that which follows propylthiouracil treatment. In the one other zit treatment study in which weight was followed after in the rat (6), no difference in growth pattern was ob- served in the treated rats. However, both the control and hypothyroid rats were operatively made renal ischemic in that study, so that no real comparison is possible. The cessation of growth at three weeks after radiothy- roidectomy observed in the present study is probably a manifestation of hypothyroidism. Whether the three week lag before the appearance of this manifestation is re- lated to the technique used for the production of hypo- thyroidism remains to be determined. Hypothyroidism in the rat did not lead to hair loss or change in heir texture, noticeable edema, or any be- havioral changes in this study. This is in agreement with previous investigations on the hypothyroid rat (i-6). It is of interest to note that this is in contrast to the dog, which has been demonstrated to show the classical signs of increased hair coarseness, hair loss, thickened and edematous skin, and apathy and listlessness.(10). A striking finding was the fall in basal blood pres- sure in the hypothyroid rats to 129 mm. Hg at two weeks after yt) treatment, before any significant weight dif- ference appeared (figure 3). The blood pressure in these rats remained significantly lower than the control blood pressure for the duration of the study. Fregly (4) ob- served the same phenomenon after propylthiouracil admin- istration in the rat. In his study, the basal blood Of we a ibs nt add ai tinosmtdsett Lfost woidd Lygomg to seano ent ani wp Liat tuondtiw .¢fedseibommt atyooe att | tar, a a) tea aniworg aSo Suovaek tout Adworx Lemron to fevrotai omid yas | ni miay Jdgisw ai sesetosd s of bast of nwore ood coals dotdw ted3 es anttixrfa as ton tud (er, +3 edar gaiwors sodfo sno ont al .dnemissts fiostmoidd Lygotg ewolLot jnemni sed reg asits bewoliot asw idgtow do tetw ni ybute do aew mtetisq déworn mi sonetettib on. (a) ed odd ni fordneo sdi diog ,TevewoH cist bedsexd ead gi beviea. otmedoei Isne1 9 ban yievitsiege stew ed et bioryitog yd bas -oldiaacg at moairsquos Isex on teds oa etbuda daca ai =UntoLbsy ~ottse etesw osidd se ddwors to soltseass edt sg yidedotg at yoda ¢aeastg oft mi bevieado mod osbior xoow guxdt add rvortedv smetbiotydtogyd to noiisiestinam | -ot et mottedaotinem eidt te sonstaeqqs eld eto'ted gel ~ogyd to notiouborg edd rot bea supinsioss ang od bese l | ebenimtressb ed oF anignst meibiorydd { don Bib dex od nt marbtovyitoqyl fabs oldesatdon ,oivixed tied ai sgsedo x0 inameetgs Ai at eiAT .ybsde aint me aepnsdo Latoived (d=f) tat avack oH Sait mo anolissyitaevai auoLveig aAgiw od dasedmoo At et oid Gadd adon od $e ersini To-et i festeesste eft woda of bedstdanomeb nosed 2sd No faw sBOd” eid henesvtoidd: ,eaol ried vacageehne tisd beametomt te angie yltsgs bas ,mide exoismabe bas | im os He th »(Gli.easneaotiag£s -natg hoold [seed mi {let eft agw anibat? gaiwtitte A edeow owd 3s Qi .om Ost of edat biorydsoqyd sid ni save ~tib tmsiew Jnsotiiagta yas et0oted tagmtsord fery astis aaant at avueesty boold eT .(® etvgil) beiseqqs somptet beold flortace edi naAdt zr9ewol (linsottiagtia beni smet ats -Jo ($b) vine1T sebuda add to gottaiwb sad act siveestd. ~iimbs Lion isoldd Lyqgorg tests monsmonsdg smsa sit hevise booid [seed oNd ,ybude eid al tat edd ni notdertei ee pressure fell to a low point three weeks after the onset of treatment, and it remained significantly lower than the mean control blood pressure throughout a seven week period of observation. As was noted above, no behavioral differences were observed in the hypothyroid rats. Thus it appears unlikely that the decreased blood pressure was secondery to a decreased state of excitement in the experimental situation in the hypothyroid rats. Another factor that must be considered as a possible cause of decreased basal blood pressure in the hypothy- roid rat is adrenal cortical insufficiency. Thyroidectomy and thiouracil treatment in rats has been demonstrated to lead to a decrease in adrenal weight by many investi- gators (19,20,21). On the other hand, Gabrilove and Soffer (22) demonstrated thet propylthiouracil adminis- tration in rats for periods.up to six weeks did not alter the adrenal response to ACTH or epinephrine, as measured by the change in ascorbic acid content, in spite of the fact that adrenal weight was reduced. Finally Fregly (18) demonstrated no decrease in adrenal weight or cho- lesterol content following prolonged propylthicuracil administration in the rat. There have been no studies of adrenal weight or function following ead treatment in the rat. From the evidence presented here, involution of the acreual seems to occur following thyroidectomy or thiouracil administration. Whether this is reflected in a decrease in adrenal function is not known. “ith propylthiouracil, no real impairment of adrenal function seems to occur. From this information it is impossible to predict adrenal cortical function in the yi?! treated rat. However, since a decrease in basel blood pressure occurs following propylthiouracil administration, where there appears to be no adrenal insufficiency, it seems unlikely that the adrenal plays a role in the hypotension qiol following treatment. secao oft ratte afedw sexsi duteg wol 8 oF, i fet ormdeeta anatt tewol Ultasoitingta bontehet ti bas dqdud sett ‘Yo Nosw meves s tuornguoids sivecstg ‘boo td forssoo nse oft [s1civaded on ,g9vode beton esw ah \nottavisedo to ported audt vadat brorydtoqyd sav ni bevireedo stew esoneiettib stuaserg boold beesetoab old dead yledti ing ats adds ‘tt end mi taemetioxs to stade beasetosb | a ‘os yishaoss2 as | water biorydteqyd ems af notisnd fa Isditemitegxe gidieang 3 &é8 bersbianes od dteum sad 10d oat vordenn -Yisioqyt ort mi stueeetg hoold isasd pesso199b to sauso yrodoebioryls ,yousiorttuant isoii109 Isnetbs é at det bior bodardenomeh oeed aad edst at tnourtast? frostwotAt bas witasvai yosa yd siigtew Isnotbs mt sae1995 s ot beat of base evolitdsd ,basd t6eAso oilt 0 Bers OS eT) 21OTS3 wstnimses Liostwotddiyqorg tadd 5e terdenomed (ss) ‘yttos satis ton bib adeow xia o¢ qu aboizeay 10t ater nt ‘poitars hetyasou ae ,amitdgentgqe ro HIivA ot semeqeet fenorbe ott aig to etiga wt ,tnetaes Bros oidicsas ai egasdo sig yd yigetd yllenti .bsogbet esw idotew Lsnorbe tsae sost oo to trgiew [sneths af sass199> on bedstsanomeb (1) fiostvoidslygerq besrolotg aniwolfot inesinos fotetest aatbuda on aged svaed oredT .da off at notisatetiainbs tirentssti rery aniwollot mottonut to dngiew feneibe ko no.gufovat , sted Setueazotg sonebive srg movi .tet edt mr ymotosbioryds aniwolfot tH990 cd emege Isnex0s off) tO bea¢ositet ei akdd terdionW .iotteiteaicimbs [Lostwoids 10 w ade _swouad doa eit mottonut Lsnetbs ai sessits9b 3 ot soidgonut Isneths to tasmtisams Leet of ~iiosimoidtiyqetg¢ | oidtesogmi af Ji mottsmrotar aids sort “Sawooo od amsse rét , . y i a eee “ly cag ni moitonut Lsoti109 fsadtbs Joibetg og eiuneetq boold [sesd ai sesstoeb s conte ,tevewor .s&t sisiw .noidstdainimbe Liosiwoiddéiygotg gniwollot BINIIG amsoe Jt ,youototttvanit Isnetbs on od od etseqge etedd noianetoaqyl oft mt efor se aysiq fenetbs eft dant y fou Loss toomds sett pets aaheptior 12. The onset of decreased pressor responsiveness to the humoral agents involved in blood pressure control in the rat, as thyroid hormone disappears from the cir- culation, could also explain the relative hypotension observed in the hypothyroid rat. Since a decrease in basal blood pressure has not been noted in man or in the dog in the hypothyroid state, one might wonder if blood pressure regulation in the rat was more reliant on arter- iolar responsiveness to norepinephrine and angiotensin ‘than either the dog or man. From the available evidence, no conclusions as to the mechanism of decreased basal blood pressure in the hypothyroid rat can be made. The problem of evaluating pressor responsiveness in the intact rat in this study was complicated by the fact that the blood pressure of the hypothyroid rats was sig- nificantly lower than thet of the controls at the time of testing (see Figure 3). During the angiotensin re- sponse measurements, the mean hypothyroid blocd pressure ranged from 134 to 139, while the average control press- ure was 149 mm. Hg. Likewise, during the norepinephrine measurements, the mean hypothyroid blood pressure was 142 mm. Hg and the control blood pressure was around 153 mm. Hg. In-vitro studies with aortic strips have demonstrated that responsiveness to norepinephrine is related to the amount of stretch force applied to the strip at the time of norepinephrine infusion (23,24). With increasing stretch applied to the aortic strip, its contractile response to norepinephrine is increased. On the basis of these studies, one might expect that at higher blood pressures, when an increased stretch force is acting on the arterial tree, an increased contractile response will follow the injection of a pressor agent. Conversely at a lower blood pressure, a decreased contractile response might be expected to occur after pressor injection, yielding a smaller increase in blood pressure as measured in the intact animal. bh =tio ant mort eee a ceomeee boas 25 st tat hs aotansiogyd avidsisy alt ois algqxe oats. bivoo ,noitsiua mi pesotoeh & sonic 38% browydd og ed eat ak be evigedo efit ni to asm ai bedon seed ton aac atvazstq boo kd isaad boold ti toebmow ddgim Qo petsse. biorydtogyd | on: -tsits so taeilet siom eaw tet oad. mi aoiietvaet otuaaetg micessotinus Se antidgemt gox om gs 22 gnevierocaet “Ge lot y eabeee eidalisva odd aor Set 10 gob edd tedtis nedd isead Bensetoaab to ne beacio om ond od as | ‘anoian Lomo on ,obam od mo JES biorydsogud as ne e1seaotd boo ld ni eeoneviencqsot Toaeety eat tteulave ‘Yo meidorg oat * edd yd b shes i Lomoo 26w Youse . eins ai tet tosdini and -ple esw adat bic Led oryal aft to ei got boold ond dackd emigd aft ts 2lotiaoo eAd to sacs nedd eovol elinsoitia mat ntaastoizas elt anbtud °§.(e ought ‘gan) gatiesd io Rrouyndoged neem ot einem tsesem eencga “82 STG ase eer eid silidw ,2&f os he f wort Hearst aniingentgs yt est aniavh aes spi sm @ht asw ots 2h, ssw etuaeeta boold hhoryddtogy om neem edi ,es hems ivesom wx F@t Bavow: sew otveaetg Doold Lordmos end foe BH oa otervjenomeh over agizvde otdi0es dtiw aelbude ond ivaal ait ot Getaler ch snitdgqeniqeton of gagneviehogast tend amté¢ ond te cittie add of pstiqqe soot doterte to die ome iofeida gatassront ats .(hs,€5) goOtavsini amiidgesigeron to ot sanmuqes% alitosusnoo ati ,qitta ofsi0e adt ot bsiicgs sisauts egeendd to alesd eft mu .beesstoai éi onirdqenigeios ye nodw ,estvesetq boold tefgid je iad josgxe tdgim eno us ,9ert Istredts sad no gnrsos at enrot dodetia beaesetont acidesint eit wolfot Ifiw semegest olitoatines beers iont »ervseary boold tawol s dR yioatayao0d .SMeRe TosasTgd & to nuove od hetoaygxe od Jngia senoqest alitostdmoo beasetoel & tt esasstont sslleme s guibloty ettoo gms torasitq resis famine tostat end at betuesom 28 eTsEBatg boold 124 This hypothesis would be an argument against the results obtained here being a true reflection of any direct effect of hypothyroidism on vascular responsiveness. However, in contrast with this hypothesis, Fhelan et al. (25) have demonstrated a different relationship between pre-injection blood pressure and pressor response in the intact rat. Giving norepinephrine intravenously to 50 control rats with blood pressures ranging from 90 to 150 mm. Hg and 50 inbred hypertensive rats with pressures from 110 to 180 mm. Hg, they found no relationship between the pre-injection blood pressure and pressor response. With angiotensin, in fact, they found exactly the opposite relationship. In both control and hypertensive rats, they found that the response to a standard dose of angio- tensin decreased as the pre-injection blood pressure in- creased (p¢.01). On the basis of this study, the de- creased pressor responsiveness to angiotensin observed here, inspite of the decreased pre-injection blood press- ure, is even more striking evidence that thyroid function is an important factor in pressor responsiveness. In order to minimize the difference in basal blood pressure in calculating pressor response, the data, or- iginally presented in terms of absolute elevation in mma. Hg (Figure 6) following pressor stimulation, was recalculated in terms of percentage change in blood press- ure (Table 7). Thus, a 25 mm. Hg response at a pre-in- jection blood pressure of 125 mm. Hg would be considered as identical to a 30 mm. Hg response at a blood pressure of 150. By this method of calculation, responsiveness was still found to be significantly decreased in the hypothyroid rats, except for the response to 120 mug. of norepinephrine. These data demonstrate that differ- ence in blood pressure was not an important factor in the decreased responsiveness observed in the hypothyroid rats. et - Se aid tanisae inemegis ome od bivow siaadéogyd 2idT (0) doeiih yns to noftoslies smut s sated siof beniatde ad iveer -2HONSVianogest telwoeRv AO maibioryddogyl to sooltts: .is de saledt ,eiesdteqyl eiAd déiw taattnoo mi, ,rovewol neewied gidenolisier 1 énexettib & betsatanonsd sved (@S) eft af senoqaet Towensig das stvexstgq boot noitoetat-erq O02 of vyiavonevertnt enitdgeniqeton ymtvbd 8% soad nt of OC mort goignss aetweastq boold déiw eter: fordnoa asivegssig usiw adat svienetreqya berdni 02 bane gh .ma Oct” nsewded qidencilsiet on Dasot ygeds .3h mm OSf of Ort mort ,8270CZS%- To.aetg bas siwcastc Sooke notine;mt-exg ead stteoggs ant ylioaxe Bayot yond ,dosi af ,ntenstoigns di’ 81 svicnstieqyd bas Lorimoo tod al. .qittemordslox ~ciyae to 9eob brsbaeda 6 ot semcgest eff) Jedd. bowot yout ~afb exuasety boold. moitosfmi+sig odd es beeso tosh mianet “gb ait ,ybute aint to efesd edd nO.>,.(fTOs"> g) beaseto hevuisado nianstoigns od Basasvienogae®t toscestg beass1s ~ceety Dbould colijoetmr-s1g hesse1osh afd Fo atiiqent ,etord noitons:? bretvdd ¢edd sonebive zortirzte stem neve at .ete -2aonsvVienogest Toeestq ai totogt tnetroqmi ns et: boold Igaad mi eonetettib sdv ssinintm ot aebro al “190 ,B3sb sid ,senogest toezotg anitsaivolso at stueesig si sotéavetls stuloads to emtet ai betmseetq ylisnist eav ,soidelumida roaesiq amiwoilot (od exugit) BH mm -ca9tq boold wi ognsde sgstneotsag to amted ai betsivolases ~tiegSIg 8 38 sanoqeer BH um @f = ,cunT AT ofdel) ot petebianos od bilyow gH .om of to etuaaetg boold mottioeg equeasig boold s ts samousst gH,..mm OF 8 oF isotinebi as sesnevienodeast ,ncitaluolss to beniem aind yd ..0eGF To ey mi bessetoceab yitnsottingte ed of bawot Iitvda.esw apm OST o¢ sanogeet et 10t ¢gaoxes ,atey biorgdieqyad ~Istiib isdd stsitanomseb sisb saedl enitigeniqsten to mi to¢gost tnstiogat ns ton paw stueezoag Socld ms eone bioaycioava oi mt bevisedo eaemevicnoyast beeceiseb ont sad58T wt SS ce Pressor response to norepinephrine in the hypothy- roid dog was studied by Page and McCubbin (10) in 12 dogs made hypothyroid by either thyroidectomy, I'°! treatment, or propylthiouracil administration. They demonstrated a reduction by one-half of the pressor response to intra- venous norepinephrine. 150 ms 2 ys 140-4 60mug 30 mug 60mug 30mug Oo 60 | Oo 60 | | Oo 60 | Oo 60 Time in Seconds SYSTOLIC BP 160 mm HYPOTHYROID RAT # 37 Hg 150 BAG @ \207 mS PS PS Time in Seconds Figure 4: Blood pressure response to angiotensin in a con- trol rat (above) and a hypothyroid rat (below). agenessot tes biorydtoqyd s brs (svods) tat Joi gas of gamogast oWeaeitd boold :& siveit 24. BLOOD PRESSURE RESPONSE TO NOREPINEPHRINE SYSTOLIC BP 210 We Cee ee 9 20 RAT # 190 180 170 \ 160 & 150 240 myg 120 mug a 240 mug 120 mug (0) 60 O 60 0) 60 Time in Seconds SYSTOLIC BP mm 1!60 Hg HYPOTHYROID RAT #25 150 140 ay 130 -\ dp \ 120 = 240 mug fs I2O0mpzQg 240 mug O 40 Time in Seconds Figure 5: Blood pressure response to norepinephrine in a control rat (above) and 2 hypothyroid rat (below). 17> a ho oe. om | : 1 A +." he i} . } Pg ra i a i 4 it é = : « a ni entidgsnigeton of saneqast sTweretg poolk 18 Eee gar biowyasoqyd 8 Dns (gvods) jst Loxtaoo BS te (woled) 7 Mean Change in Blood Pressure oe Control Control mm I5 Rats 8 Rats Hg 40 \ wl \ 20 5 Hypothyroid Hypothyroid re IO Rats 7 Rats | I2Omeg 240mzQg | ANGIOTENSIN NOREPINEPHRINE Figure 6: Mean rise in blood pressure following the intra- venous injection of angiotensin (left) and nor- epinephrine (right) in the control and hypothyroid rats. 22S astq boold ak gait mseM :0 eipaid ~Sidnt afte gaiwollot sta tei} atenesotans To noirsoopar asronev fer¢yoo sid oft (tetgiat) entisgemiqe +e2d37 =ton Das. (J hrorydtogqgyl Des Table 1 Plasma PBI Hypothyroid PBI 0.6 ug.% ee 02 aes 0.5 tet 0.4 0.4 Oe 4 Lee 152 O14 = 3 tao. Mean 266 Control ug. 2.9 z ~ 14 ug.’ t olde 1d%_ emas 9 a de tek Rau a ¥ ane AL fF a G CAT eek Bok as OS% a. 2 J + Go oc M ky 7 + . sak Pf. = hes fe 9 Rms fl. = 4 nw wa * «s&s «© © @ © ® 772000707070 ° Table 2 Angiotensin Individual average pressor response and number of test injections carried out at each level. A. Control Av. Pressor Response No. of Injections Rat # 30 mug. 60 mug. 30 mug. 60 mug. #13 15mm. Hg 50mm. Hg 1 9 #45 15 52 2 2 #37 22 42 3 2 #47 17 40 2 5 #30 18 34 5 5 #28 13 29 5 6 #47 11 214 4 6 #33 20 27 2 2 #29 25 45 a 3 #6 16 34 4 4 #18 13 52 3 3 #26 17 25 2 5 #35 27 : 40 3 3 #3 18 40 3 3 #32 23 40 3 2 B. Hypothyroid #45 15 26 3 A #37 14 22 7 8 #47 9 16 6 4 #4 5 16 4 4 #25 10 20 2 3 #21 12 17 4 4 #40 12 16 3 4 #7 14 23 5 5 #38 10 16 3 5 #52 15 22 3 4 $ eldal gienotoinga +o yedmun bas eanogest toaaetg exstevs Levbivibal _fevel doses ts tue botvie9s enoitosfat taed . Lorsno0¥ anoistogpai to .oW sancgesf tozge1d VA sau 09 «gym OF ava 08 -aym OF ~ tei Q 7 aH .amO@ 3H .mmet Ef ¢ : Se at hh Sh ss TEX é Q Of yr Ta é ant he 8t : 5 OER 3 a es Fay Bs a b rs rt yAR : | rs. os ETH : 3 ap ag — -RS* h h Re ar ak e e aa er | Bry é 8 as Te as*% é é Os iS | att é = Os at eh c é Os 8 Cth broryadt ogy i. é as et Che 8 | g A vee B A ar e The h ‘ at re, AX = g OS on eS % h h vt fae rS% a or CT Ob% a a eS hr Tt é e ar or Be i é ss ef Sek “2 ryy Table 3 Angiotensin Mean Pressor Response Control 30 mug. 15 rats 18.2 4.7 mm. Hg Hypothyroid 10 rats 12 £ 4.0 mm. Hg Pp < 001 Table 4 Angiotensin Self Control Comparison Rat # 40 mug. oe Ae se a #45 before t 15 28. 60 mug. 35 = 2.0 mm. Hg 200 + 1.2 mm. Hg < 001 60 mug. 42 mm. Hg 22 40 16 52 26 88 ganogaoh "s ; << 4 7 “3 ‘ : e F ' h oldal giages ota 4 nogitsqsoD forsn0d tilee Fehr sroted pf rstits TT refs e1oted e | 193% rely sroted tS Its 29. Table 5 Norepinephrine Individual average pressor resoonse and number of test injections carried out at each level. A. Control Av. Pressor Response No. of Injections Rat # 120 mug. 240 mug. 120 mug. 240 mug. #18 22 mm. He 50 mm. Hg 3 5 #26 25 57 ) 5 #29 17 48 S e #35 14 a2 5 5 i) 22 48 % . #6 27 63 5 3 #33 Se 50 3 3 #32 18 34 3 4 B. Hypothyroid #7 17 be) : 3 #4 20 32 5 3 #25 7 17 5 4 #21 10 21 3 4 #40 vi 29 2 ) #37 18 26 5 4 #45 13 30 b) 2) [eebivibsal — to todmun bas sutoqaet Toaestq 9Bet fevel doses ga tuo beitisao anottos ancijoei al to .o rman HOS we sek brorydteqyH . vs oS ask a 2 One vex , any Table 6 Norepinephrine Mean Pressor Response Control 120 mug. 240 mug. 8 rats 99 = 2.0 mm. Hg 48 = 3.7 mm. Hg Hypothyroid 7 rats 15 = 4.8 mm. Hg 26 = 2.2 mm. Hg Pp < 03 < .001 Table 7 Pressor Response as % Change in Blood Pressure Angiotensin 30_mug. 60 mug. Control 12.2% — 94,4% Hypothyroid 8.4% 13.9% p gf -001 < .001 Norepinephrine 120 mug. 240 mug. Control 14.0% 30.6% Hypothyroid 10.1% 18.5% p < .06 < .001 =. fo i" 3 sidel eciigonigotol sanogaeH togaetl neem ~aum ObS “Rim OST Lori nod ets os batax 8 ¥ biowgdfoayll A de . ef .um $.S = 38 3H ,.om S.f = df. e¢dat VY T eidst stuceaett boolf nt exusdd K as eemogesh tozcstt te oe a NN miagetoiagné tabi Deviations ener ye meses KAAS Ro ST JIouino. fo0. > too. > a antaudgentgorou omisar OS ~aua OST RA, 0F HO .Ef fortmo? o_ ae. Gt ar .OF biorwdstogya roo. > a0. > q q mA ne 10. 11. Die References Braun—-Menendez, E.: "Thyroide et hypertension arterielle." Comptes Rendus de Soc. de la Biol. 148:16063, 1954. Salgado, E.: "Effect of Thyroidectomy on Hypertension, Nephrosclerosis, and Cardiac Lesions Produced by DOCA Treatment in the Rat." Endocrinology 55:377, 1954. Chappel, Geen ee Rona, G., Revesz, ©., and Cahill, d.: "Effect of Proplythiouracil on Adrenal Regeneration Hypertension in the Rat." Proc. Soc. Exp. Biol. and Med. 98:23, 1958. Fregly, M.d.: "Effect of Propylthiouracil on the Devel- opment and Maintenance of Renal Hypertension in Rats." Am. dour. Physiol. 194:149, 1958. Fregly, M.d.: ment with Proplythiouracil in Rats." Proc. Soc. Exp. Biol. and Med. 102:<99, 1959. "Prevention of Salt Hypertension by Treat-— Fregly, M.J., Gennaro, J.F., and Otis, A.B.: "Effect of Treatment with Radioactive Iodine and Iodine Deficient Diet on the Development and Maintenance of Renal Hyper- tension in Rats." Circ. Res. 8:749, 1960. Schneckloth, R.B., Kurland, G.5., and Freedberg, A.5S.: "Effect of Variation in Thyroid Function on the Pressor Response to Norepinephrine in Man." Metabolism 2:546, 1953. Murray, J.F. and Kelly, J.d.: "The Relationship of Thy- roidal Hormone Level to Epinephrine Response: A Diag- nostic Test for Hyperthyroidism." Ann. Int. Med. 571: 309, 1959. Brewster, W-R., Isaacs, J.P., Osgood, P.F., and King, i.L.: "The Hemodynamic and Metabolic Interrelationships in the Activity of Epinephrine, Norepinephrine, and the Thyroid Hormones." CGirculation 13:1, 1956. Page, I.H. and Function on tion 52590, McCubbin, J.W. on Vascular genic and Renal Hypertensive Dogs." Circulation 5: ei ue fae McCubbin, J.W.: "Influence of Thyroid Vascular Reactivity in Dogs." Circula- pve an and Page, I.H.: "Effect of Athyroid State Reactivity and Arterial Pressure in Neuro- ene " aflsetisixs moLans eer soLenstirsqyk. 1 ADOC xd beowbotd .paer ,TVC:68 yaofoatrsebas g90neS ts ten dxscyd te shrotydT” :.8 ,sebooaeM-overd «Tf ,fadf:Ap! .foth af ob «506 9b au buen -odgmoo o ymotosbioryd? to sostta* :.d ,obsgisd, enoteed osthisd bas ,cleors = elozodigeli "tei edd ai taomisott. :.&6 .{fiseD bus ,.0 .sasveH ,.0 ,snoH ~-1.9 rfeqgedd W me d aw t * : ; ‘ notfetsnoueh LenembA mo L[tosiyoidtylqord to soeTtTe bo ra: afays@ snd mo af " aged gi nmotenstty — ged ,90/ .9079 a a Ue me a 47 f mB ARE DON 8 yA EE RT EOD EEE AEBS IE sO eee A he bea eH Ds ime) osrTe 3 cA * Adem ores! ,8aer ,eS:8e saisoidtiyaetl to gootta" :.6.M o08 .90%%- "tse elt at aotanedieqgyh -boM -Yigett eqyH isaef to gonsnetaisM bas snsago ,oeer ,ehrsser .Loteyd#d .twob at a ete at Lrostwotdiytgord Atiw jss1t yd notenedieqyH ¢is@ te sottmnever<" 2.L.M ,yigoert trem -eC@er ,C@S:SOr .boM bas Lott ,2idO bas ,..7T-6 ,o1snmed ee bM eyigert inetofted anibol bas entbol evisosotbsh diiw snems sor atsgvyi IpneH to sonsnetaieM bas tasmgofeved oft so sold MAO ® + Gay t :,0.A .Rrsdbset a BS 9us mo nord .che:S gat fodsiel :9anogasi hoM 78h on wl.4 , BALA bas ,.d. ni eqidanoitsist aid bans ,Ssniitags wt Anke ~220, 4 | ChT:8 -2af .owid “eta ai nol ena? Tbne ,.u.9 ,baslivt ,.d.8 pit oLaoensios smut bLoryal aL aoiéstisV to toetta" " cal ot sntwicgeniqs1ok ot sanoqest * freer to qinlanctisieA oT" 2.6.6 ¥ifet bas .i.b , yet aniviigentgd o¢ Ieved snomtoH [sh£0% eRECh . G ,booyed ..4.b ,sossal ~-8eW Y redml oifodsteM bas oimseybomell - A " ,meibioryddteqyH rot teeT oiseon (Q0€ stawetd ant " xigetel ,eaiidgsnigd to ytivisoA ond : 4 rer. :€' goisslyorio " eenomied. birowadT biotyaAT to soneu{tal" +:.W¥.b ,aiddsJom ous .H.l .9ged G nt vwhividses® wefsoesV mo notsoaut | Seer ,Ok¢:e moss a . ry 2 ey ry ¢ ~Sf{yotid ”.ag0 stsic birorydiA to “Otnal mi oiueee tt 72 mofis ivoire _/ +8 sOF fostta" :.H.I ,eyed bas «W.b ,aiddsdoM «fT Istred1A bas ytivitosel wiso s "enol evienstteqyH [ane bas a es C@r VY ro ines ry RE 12. 13. 14. 1D. 16. Ve 18. 19. 20. 21. 22. ee 24. 52 Friedman, M. and Freed, &.C.: "Microphonic Manometer for Indirect Determination of Systolic Blood Press- ure in the Rat." Proc. Soc. Exp. Biol. and Med. 70:670, 1949. Fregly, M.d.: "Effects of Extremes of Temperature on Hypertensive Rats." Am. Jour. Fhysiol. 176:275, 1954. Cotlove, E.: "Simple Tail Vein Infusion Method for Renal Clearance Measurements in the Rat." Jour. Applied Physiol. 16:764, 1961. Seligson, D.: unpublished. Taurog, A. and Chaikoff, I.L.: "On the Determination of Plasma Iodine." Jour. of Biol. Chem. 163:313, 1946. Feller, D.D., Chaikoff, I.L., Taurog, A., and Jones, H.B.: "Changes Induced in Iodine Metabolism of he Rat by Internal Radiation of its Thyroid with I a Endocrinology 45:464, 1949. Fregly, M.d. and Hood, C.1.: "Physiologic and Anatomic Effects of Propylthiouracil on Normal and Hyper- tensive Rats." Circ. Res. 7:486, 1959. leblond, ©.P. and Hoff, H.E.: “Effect of Sulfonamides and Thiourea Derivatives on Heart Rate and Organ Morphology." Endocrinology 35:229, 1944. Baumann, E.d. and Meine, D.: "Involution of the Adrenal Cortex in Rats Fed with Thiouracil." Endocrinology 363400, 1945. Freedman, H.H. and Gordon, A.S.: "Effects of Thyroid- ectomy and Thiouracil on Adrenal Weight and Ascorbic Acid." Proc. Soc. Exp. Biol. and Med. 75:729, 1950. Gabrilove, J.L. and Soffer, L.d.: "Adrenal Cortical Response of Fropylthicuracil Treated Rats to the Administration of Epinephrine and ACTH." Endocrin- ology 47:461, 1950. Speden, R.N.: "The Effect of Initial Strip Length on the Noradrenaline-induced Isometric Contraction of Arterial Strips." J. Physiol. 154:15, 1960. Gordon, D.-b. and Nogueira, A.: "Increased Vascular Re- activity in Experimental Hypertension." Circ. Res. 10:2609, 1962. as¢amouaM otmengotoiM” 7.9. a »boetl bas .M ,asmbettT -2291T2 bool otLeodeya to noitanimred ef tostbbnl tot .baM bos .foif .gxd 908 .907F "deh edd of sity »CSOh , OVA OF no srutsisqmeT to asmo1sxd to avooltta" 4b .M eYLgetd avs :aTt .fotaydd .me% ai ",atah evianss teqyl if oe Pf BOL tot boriteM sotaytal ateV fieT eiqmte" 2.4 pov oreo wok “taf edt at atasmetvesoM somsisel. SAR « eet bdvial afofeyem. | [a wbodetiduqns #24 neem rhee sortsaxisreded sddsnO" tad. ,Dtodiatd bag .A .potust ere: Sat spd) .fots to .iwo0b Kaeet bod lop 2 Ee OR he = sie mw ObRE enol bas ,-A ,gotmsaly, od. L.., tiedied) ..f.@) .rebhet eae ro maktlodsteM. satbel mi beoubal gepnsao” «fH: es Y dsiw Hbiorydt ati to motssibad fsniust al ud je 2eher ,Aabs ch yao Loni i90ba sA bas sinelotayii" «.1.0..f00H bas oie «J vigett spans bos Lewro mo Lrostmoidd Lygort te atoeltd ,Paef ,a8hsl .eeH .97id ".ete® ovianed ane manctive to soettS" #.a 41... trol base .2,0 prot ol qogt0 bas etek Jisesh m0 aovisavired seme idl Dre. .baCi ,OSSrAe yrelontrsebad ".ygodorquol fenetbA off to softtufoval"” :.C.,9nisM bas .bil xasmuad ysolonits0bn4 " Cinstsoid? déiiw bel. ade ak xod 100 sebe f, VORS ot | BA .mobtod bas .Hel .nembootT niddooad bus idaisW LenmeibA ao froatnofAl bas qmotos Ofer ,eST:2@f .boM baw .ford EA 2ock, .907F> ".hf0A NR erence ae ie IT to esootta™ :.¢ fm eotize® fLanoibA" s.G.d ,tertted bas eds b evolixdsad 5% boteett Ltosiwotdd Iyqori-te sanoqaed 'HTOA bas eniyAdgentgh to soitésteeinimbA ~veet ~fobe Nes yap le no déyned qitsde@ Isitinl to dosttd ait" a ae nebege ™y pottosvino) otittsmoel Seonhat-aniisnetbseioK edd Ode! ,a@rrset .foiaydt .b “.agirie Isited tA -eil 4 TsivoeeV beasetoni" :.A ,stiesgo bos .d.% ,sebr0d ef ,otko “.nolenetieqyA {siasmitegqxe ai eek ~So@f ,eaSsOF «Sf af df Cf oof Vf of OS 25. 20» 21. 286 ao « 30. 31-6 336 34. DD 35 Phelan, E.L., Eryetishir, I., Dah, M., and Smirk, F.H.: "Observations on the Responses of Rats with sponten- eous Hypertension and Control Rats to Fressor Drugs and to Hexamethonium." Circe. Res. 10:817, 1962. Salmoiraghi, G.C. and McCubbin, J.W.: "Effect of Adrenal- ectomy on Pressor Responsiveness to Angiotonin and Renin." Cire. Res. 2:280, 1954. Houssay, B.A. and Dexter, L.: "The Sensitivity to Hyper- tensin, Adrenalin, and Renin of Unanesthetized, Normal, Adrenalectomized, Hypophysectomized, and Nephrectomized Dogs." Ann. Int. Med. 47:451, 1942. Silva, V. and Croxatto, H.: "The Administration of Desoxycorticosterone and the Response of Intact and Adrenalectomized Rats to Renin and Hypertensin." Rev. Canad. Biol. i1:12¢, 1952. Parrott, M.W., Durbin, P.W., and Burg, Jd.J.: "Serum Calcium Levels in Thyroid Ablated Rats." Proc. Soc. Exp. Biol. and Med. 98:404, 1958. Spinks, A. and Burn, H.: "Thyroid Activity and Amine- Oxidase in the Liver." Brit. Jour. Pharm. and Chem- other. 7:93, 1952. Levine, R.d., Oates, Jd.A., Vendsalu, A., and Sjoerdsma, A.: "Studies on the Metabolism of Aromatic Amines in Relation to Altered Thyroid Function in Man." Jour. of Glin. Endo. and Metab. 22:1242, 1962. Fregly, M.Jd., Galindo, O., and Cook, K.M.: "“Spontan-— eous Sodium Chloride Appetite of Goitrogen-treated Rats: Effedt of Hypophysectomy and Adrenalectomy." Endocrinology 69:1060, 1961. Fregly, M.d., Brimhall, R.L., and Galindo, 0.d.: "Effect of the Antithyroid Drug Propylthiouracil on the Sodium Balance of Rats." Endocrinology 71:693, 1962. Bock, K.D. and Gross, F.: "Abschwachung pressorischer Wirkungen durch Sali-Diuretica." Arch. exptl. Peth. Pharmakol. 238:339, 1960. Olsen, N.S., Schroeder, H.A., and Menhard, E.M.: "Effect ot certain Amines on the Blood Pressure of Normal and Hypertensive Rats." Proc. Soc. Exp. Biol. and Med. 74:581, 1950. rh * if € ir im p ets Fees a * Ny . asd red iL ¢ et a f | avid ia | ae ra A & , FE fant . #s 8 fc SS gad agenocaek odd no auettevtesdO" ene i4eqyl Bkos denaxeh oF Bris he Gt re 2 £ t& a. Ba ond foxvdno?0 Bas mat : oe a neddsJoM bre .9. {idgetiomis& .o$ 22eneaylanogaek Yceesti mG , eee ee Keer ,OBEss .aeah tho, ".Atnee * os wo udivitienes oT? 3 .uf athe bie «A.2 ,YeeawoH *. ;besidsddasasnl te Bir Has lisse tBA , arene? = ,besimosogs eee anstbA , Lauro ry fk ie Ae & a beM .¢al spd bes imos se1siqoll s.H ,o¢¢ex010 Bas .V ,sylia .88 yas one -srorsfeootdyoo yxodel is rere mull boe atoas i sf. of eget bestmotoe leme1bA bits ase? i p2Sh2 t i «fod bene ow vou Sd a* 2.5.6 ,giv& bas ..W.2 ,midred . WM estotist . es 7 ” se (dA brow? al alsved mutofsd Beer bOK:38 -beM bos shoid .oxe »fuebtas0f°0 bas ,-A ,uis ahve’ weA.& ,28d80 466.5 ik eer teacorA ty eifLodadeM sad wo zetbeea 3. edogucd torent bared iA ot noite lon ‘et r:°S .dsjieM bas baa atid bo .tweb ee ee 8 re set hom meine, fy tne D4 AP LM ELMO LO MAAN LOL ELL NEN ELL AO DN lg nll aa we ‘Oi. a ~, ep dM . eee td St é cs eee murbes aves dpoTtte eaten - Vee Lomi io come as r ©) f noe ¢ rie Posy ay oy of eX sett 2.5.0 ,ebatilsd bas ,.1.H rae ~voeM ,Yigott .c€ no LLos to tii. ed foxy bana ons a GEL ef Fes rit ysolonitpobad “.atai to eonelad auibe foot «he stroessig anunoswihoadA" : : : 4 “,sottetsidtisc doyeb neural rw Od0f ~OEEs BE dented goeiid Ts i {© esis a 2A 30» 37. 38.6 39. 40. 41. Ae. 43. 44. 54. Cariini, E.A., Sampaio, A.H., and Paiva, A.C.M.: "Vas- cular Reactivity of Rats with DOCA and Metacorticoid Hypertension." Acta. Physiol. Latinoam. 9:138, 1959. Sturtevant, F.M.: "Studies on the Vascular Reactivity in Normotensive and metacorticoid Hypertensive Rats." Am. Heart Jour. 52:410, 1956. Masson, G.M.C., Page, I.H., and Corcoran, A.C.: "Vase cular Reactivity of Rats and Dogs Treated with DOCA." Proc. Soc. Exp. Biol. and Med. 73:434, 1950. Mallov, S.: "Comparative Reactivities of Aortic Strips from Hypertensive and Normotensive Rats to Epin- ephrine and Levarterenol." Circ. Res. 7:196, 1959. Redleaf, P.D. and Tobian, L.: "Question of Vascular Hyper-responsiveness in Hypertension." Circ. Res. 6:185, 1958. Tobian, L.: "Interrelationship of Electrolytes, Juxta- glomerular Celis and Hypertension." Phys. Reviews 40:280, 1960. Abrams, M., DeFriez, A.I., Tosteson, D.C., and Landis, E,M,: "Self Selection of Salt Solutions and Water by Normal and Hypertensive Rats." Am. Jour. Physiol. 1563233, 1949. Fregly, M.d.: "Effect of Hypothyroidism on Sodium Chlor- ide Aversion of Renal Hypertensive Kats." Endocrin- ology 71:683, 1962. Diaz, J.T. and Levy, 5.h.: "Studies on Experimental Hypertension in the Rat." Am. Jour. Physiol. 125: 586, 1959. .M.D.A ,evist brs ,..H.A ,oraeqmee ..As G ,intiisd ste bas AVOd dtiw ateh To a) teivo e .msornideel £0 fotaydd yBIOA noiens? reqyH +O2er vtivitosesa winoes¥ edt mo eotbute" 2 .M.F -iraverips 2 si evizaetisqyH biroorttisostem Dna evienetomirol’ mek .aaer ,Ofh:Se@ .au0b giseH .mA ~2R¥™ ':.O08 STH TIO bie , HI eget he MD ,noeasm _AD0@ dtiw beteetT encod base ated to Wwivitopel reine et RED EF Bai bag .fof% gx 2902 ~ 90 8F sattivitosed eviterasqnod™ :.2 ,volish evizastowrol ins av tenefteg vo mont oTi 0 ". onered taved bes oenirtdags rafioces¥ to motdaeuO" :.d ,asidoTt bas @.2 ,tssibed 29h .ati0 " nofanedTsqylH mi aeanevian oge1—t9qyit _Saet - CBF fol m2 ot xcse | tu ~usidol aws fy Lu19moLg , 088 :08 aot ,.1.A ,soitio® ..M ,amaidA 2 to noitosie? tisa® My avienetreqyh base igarro% yd Oper ,etss act old? suiboS no maibLotydiog ae to toottd" :.be4 ,ytigert ~tiwoobae * tea avienesreqyh Leneh to notemsvA sbe Seer ,f600nE veote isqgx% no esibyta" 1.8.0 ,yved Dis al. & gssid i .is0b .mA * gf edt nit soiamet1egyh ~CGer , dS ae ~¥E » St Of fh ebh be : OO — Oo Oo a YALE MEDICAL LIBRARY Manuscript Theses Unpublished theses submitted for the Master's and Doctor's degrees and deposited in the Yale Medical Library are to be used only with due regard to the rights of the authors. Bibliographical references may be noted, but passages must not be copied without permission of the authors, and without proper credit being given in subsequent written or published work. This thesis by has been used by the following persons, whose signatures attest their acceptance of the above restrictions. 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