Effects of blockade of vasopressin V-1 receptors on post-burn myocardial depression

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Burns (1967) 13. (6). 45k457

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Effects of blockade of vasopressin v-1 receptors on post-burn myocardial depression J. G. Hilton, M. Blake McPherson and D. S. Marullo Department of Pharmacology and Toxicology, University and Division of Pharmacology, Shriners Burns Institute,

Summary II has IWCII rugp~cd that lx)sl-burn myocardial dcprcssion may hc tluc 10 coron;lry cow;triction which rcsul[s in nwocartli;d ischacn~i;~. It ha IWCII &wonstriitctl 1hal ilw Icvcls of v45olwAn. il polcnl milwil vcswls. incrcwo four- lo six-kdd constriclor of blood immcdia~cly ;dtcr thcrmd tr;mm;t. I’hcrck~rc. this sub sImicc coultl hc rsspmil~lc for post-hum corimiry constriction ;III~ naycr;mli;d dcprchsiou. This was tc~tctl uhing Ihc dog iIll;lCSth~ti~Cd with sodium pcnlol~;irl~il~d rccciviiig ;I 15 per ccnl lot;11 body budxx MCil full Ihicknb-shIl;uiir hum a4 lhc cspcriiiicn~;il motlcl. <‘;irtkic oull~t was mxsurcd by llic Hicrnial tliluricW lcchnicluc. Artcrid blood prcssurc was ssusctl Iry a !iI;~Ihciii I’-23 Ir;mduccr. C;irdi;ic force of cimtriiclioil was mc;Isurcd hy ;I W;&on-lirody drain gmgs arch SCWII on lhc Icll vcntriclc. ‘l’hc rssults of lhis s~uly bhowcd ;I signilicmr dccrc;i\c in cilrdi;lC oulpul. incrc;bc in pcriphrrd rcsi!&incc ;inrl dccrcaxr in niyixxrilllsr 1hcrm;il dial forcc of conlraclion immctliatcly 1r:1um;1 in untrr;~Isd ;mim;d\,. ‘l’hc dccrcac in cardiac ou1lW ;ind incrc:ixc in psriphcrid rcdancc rcmilind for rhc tlura~ion of (IIS cxpsrimcnt;d observations (3 h).

‘I’hc dccrcw in force ol contrxlion returned to prsburn Icvsl~ I h pod-burn. I’rclrc;~~mcnt of the cxpcrimcnd :mimds with cl(Cll,), I’yr(blc)AVI’ (SKkF lIlIC73). ii vaclprcrhin V-l rcccl~tor hlcwkirrg agcn1. prcvcnkxl the ini(i;d dccww in cardklc outpu1, inc’rc’;l\lc‘ in pcriphcrd rcsixkmcc aciddccrtxsc in the force of amtrxlion. A corrzldion plot of pcriphcrnl rcsixl;mcc’v\. cardiac brcs of comr;cIion showed :I pdivc correlation I~wccn thrhs two v;lri;tldc\ in Ihc prstrc;lkxl ;mim;A. ‘I’hcw rcdr> suggcs~th;ll vasoprck

phys ;m import;m~ role in thr inili;ll cIccrc;w in row of conlr;wlion ;md 11131coron;iry ccm\lriclicrnmay IIc rcxponddc for rhr po\l-burn dcprc&m d niycx;di;~l for02 d ccmtr;tcli~m.

of Texas Medical Branch Galveston, Texas, USA

INTRODUCTION KI:CIWI. stud& in this lahl>r;ltl>ry h;lvc shown that the tkcreasc in cardiac output following thermal trium~;l dcpcnds more on ch;mgcs in pcriphcrd rosislnnce thiul upon ch;ulgcs in cardiac force of contraction (I lilton antI M:lrullo. IOXO). This study iIlstlil;\blion produccd hy the calcium chonnclhlockiiig ilgcllt Vcr;lpNllil did not signilici1ntly illtcr post-burn n~yoc;irdid dcprcssion. I lowcvcr. this rcsponsc could h;lvc hccn ohscurctl hy the myoc;lrdiill tlcprcssant action Of Wrilpilmil. Arltlition;d studies in this I;bor;lhlry OWL’ SHOWN il signiliamt incrcasr: in plilSrl~i1 VasOprL!SSin after burns (I lilton ct ill., IWO). Il;llli0il~~~~Ulll~ilSSil~ lcvcls of Vilsoprcssin inCrcilsC,d four- to six-fold within IOmin uftcr the hum. Oki~m~~t~~ ct ill. ( 1974) rcportcd dccrcascd corollary hloOd IlOW after burn and suggcstcd thilr this could result in iI myocardial dcprcssion due to ischilcmiit. Kopi;l and Valocik (IN) studied the cffccts of d(C1 I?)$ Tyr(Mc)AVP (SK&F lW!73), ;I new vasoprcssin V-l receptor blocking agent, and rcportcd that this ogcnt is cffcctivc in blocking vasopressinThis SUggCStS thilt ii&d COrOllilry constriction. the post-burn dcprrssion of myocardial force of contraction may bc rclutccl lo vasoprcssin rclcase nnd th;lt cI(CII~)~ Tyr(Mc)AVP would hc cffcctivc in prcvcnling this rq~onsc. The following is a report of stutlics in the im;lcsthctid clog to test this hypothesis. METHODS Throughout

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nxrls wcrc niongrcl dogs weighing hctwccn Y ;uiil with 3Onigkg of pcntoharhiIS kg ;ui;uxthctirctl Id sodium. A Ilow-directd Swmz-(kuiz thcrniodiluticui cathctcr w;is introducctl into the pulmmlry ;mtcry vi;r the jugular vein. The mrta W;IS cathcterizctl via the fcmtml artcry. The trachtxr W;IS intuhated for irrtilici;d respiration during the period of open chest surgery. A W&on-Brotly strain g;~ugc ;irch (Bonifxc et d.. lY.53) w;is sewn on thr Icft vcntrick through an incision in the Icft thorax. To ;Issure th;lt the force of contraction w:Is indcpcndcnt of venous return md cmlix output the stmin g;~ugc W~IS djustcd to IOg initial tcmion (Cotton, lY7-1). The chest W;IS closed illld the mind wits allowed to hrc;ithc without assistmcc. Thcrml tr;uun;r consists11 of iI IS per cent surfxc ilrc;I full thicknrrss fl;~mc

burn on the dorsum of the cxpcrinicnt;il ;mim;il. Fluid rcsuscit;ltion wits not adniinistcrctl. Cnrdi;ic output w;is mcasurrcl by thc’ thcrniodilution technique using an Edw;uds L;thoratorits cardiac output computer. Systoiic d diastolit prrssurcs were mcasurcxl using a Stathcm transtluccr ;mcl rccordd on it Grass polygraph. Mean ;irtsriiil blood prcssurc w;Is c;llcul;ltccl ;is diastolic prcssurc plus one-third of the p&c prcssurc. C’ilrJi;lc force of contraction w;is nicasurcd in gr;mls by ths str;lin gauge arch and rccordd cm the polygraph. Thcsc v;Gbks wcrc mcasurccl 3Omin and immctkltcly bcforc burning ;Ind ;It 30-min intcrv;A for 3 h after ths burn, TWO groups of ;mim;ds

Burns (1967) Vol. 1YNo. 6

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120. ZllO* bo8 c 90. k? ; 80. ; j ;

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Fig. S. Correlation plot of pcriph~rd resistance vmus force of contruction in d(Ctl,),Tvr(klc)AVP-trcatcd animals. Open circles. SK&F ItH1272-treated anim:ds. Straight lint is best calculated fit.

were studied. One group of nine animals rcceivcd no treatment after burning. The second group of nine animals rcccivcd IOmgkg of d(CllJ)5 Tyr( Mc)AVP administered by slow intravenous injection 2Omin hcforu burning. The varinhlcs for each ohscrvation wcrc colIccted ilnd illcans ;lnd standard errors wcrc calculatcd. Comparison of values wifhin c;dl ;lllilllill group was made by the paired I test illld comparison hctwccn pups of ;lllinl~llS W;IS IlliltlC by thC unpaired f tat. Diffcrcnccs wcrc considcrcd significant if the prohahility of chance occurrcncc was Icss than S per cent (I’
of thcss experiments arc shown in Fix. I shows th;\t d((‘liJ)$ ‘I’yr-

hlockcd the initi;ll incrcilsc in (Mc)AVI’ pcriphcrd rcsistarlcc. A slow gradual iiicrc;ac continucrl over a 2-h pcriotl. At the end of :! h, pcriphcral rcsistancs wlis not significantly diffcrent in the trcatcd animals from that in the untreated animals. +. * 7 _ shows that the immediate decrease in cardtac output ohscrvrd in the untreated animals did not occur in the d(CII& Tyr(Mc)AVP-treated animals. There was ;I gradual decrease in cardiac output par;dlcling the increase in peripheral resistance. Despite this, 2 h after burning cardiac output remained significantly higher in trcatcd than in untreated animals. Q. 3 shows that the initial hricf rise in mean ilrtcrial blood prrssurc observed in untrcatcd ;Ininl;ds did not occur in d(CI I,)5Tyr( Mc)AVPtrcatcd animals. Thcrc was a gradual continuing increase which spanned the entire period of ohscrvation. At 3 h post-burn the mean arterial pressure in the trcatcd animals was significantly

higher than that in the untreated animals. Fig. 4 depicts the cardiac force of contraction in the treated and untreated groups of animals. Immediately after burning in the untreated group there was a significant decrease in force of contraction which rose to levels not significantly different from the pre-burn period by 1 h postburn. Animals treated with d(Cfl:);Tyr(Me)AVP did not have an initial decrease-in force of contraction. Force of contraction was significantly greater in treated than untreated animals 3Omin post-burn. At I h post-burn there were no significant differences between these groups. The group of animals treated with d(CHJ)FTyr(Me)AVP experienced a gradual continuous decrease in the force of contraction. This decrease appeared to parallel the increase in peripheral resistance.

DISCUSSION The results observed in the untrcetcd group of animals were not significiintly different from those previously published. Pretrcatmcnt of the animals with d(Cf I,), Tyr(Mc)AVP significantly rcduccd the initi;ll post-burn dcprrssion of myocardial force of contraction. This finding sugvasoprcssin plays a significant role in gcsts thill this rcsponsc. One possihlc mechanism for the v;Isoprcssili-intluocd myOc;lrdi;ll dcprcssion is coronary artcry constriction. This could C;IUSC ;I myocardial ischacmia similar to that suggested by Ok;lmoto ct itI. (1974) in their study of anacsthctizcd dogs. Although d(C‘1 IJ)c Tyr(Mc)AVP hlockcd the initial decrcahc in force of contraction, thcrc was ;I continuous gradual dccrcasc in flora throughout the rcm;rindcr of the cxpsrimult (k’ig. 4). This tlecrcasc in force appears to parallel the increase in peripheral resistance (Kg. 1). A correlation plot of peripheral resistance vs. force of contraction shows a significant relationship hctwecn these two variables (Fig. 5). The correlation coefficient (2) was 0~017. A similar comparison of peripheral resistance and force in anim;ds treated with the calcium channel-Mocking a!cnt vcrapamil failed to show II significant corrcl;ltrcm. The correlation coefficient was 0412. The lack of correlation between peripheral rcsistimcc and cardiac force of contraction in ver;lpnmil-treated animals might be related to ;I direct myocardial depression produced by calcium chnnncl hlockadc. We are currently investigating the cffccts of the peripheral vilsodikltor sodium nitroprusside on burn-induced dcprcssion of cardiac force of contraction.

457

Hilton et al.: Vasopressin and myocardial depression In summary. these studies indicate that postburn myocardial depression is directly related to the activation of vasopressin (V- 1) receptors and suggest that this hormone may be the proposed ‘myocardial depressant factor’.

Acknowledgement The d(CH1)5 Tyr(Me)AVP (SK&FlW73) used in these studies was kindly supplied by Dr Lewis B. Kinter of Smith Kline and French Laboratories. 1500 Spring Garden Street, Philadelphia. PA IYIOI. USA.

Cotton M. Deb’. (lY7J) Circulutory changes affectmg measurement of heart force in situ with strain gauge arches. Am. /. Physiol. 365. 370. Huvs R. M. (IYXS) Agents affecting the renal conservetion of water. In: Gilman A. G.. Goodmxt L. S.. Rdll T. W. et al. (6). 7%~ Phurmacu/ogicu/ Buw oj Thrrupt~i~s. 7th edn. New York: Macmilkm. Hilton J. G. and Mrtrullo D. S. (IYXh) E’ffccts of thermal trauma on cardiac force of contraction. Burrrc 12. 167. Hilton J. G.. McPherson M. B. and Marullo D. S. ( IYXh) The relntionship between posthurn increclses in peripheral rcsistnnce and vasopressin. Burns 12. JIO. Kopia G. A. ;md Valocik R. E. (IYSS) Antagonism of vasopressin-induced coronary artery constriction by the vasopressin antagonist d(CH,), Tyr(Me)AVP. J.

(irrctiorwc. REFERENCES Bonifncc K. J.. Brodic D. J. and W;dt~n R. P. (10.53) Resistance str;tin p;tu~e arches for direct mc;thuremcnt of heart contrxttlc force in anim;tl%. I’roc. Sot. &X[l. Rio!. ,\lctl. fu. %?.

Important

Phurmucol.

7. 05X.

0k;tmoto A., Kaye M.. Coleman T. B. et aI. (1’974) t lcmodynamics and metabolic alter;ttions of the heart in hum shock. C’irc-. Shock I. l?J3. Pxpcr ;~cccptcd 31 M;lrch

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