Possible Involvement of an Endogenous Opioid in the Antihypertensive Effect of Clonidine in Patients with Essential Hypertension

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1 Possible Involvement of n Endogenous Opioid in the Antihypertensive Effect of Clonidine in Ptients with Essentil Hypertension CABA FARANG, M. D., C. C., JUDIT KAPOCI, M. D., ITVAN JUHAZ, M. D., C. C., AND GEORGE KUNO, M.D., PH. D. UMMARY The effect of nloxone on the hypotensive nd brdycrdic ction of clonidine ws studied in 27 hospitlized ptients with uncomplicted mild-to-moderte essentil hypertension. In double-bl'ind, crossover study, clonidine,.3 mg/dy orlly for 3 dys, significntly reduced systolic nd distolic blood pressure nd hert rte, wheres plcebo ws ineffective. Nloxone,. mg given intrvenously on the third dy of clonidine tretment, cused rpid increse in blood pressure nd hert rte in 1 ptients (recting group), but ws ineffective in the remining 13 ptients (nonrecting group). Nloxone given during the plcebo period ws ineffective in ll ptients. Both the clonidine-induced hypotension nd the rebound increse in blood pressure fter cesstion of clonidine were significntly greter in the recting thn in the nonrecting group. These observtions suggest tht relese of n endogenous opioid contributes to the ntihypertensive ction of clonidine; this mechnism my be lso involved in the discontinution syndrome fter cesstion of clonidine. Downloded from by on Jnury 13, 219 ENDOGENOU opioids of the brin hve well-documented effects on pin senstion,' behvior2 nd the endocrine system,3 nd hve been implicted in the control of crdiovsculr functions. The hypotension ssocited with vrious forms of shock,7 inhltion nesthesi8 nd surgicl trum' hs been reversed by nloxone, which ws interpreted to indicte tht these hypotensive sttes were ssocited with the relese of n endogenous opioid. We recently reported tht in spontneously hypertensive rts (HRs), the hypotensive ction of clonidine nd methyldop could be prevented or reversed by opite ntgonists.1, 1' Becuse clonidine nd nloxone did not interct with the sme receptor site in the brin," we suggested tht the ntihypertensive effect of centrl -drenergic receptor stimultion in HRs involves the relese of n endogenous opioid. Direct evidence for this ws provided by the demonstrtion tht in n in vitro brinstem preprtion from HRs, clonidine nd L--methylnordrenline incresed the relese of /3- endorphin-immunorective mteril. 12 Becuse,3 endorphin hs potent hypotensive effects of its own, 13 1 these findings strongly suggest tht relese of n endorphin-like substnce from the brin is involved in the ntihypertensive ction of centrl -receptor gonists in HRs. Hypertension in HRs is different in some respects from essentil hypertension in mn,'5 nd it is not certin tht the drenergic-opioid interction in HRs lso exists in hypertensive humns. We tested this possibility by studying the interction of clonidine nd From the econd Deprtment of Medicine, emmelweis Medicl University, Budpest, Hungry, nd the Deprtment of Phrmcology nd Therpeutics nd the Deprtment of Medicine, McGill University, Montrel, Quebec, Cnd. upported by grnt from the Cndin Hert Foundtion nd by Boehringer Ingelheim of Cnd Ltd. Address for correspondence: George Kunos. M.D., Ph.D., Deprtment of Phrmcology nd Therpeutics, McGill University, 3655 Drummond treet, Montrel, Quebec, Cnd H3G 1Y6. Received December 23., 1981; revision ccepted My 28, Circultion 66, No. 6, nloxone on rteril blood pressure nd hert rte in 27 ptients with mild-to-moderte hypertension. Methods Ptients A double-blind, crossover study ws done on 27 hospitlized ptients, ges yers, with mild-tomoderte essentil hypertension. Volunteer prticiption ws bsed on informed consent nd bsence of crdic, cerebrl, renl or peripherl vsculr disese by history, physicl exmintion, ECG nd cretinine clernce. Other forms of hypertension were excluded by pproprite clinicl nd lbortory exmintions (urinlysis, intrvenous urogrphy, serum electrolytes, plsm cortisol levels t midnight nd in the morning, 2-hour urine vnillyl mndelic cid, phentolmine or glucgon test, chest rdiogrph nd renl scintigrphy). All ptients hd norml weight for height nd were crefully screened for possible nrcotic drug buse. Blood pressure in the bsence of mediction ws 18-21/9-12 mm Hg. Tril Design The ptients hd not tken mediction for t lest 7 dys before the tril. Their previous ntihypertensive mediction included methyldop, oxprenolol, dihydrochlorothizide or dihydrlzine. Ptients whose distolic blood pressure exceeded 12 mm Hg during the drug-free period were excluded from the study. Blood pressure ws mesured by sphygmomnometry fter 15 minutes of recumbent rest in quiet environment; the disppernce of Korotkoff sounds ws used to mesure distolic pressure. Hert rte ws mesured from the rdil pulse. The ptients entered the doubleblind, crossover study fter their blood pressure nd hert rte mesurements hd stbilized nd remined constnt for 3 consecutive dys. The ptients were then given clonidine (Ctpres, Boehringer Ingelheim),.1 mg orlly three times dy, or plcebo, for 3 dys. The sequence of plcebo or ctive drug ws determined by rndom lloction. Blood pressure nd hert rte were

2 CLONIDINE-OPIOID INTERACTION IN HYPERTENION/Frsng et l Downloded from by on Jnury 13, 219 mesured 3 times dy, 1 hour fter ech dose of mediction. On the third dy nd 1 hour fter the second dily dose, n i.v. infusion of physiologic sline (1 ml/min) ws strted through n indwelling ctheter in n ntecubitl vein. The ECG ws monitored continuously nd blood pressure nd hert rte were determined frequently over 15-minute period. Without knowledge of its timing by the ptient,. mg of nloxone (Endo Lbortories) or physiologic sline ws injected s 2-ml bolus into the i.v. line. Blood pressure nd hert rte were mesured 1, 2, 3, 5, 7, 1, 2, nd 6 minutes fter the i.v. injection. Then, the second injection (sline or nloxone) ws given nd blood pressure nd hert rte were mesured s before. In five of the ptients whose blood pressure nd hert rte were not influenced by nloxone (nonrecting group), the test ws repeted with 1.2 mg of nloxone. After this session, the second 3-dy tretment period ws strted with crossover for clonidine-plcebo. The following effects on blood pressure nd hert rte were recorded: sline during plcebo, nloxone during plcebo, sline during clonidine, nd nloxone during clonidine. Rebound hypertension nd tchycrdi fter cesstion of clonidine therpy were nlyzed retrospectively in ptients who received clonidine first. Rebound ws chrcterized by the highest blood pressure nd hert rte redings during the subsequent 3-dy plcebo period. ttisticl Anlysis Differences in blood sponses to clonidine in pressure nd hert rte re- recting nd nonrecting ptients were nlyzed by the Mnn-Whitney U test. Chnges in blood pressure nd hert rte cused by clonidine, nloxone, or by withdrwl of clonidine within the sme ptients were evluted by two-wy nlysis of vrince followed by Duncn's multiplernge test. The correltion between the nloxone-in- C ; E E cm - co C n 18 r 1t N A) Clonidine N B) Plcebo I_t 'It duced mximl increse in blood pressure nd the mximl increse in blood pressure observed during withdrwl of clonidine in the sme ptients ws ssessed by liner regression nlysis. The possibility of nonuniform distribution of ptients ccording to their men blood pressure response to nloxone ws tested by the Kolmogorov-mirnov test for goodness of fit for norml distribution. A p vlue less thn.5 ws considered significnt. Results The men systolic nd distolic blood pressures t the end of the drug-free period (t+ EM in 27 ptients) were nd mm Hg, respectively. The men hert rte ws bets/min. By the third tretment dy, clonidine significntly reduced blood pressure to / mm Hg (p <.1) nd hert rte to 6.2 ± 1.2 bets/min (p <.1). When. mg of nloxone ws given during clonidine tretment, 1 of the 27 ptients hd rpid nd mrked increse in blood pressure nd hert rte to or bove the preclonidine levels (fig. la). The increse in blood pressure nd hert rte peked within 3-1 minutes nd returned to prenloxone levels within 1 hour. The mximl increses in systolic nd distolic pressures rnged from 16 to 15 nd 6 to mm Hg, respectively, nd hert rte incresed by 7-2 bets/min. In the remining 13 ptients, nloxone cused no chnge, slight decrese or n increse of less thn 1 mm Hg in men blood pressure, nd cused no significnt chnge in hert rte (nonrecting group, fig. IA). In five of the ltter ptients, nloxone ws tested t three times the originl dose (1.2 mg). The men blood pressure declined from ±.2 to 18.8 ± 3.8 mm Hg nd hert rte remind un- -chnged. Becuse these effects were the sme s the effect of. mg of nloxone in the sme ptients, the remining nonrecting ptients were not tested with the higher dose. Nloxone given during the plcebo w ~ ~~~~~~ FIGURE 1. The effect of intrvenous nloxone on blood pressure nd hert rte during clonidine (A) or plcebo tretment (B). Points nd verticl brs represent mens nd stndrd errorsfrom 1 recting ptients (-@) nd 13 nonrecting ptients (- -). The higher blood pressure vlues re systolic nd the lower ones re distolic. Nloxone (N,. mg) ws injected intrvenously t time. min

3 127 CIRCULATION VOL 66, No 6, DECEMBER 1982 L zi FIGURE 2. Distribution of ptients ccording to men blood pressure response to nloxone during clonidine tretment. Twenty-seven ptients were clssified ccording to pek chnge in men blood pressure. Downloded from by on Jnury 13, 219 A Men blood pressure (mmhg) period did not significntly chnge blood pressure nd hert rte in the recting or the nonrecting group (fig. IB). Although the distribution of the men blood pressure response to nloxone looks bimodl (fig. 2), goodness-of-fit testing for norml distribution in this reltively smll smple (27 ptients) could not reject the possibility tht the dt were drwn from normlly distributed popultion. Thus, the terms "recting" nd " nonrecting" re used only to describe quntittively different responses to nloxone with cutoff of 1-mm Hg increse in men blood pressure. Blood pressure nd hert rte during the drug-free control period were not significntly different in the two groups; nor ws there difference in verge ge, durtion of hypertension or in the type of previous ntihypertensive mediction. However, n nlysis of the effects of clonidine indicted tht the decrese in men blood pressure ws significntly greter in the recting thn in the nonrecting ptients, wheres the reduction in hert rte ws not significntly different in the two groups (fig. 3). Another difference between recting nd nonrecting ptients ws in the degree of rebound hypertension nd tchycrdi fter clonidine tretment ws stopped. Rebound ws nlyzed retrospectively in eight recting nd six nonrecting ptients who received clonidine first, followed by plcebo. The mesure of rebound ws the highest reding of blood pressure nd hert rte during the plcebo period. The pek vlues were lwys detected on the first dy, nd by the third dy of the plcebo period blood pressure nd hert rte were not different from the highest control vlues during the drug-free period. Figure shows the pek men blood pressure nd hert rte vlues in these ptients during the drug-free control period nd vlues obtined on the third dy of clonidine tretment. Pek "withdrwl" effects observed during the plcebo period, s well s the pek effects during the nloxone test on the lst dy of clonidine tretment, re lso shown. In the eight recting ptients, nloxone significntly incresed the men blood pressure nd hert rte, nd similr or greter increse in these vribles occurred during the first dy of the plcebo period. These rebound vlues were lso significntly higher thn the preclonidine control vlues. The six nonrecting ptients showed no significnt rebound, nd nloxone did not significntly lter blood pressure nd hert rte. The highest vlues registered during plcebo did not exceed the preclonidine control vlues. When the increse in men blood pressure cused by nloxone ws plotted ginst the increse in men pressure during withdrwl in the bove 1 ptients, significnt liner correltion ws found (r =.72, p <.5). Discussion Nloxone, potent opite-receptor ntgonist, is remrkbly free of phrmcologic ctions of its own. Therefore, nloxone hs been used to unmsk the ctions of exogenous opites or to suggest the involvement of endogenous opioids in vrious physiologic processes. Our findings indicte tht in ptients with % I. Or E -1, -2t_ -3L_ c \ U N.. or -5'. - 1k -15L FIGURE 3. The effect ofclonidine on men bloodpressure nd hert rte in recting nd nonrecting ptients. Open columns indicte recting ptients (n = 1); htched columns, nonrecting ptients (n = 13). Columns nd verticl brs represent mens nd stndrd errors. *p <.5 vs corresponding vlue in recting group.

4 CLONIDINE-OPIOID INTERACTION IN HYPERTENION/Frsng et l Downloded from by on Jnury 13, OF i oo ~ 9. I or 8-7 A I1 I ni---i I B C Cl CI+N WD FIGURE. The effects of clonidine, withdrwl of clonidine, nd nloxone given during clonidine tretment on men blood pressure nd hert rte. Open columns indicte recting ptients (n = 8); shded columns, nonrecting ptients (n = 6). Verticl brs show stndrd error of mens. Vlues connected by brckets within the sme ptient group re significntly different (p <.5). *ignificnt difference from corresponding vlue in recting ptients. C = pek vlues in drug-free control period; Cl = vlues on lst dy of clonidine tretment; Cl +N = pek effect of nloxone during clonidine tretment; WD = pek vlue during plcebo period (withdrwl). mild-to-moderte essentil hypertension, clonidine-induced hypotension nd brdycrdi cn be cutely reversed by nloxone. Clonidine nd nloxone do not interct with ech other' s specific binding sites. "I Therefore, we propose tht the ction of clonidine in these ptients involves the relese of n endogenous opioid. The ntihypertensive ction of clonidine is believed to involve stimultion of sympthoinhibitory - drenergic receptors in the centrl nervous system.'6 Relese of n endogenous opioid could occur distl to this site, nd the relesed opioid could then stimulte opioid receptors tht inhibit sympthetic tone. This sequence of events is supported by evidence obtined in HRs, in which similr interction between clonidine nd nloxone hs been reported. 11 I2 In these rts, the hypotensive ction of clonidine could be inhibited by nloxone or by the 2-receptor ntgonist yohimbine, wheres the hypotensive ction of morphine ws only inhibited by nloxone nd not by yohimbine, which suggests tht 2 receptors re ctivted before opite receptors during the ction of clonidine. 12 The nture of the opioid involved in humns is lso not known, lthough n endorphin-like substnce my be suspected on the bsis of findings in HRs.'3 The involvement of n endogenous opioid ppers to be contributory rther thn indispensble for the ntihypertensive ction of clonidine. Nloxone did not reverse the effect of clonidine in hlf of the hypertensive ptients studied (nonrecting group), nor ws there n interction between the two drugs in normotensive rts'2 or in normotensive humn volunteers.'7 Hypotensive nd brdycrdic ctions of clonidine cn be elicited from vrious sites in the pontomedullry region,18 nd the pthwys in which n endogenous opioid my be relesed could become more importnt in certin forms of hypertension. It hs been reported tht destruction of the nucleus of the solitry trct elimintes the hypotensive effect of clonidine in HRs but does not influence it in normotensive rts.'9 It is therefore tempting to speculte tht endogenous opioid peptides in the humn brin my contribute to the centrl control of sympthetic tone nd blood pressure, nd tht this mechnism is normlly inctive but becomes functionl in certin forms of hypertension. Nloxone did not increse blood pressure nd hert rte in ny of the ptients during plcebo tretment (fig. lb). Therefore the resting tone of the "opioidergic" neurons my be low, lthough they my be ctivted by sympthoinhibitory stimuli, such s centrl -receptor ctivtion. A sttisticlly significnt bimodlity in the distribution of ptients ccording to their blood-pressure response to nloxone could not be demonstrted in this reltively smll group of ptients. However, recting ptients responded to clonidine by greter reduction in blood pressure thn did the nonrecting ptients. Becuse clonidine cts by reducing sympthetic outflow from the brin, bsl sympthetic tone my be incresed in the subset of recting ptients. Other studies lso indicte tht essentil hypertension is not homogenous entity. For exmple, Kuchel et l.2 could distinguish ptients with lbile essentil hypertension s "normodrenergic" or "hyperdrenergic"; the ltter showed signs of excessive sympthetic rectivity. De Chmplin et l.2" found tht bout 5% of ptients with either lbile or stble essentil hypertension were hyperdrenergic, chrcterized by enhnced ctecholmine nd hert rte increses in response to chnge from the supine to the upright position. These hyperdrenergic ptients lso showed greter hypotensive response to chronic proprnolol tretment thn did the normodrenergic ptients.2' Further studies re needed to determine whether ptients in whom nloxone cn reverse the ntihypertensive ction of clonidine correspond to the hyperdrenergic ptients identified in either of the bove studies. Alterntively, it is possible tht recting ptients re more prone to endogenous opioid relese thn nonrecting ptients, which my hve etiologic relevnce in certin forms of hypertension. Finlly, the possible involvement of n endogenous opioid in the effects of clonidine my lso be relevnt to the mechnism of the so-clled clonidine discontin-

5 1272 CIRCULATION VOL 66, No 6, DECEMBER 1982 Downloded from by on Jnury 13, 219 ution syndrome. igns of sympthetic overrectivity with rebound or overshoot hypertension hve been noted fter cesstion of clonidine therpy, but the incidence nd severity of this syndrome vry widely in different reports. 22 Our observtions on rebound re ffected by the reltively few ptients studied nd by the retrospective nture of the nlysis. Nevertheless, overshoot hypertension nd tchycrdi were present only in the recting ptients; in the six nonrecting ptients (fig. ), blood pressure nd hert rte returned to, but did not exceed, pretretment levels. Furthermore, there ws significnt liner correltion between the bility of nloxone to reverse the hypotensive response to clonidine nd the degree of rebound hypertension fter cesstion of clonidine tretment. These observtions suggest tht temporry deficiency in sympthoinhibitory endogenous opioid my contribute to the rebound fter clonidine tretment is stopped. Acknowledgment We thnk Dr. John Kreeft for his dvice on sttisticl nlyses. References 1. Foley KM, Kourides IA, Inturrisi CE, Kiko RF, Zroulis CG, Posner JB, Houde RW, Li CH: /3-endorphin: nlgesic nd hormonl effects in humns. Proc Ntl Acd ci UA 76: 5377, Kstin AJ, Olson RD, chlly RV, Coy DH: CN effects of peripherlly dministered brin peptides. Life ci 25: 1, Meites J, Bruni JF, Vn Vugt DA, mith AF: Minireview: reltion of endogenous opioid peptides nd morphine to neuroendocrine functions. Life ci 2: 1325, Holdy JW, Fden Al: Nloxone reversl of endotoxin hypotension suggests role of endorphins in shock. Nture 275: 5, Fden Al, Holdy JW: Opite ntgonists: role in the tretment of hypovolemic shock. cience 25: 317, Curtis MT, Lefer AM: Protective ctions of nloxone in hemorrhgic shock. Am J Physiol 23: H16, Jnssen HF, Lutherer LO: Ventriculocisteml dministrtion of nloxone protects ginst severe hypotension during endotoxin shock. Brin Res 68, Amdt JO, Freye E: Opite ntgonist reverses the crdiovsculr effects of inhltionl nesthesi. Nture 277: 399, Dshwood MR, Feldberg W: Relese of opioid peptides in neshetized cts? Br J Phrmcol 68: 697, Frsng C, Kunos G: Nloxone reverses the ntihypertensive effect of clonidine. Br J Phrmcol 67: 161, Frsng C, Rmirez-Gonzlez MD, Mucci L, Kunos G: Possible role of n endogenous opite in the crdiovsculr effects of centrl lph drenoceptor stimultion in spontneously hypertensive rts. J Phrmcol Exp Ther 21: 23, Kunos G, Frsng C, Rmirez-Gonzlez MD: 13-endorphin: possible involvement in the ntihypertensive effect of centrl -receptor ctivtion. cience 211: 82, Lubie M, chmitt H, Vincent M, Remond G: Centrl crdiovsculr effects of morphinomimetic peptides in dogs. Eur J Phrmcol 6: 67, Lemire I, Tseng R, Lemire : ystemic dministrtion of,3- endorphin: potent hypotensive effect involving serotonergic pthwy. Proc Ntl Acd ci UA 75: 62, Trippodo NC, Frohlich ED: imilrities of genetic (spontneous) hypertension. Mn nd rt. Circ Res 8: 31, chmitt H, chmitt-jubeu H, Dsklopoulos NT: Centrl mechnisms of clonidine. Trends Phrmcol ci 1: 71, Wtkins J, Fitzgerld G, Zmboulis C, Brown MJ, Dollery CT: Absence of opite nd histmine H2 receptor-medited effects of clonidine. Clin Phrmcol Ther 28: 65, Vn Zwieten PA, Timmermns PBMWM: The role of centrl - drenoceptors in the mode of ction of hypotensive drugs. Trends Phrmcol ci 1: 39, Rockhold RW, Cldwell RW: Effects of lesions of the nucleus trctus solitrii on the crdiovsculr ctions of clonidine in conscious rts. Neurophrmcol 18: 37, Kuchel, Cuche JL, Hmet P, Kuchel, Cuche JL, Hmel P, Tolis G, Messerli FH, Brbeu A, Boucher R, Genest J: Lbile (borderline) hypertension. New spects of common disorder. Angiology 26: 619, de Chmplin J, Cousineu D, Lpointe L: Evidences supporting n incresed sympthetic tone nd rectivity in subgroup of ptients with essentil hypertension. Clin Exp Hypertension 2: 359, Weber MA: Discontinution syndrome following cesstion of tretment with clonidine nd other ntihypertensive gents. J Crdiovsc Phrmcol 2 (suppl 1): 1-73, 198