PATHOPHYSIOLOGY AND NATURAL HISTORY HYPERTENSION Reversal by naloxone of the antihypertensive action of clonidine: involvement of the sympathetic nervous system

The effects of clonidine, naloxone, and their combination on arterial blood pressure (BP), heart rate (HR), and hemodynamic and biochemical parameters were examined.in 29 patients with essential hypertension. Treatment for 3 days with 0.3 mg/day clonidine reduced BP and HR, and these effects were quickly reversed by a single injection of 0.4 mg iv naloxone in 17 of the patients (responders), but not in the remaining 12 (nonresponders). Responders had higher control values for cardiac output, stroke index, plasma renin activity (PRA), and plasma epinephrine levels than did nonresponders. Basal BP was similar in the two groups, but clonidine decreased BP, PRA, and plasma epinephrine more in responders than in nonresponders. Naloxone given during placebo treatment had no significant effects. During clonidine treatment naloxone increased BP, HR, total peripheral resistance, PRA, and plasma epinephrine and norepinephrine, and decreased stroke volume in responders, whereas in nonresponders its only effect was a small increase in HR. It is concluded that in a subset of hyperadrenergic, hypertensive patients the antihypertensive effect of clonidine involves a naloxonereversible inhibition of central sympathetic outflow, probably mediated by the release of an endogenous opioid. Circulation 69, No. 3, 461-467, 1984. THE ANTIHYPERTENSIVE AGENTS clonidine and a-methyldopa are believed to produce their cardiovascular effects through a central mechanism. They stimulate a2-adrenergic receptors in the pontomedullary region, which results in a reduction of sympathetic and increase in parasympathetic tone. 1 Recent reports have demonstrated that in hypertensive rats the antihypertensive action of these drugs is inhibited by the opiate antagonists naloxone and naltrexone,24 or by central administration of an antiserum to /3-endorphin.t5 Furthermore, clonidine and 1 -a-methylnorepinephrine increase the release of immunoreactive /3-endorphin from the superfused brain stem of spontaneously hypertensive rats in vitro.6 These findings have been interpreted to indicate that the antihypertensive effect of From the Second Department of Medicine, Semmelweis Medical University, Budapest, and Department of Pharmacology & Therapeutics, McGill University, Montreal. Supported in part by grants from the Quebec Heart Foundation,the Hungarian Ministry of Health, the Medical Research Council of Canada and by Boehringer/Ingelheim of Canada. Address for correspondence: George Kunos, M.D., Dept. of Pharmacology, McGill University, 3655 Drummond St., Montreal, Quebec, Canada. Received June 7, 1983; revision accepted Nov. 23, 1983. central a-adrenergic stimulation involves the release of a ,8-endorphin-like material from the brain.6 A similar adrenergic-opioid interaction is present in certain forms of human hypertension. In patients with moderate essential hypertension the blood pressureand heart rate-lowering effects of clonidine were quickly reversed by a single intravenous injection of 0.4 mg of naloxone in about one-half of the patients studied, whereas in the remaining patients naloxone was ineffective even when a larger dose was given.7 In an attempt to analyze the difference beween naloxone "responders" and "nonresponders," and to clarify the mechanism of the adrenergic-opioid interaction in the former group, we have examined hemodynamic and biochemical changes produced by clonidine, naloxone, and their combination in patients with uncomplicated essential hypertension. Methods Study population. A crossover, single-blind study was done with 29 hospitalized patients from 26 to 55 years old who had moderate essential hypertension. Patients with signs of cardiac, renal, cerebral, or peripheral vascular complications as well as those with secondary forms of hypertension were excluded from the study. The absence of such factors was verified with approVol. 69, No. 3, March 1984 461 by gest on A ril 4, 2017 http://ciajournals.org/ D ow nladed from