The opioid peptides. A role in hypertension?

Abstract

SUMMARY This review is an attempt to highlight evidence that may implicate the endogenous opioid system in the pathogenesis of hypertension in humans. The evidence raised includes biochemical, physiological, pharmacological, and behavioral studies conducted in in vitro and in vivo systems, experimental models of hypertension, and humans with essential hypertension. While the compelling biochemical and pharmacological evidence in experimental animals clearly shows the presence of opioid peptides and their receptors in strategic sites of cardiovascular control and potent cardiovascular response to opioid peptides, opioid antagonists show no consistent blockade or reversal of hypertension in experimental animals or humans. One possible explanation for this phenomenon could be the vast redundancy in systems regulating blood pressure (i.e., the blockade of one system still leaves many other systems fully able to rapidly offset the eliminated system). Regarding the opioid system, the situation is much more complex, since some opioid receptors (/x-type) mediate pressor responses, while other receptors (K-type) mediate depressor responses. Therefore, nonselective opioid receptor antagonists (e.g., naloxone), which block both types of receptors, can be devoid of any cardiovascular activity, while a selective /x-receptor antagonist or a selective and potent K-receptor agonist may produce the desired antihypertensive effect. A combination of both actions (i.e., a drug that is both â -antagonist and a K-agonist) might be even more advantageous. Until such compounds are developed, this hypothesis will be hard to prove. (Hypertension 9: 561-565, 1987) KEY WORDS • /n-opioid receptors vascular resistance K-opioid receptors • naloxone • blood pressure N UMEROUS neurally localized peptides are now known to exist within the central nervous system (CNS). Many of these peptides originally were found in the hypothalamus and pituitary gland and later were shown to be widely distributed in the CNS and to possess diverse autonomic functions through modulation of sympathetic and parasympathetic tone and the baroreceptor reflex mechanism.Neuropeptides like vasopressin, angiotensin, bradykinin, neurokihins (e.g., substance P and thyrotropinreleasing hormone) have long been a subject of discussions in reference to cardiovascular regulation. The

Regional haemodynamic effects of μ‐, δ‐, and κ‐opioid agonists microinjected into the hypothalamic paraventricular nuclei of conscious, unrestrained rats

“…There is accumulating evidence to suggest a role for endogenous opioid peptides in central cardiovascular control (Holaday, 1983;Feuerstein, 1985;Feuerstein & Siren, 1987;Siren & Feuerstein, 1992). Mainly, opioid peptides and opiate receptors have been found in specific brain nuclei, with an established role in the regulation of cardiovascular activities (Atweh & Kuhar, 1977;Hokfelt et al, 1977;Fallon & Leslie, 1986;Mansour et al, 1988;Desjardins et al, 1990), and potent cardiovascular effects have been reported following central administration of opioid peptides (Hassen et al, 1983;Pfeiffer et al, 1983a,b;Appel et al, 1986;Kiritsy-Roy et al, 1986;Marson et al, 1989a,b;May et al, 1989;Siren et al, 1989;Jin & Rockhold, 1991;Siren & Feuerstein, 1991).…”

Sympathoadrenal control by paraventricular hypothalamic beta-endorphin in hypertension.

“…22 Moreover, the renal and mesenteric vasoconstrictions produced by intracerebroventricular DAGO were found to be significantly enhanced in SHR compared with WKY rats. 21 It is of some interest that the regional hemodynamic alterations produced by intracerebroventricular DAGO are similar to those produced by electrical stimulation of the PVH. 10 In light of the facts that microinjection of either DAGO 19 or /3-endorphin into the PVH produced pressor and tachycardiac responses and stimulated sympathoadrenal outflow, the PVH may be considered as one of the sites of action of enkephalins administered intracerebroventricularly.…”

“…19 Therefore, /3-endorphin in the PVH has been hypothesized to be involved in the integrative function of the PVH through regulation of sympathoadrenal function in association with feeding. Both the PVH 20 and central opioid systems 21 have been shown to be involved in the development of hypertension in spontaneously hypertensive rats (SHR). For example, ablation of the PVH delayed the development of hypertension in SHR.…”

The Opioid System in Circulatory Control

“…In general, JL-selective opiates when administered centrally in the rat induce a dose-related pressor response that is accompanied by a biphasic heart rate response (4,5,13,14). It is our view that in the central nervaus system selective activation of the JL-Opioid receptor produces cardiovascular responses in conscious animals through activation of the sympathoadrenomedullary axis.…”

“…The endogenaus opioid system consists of a large family of opiatelike peptides: the enkephalins derived from preproenkephalin A, the endorphins derived from preproopiomelanocortin, and dynorphins derived from preproenkephalin B (8 5 ]enkephalin), K (ketocyclazocine), l (ß-endorphin), and (J (SKF-10,047) has been weil established, and the existence of multiple receptor subtypes has been proposed for !l-and K-receptors based on pharmacological and biochemical studies (8,10,12).…”