Opiate receptors and cardiovascular control in conscious SHR and WKY rats.

Abstract

SUMMARY This study examined the cardiovascular, respiratory, and sympathetic effects of selective fj. and 5 opioid agonists microinjected into the hypothalamic nucleus preopticus medialis (POM) of conscious SHR and WKY rats. The /x receptor agonist D-Ala -ol-enkephalin (DAGO) at a dose of 0.6 or 6.0 nanomoles (Nmol) increased the blood pressure and heart rate in WKY rats. In SHR rats, the lower dose of DAGO similarly had a pressor effect whereas the higher dose was depressor; heart rate was increased only by the 6.0 nmol dose in these animals. In both SHR and WKY rats, this opioid caused respiratory acidosis and elevation of plasma norepinephrine (NE) and epinephrine (E); plasma vasopressin was reduced by the higher dose of DAGO. All of these effects of the \x agonist were reversed by the opiate receptor antagonist naloxone (0.5 mg/kg, i.a.). The 8 opiatereceptor agonist D-Ala 2 -D-leu 5 -eukephalin at a dose of 6.0 or 20.0 nmol increased blood pressure and heart rate in both SHR and WKY rats without affecting respiratory variables. Plasma NE and EPI were elevated at the peak of the pressor period.These studies suggest that the anteroventral hypothalamic region may be an important site in central autonomic regulation by opioid peptides. The /x-receptor agonist was more potent than the 8 agonist in eliciting cardiovascular and respiratory effects and associated sympatho-adrenomedullary activation. SHRs differed from the normotensive strain by their opposite (depressor) response to the higher dose of DAGO, a finding that may indicate a potentially different role of endogenous opioids and fi receptors in central cardiovascular control in the spontaneous hypertensive rat. (Hypertension 5: 663-671, 1983) KEY WORDS hypertension enkephalins • catecholamines blood pressure • vasopressin heart rate • respiration T HE presence of opioids and opiate receptors in specific brain nuclei known to regulate cardiovascular activity'" 3 and the potent effects of opioid peptides on blood pressure (BP) and heart rate (HR) when administered into the lateral cerebral ventricle 4 " 6 or the cisterna magna 7 suggest that opioid peptides may be important endogenous substances in central cardiovascular control.Opioid peptides are also known to produce differential central cardiovascular effects in SHR as compared with normotensive rats indicating a potential role for these substances in the genesis of hypertension. Rockhold et al. 6 have demonstrated that SHRs respond with a greater incidence in BP after injection of a stable metenkephalin analog into the lateral ventricle (ICV), while a similar phenomenon was shown with leu-enkephalin in stroke-prone SHR.

Sympathoadrenal control by paraventricular hypothalamic beta-endorphin in hypertension.

“…Spontaneously hypertensive rats have been reported to show enhanced pressor responses to intracerebroventricular leucineenkephalin, 24 ]-enkephalin microinjected into the medial preoptic nucleus of the hypothalamus. 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.…”

“…20 In addition, the pressor responses to centrally administered opioid peptides were enhanced in SHR as compared with those in Wistar-Kyoto (WKY) rats. 22 " 25 Moreover, manipulation of food intake has been demonstrated to produce differential effects on systemic cardiovascular function between SHR and WKY rats. 26 - 27 Thus, in the present study, £-endorphin was microinjected into the PVH of SHR and WKY rats to elucidate a putative role for /3-endorphin as a neurotransmitter system integrating regulation of sympathoadrenal function by PVH neurons and a role of this system in the development of hypertension in SHR.…”

The opioid peptides. A role in hypertension?

“…17 In normotensive WKY, unlike the SHR, pronounced tachycardia accompanied the pressor response. 17 Studies still in progress in our laboratory have shown that the SHR also differ from WKY in their sensitivity to the distinct regional blood flow changes mediated by /nreceptors (Figure 1). The renal and mesenteric vasoconstriction produced by DAGO (0.1-10 nmol per rat i.c.v.)…”

Binding of ³H-D-Pen²-D-Pen⁵-Enkephalin to Brain Regions and Spinal Cord Membranes of Spontaneously Hypertensive and Normotensive Wistar-Kyoto Rats

“…Administration of Z)-Ala2, McPhe4, Gly-ol5-enkephalin (D A M G O ), a highly selective ligand for p-opiate receptors, increases the blood pressure and heart rate in W K Y rats. In SH R rats, low doses of D A M G O produce pressor effects when in jected into the hypothalamic nucleus preopti cus medialis [5], D A M G O causes pressor re sponse when microinjected into nucleus ambiguus [6], The effects of opiate antagonists, naloxone and naltrexone on blood pressure have also been determined. Whereas in con scious squirrel monkeys, intravenous injec tions of naloxone or naltrexone (0.3-10 mg/kg) failed to affect blood pressure or heart rate [7], both agents in high doses produced a brief, dose-related decrease in mean arterial pressure of urethane-anesthetized SH R rats, but had no effect in W K Y rats [8], These effects of antagonists were suggested to be centrally mediated since quaternary com pounds which cross the blood-brain barrier with difficulty were ineffective.…”

“…Attempts have also been made to deter mine the effects of 5-opiate agonists on the cardiovascular system. D-Ala2, Z)-Leu5-enkephalin (DADLE) was shown to increase the systolic blood pressure, and the effect ap peared to be of greater intensity in SH R than in W K Y rats [5]. However, the relative distri bution of the central 8-opiate receptors in brain regions and spinal cord of W K Y and SH R rats is not known.…”