Vascular effects of some opioid receptor agonists

Abstract

Opioid peptides have been implicated in shock-associated hypotension. Our aim was to find out whether opioid agonists have direct vasodilator actions on vascular smooth muscle. The study was conducted on rat abdominal aortic rings. In rings precontracted with either norepinephrine, prostaglandin F2 alpha, or high potassium Krebs (HPK), the effects of the opioid agonists tested (morphine, U50488H, ethylketocyclazocine (EKC), and bremazocine) depended on the precontracting agent used. HPK-precontracted rings were relaxed by all agonists tested. In norepinephrine-precontracted rings, all caused contraction at low concentrations and relaxation at high concentrations except bremazocine, which caused only relaxation. In prostaglandin F2 alpha-precontracted rings, U50488H produced contraction at low concentrations and relaxation at high concentrations while EKC caused only relaxation and morphine or bremazocine caused only contraction. All relaxant responses were endothelium-independent and were antagonized by verapamil but not by a number of antagonists including naloxone. MR2266, propranolol, diphenhydramine, cimetidine, and indomethacin. They may reflect calcium channel blockade. Morphine-induced vasoconstriction was antagonized by high concentrations of of naloxone or mepyramine and may be due to release of histamine by a naloxone-sensitive mechanism. We conclude that (a) the opioid agonists tested exert direct actions on vascular smooth muscle; (b) the nature of the response depended not only on the agonist used and its concentration but also on the agent used to precontract the tissue; and (c) it is unlikely that direct actions of endogenous opioids contribute to the shock-associated hypotension because high doses were needed to elicit them.

Morphine is an arteriolar vasodilator in man

“…The main finding of these studies is that intra‐arterial infusion of morphine causes a dose‐dependent vasodilatation in the human forearm. A number of investigators have also previously demonstrated the direct vasodilator action of opioids in animal vessels [14–16]. This response was not subject to acute tolerance and persisted for a period of at least 1 h after the end of the morphine infusion.…”

Cardiovascular Actions of U50,488H and Related Kappa Agonists

“…In isolated rat tail veins, Illes et al (38) showed that U50,488H and ethylketocyclazocine depressed stimulation-induced contraction while naloxone (10 cLM> did not prevent such actions. In abdominal aortic strips, contractions induced by either 1 p i 4 norepinephrine or 10 prostaglandin F,, were potentiated by low concentrations (0.1-10 N) of U50,488H, but were depressed by high concentrations (50 and 100 w) (19). Verapamil(6 w) reduced the inhibitory effect of high concentrations of U50,488H.…”

Bremazocine: A κ‐Opioid Agonist with Potent Analgesic and Other Pharmacologic Properties

“…These effects are attributable to inhibition of sympathoadrenal outflow as demonstrated by reductions in plasma levels of norepinephrine (34). El-Sharkawy and colleagues performed in vitro experiments that generated evidence of the direct effects of bremazocine (32) and other opioid agonists (9) on vascular smooth muscle. The effects of the agents varied depending on the agonist used, the concentration tested, and the pre-contracting agent used.…”