dinoprost and bremazocine

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.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzomorphans; Calcium Channel Blockers; Dinoprost; Endothelium, Vascular; Ethylketocyclazocine; In Vitro Techniques; Male; Morphine; Muscle Contraction; Muscle, Smooth, Vascular; Narcotic Antagonists; Norepinephrine; Potassium; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Vasodilation

Several 'so-called' kappa-opiate receptor agonists e.g., ketocyclazocine (Kc), ethylketocyclazocine (Ekc), bremazocine, MR-2034 and U-50488H, were tested on basilar and middle cerebral arteries of the dog in vitro for relaxant or contractile activities. Ekc, Kc and bremazocine were found to produce concentration-dependent reductions in basal tone and to relax cerebral arteries contracted with prostaglandin F2 alpha (PGF2 alpha). All three agonists appear to act on benzomorphan-kappa opiate receptors which subserve relaxation in cerebral blood vessels. MR-2034 and U-50488H were found to induce contraction in the cerebral arteries. These opiate agonists appear to act on phencyclidine (PCP) or sigma-opiate receptors which subserve contraction. A variety of pharmacological antagonists (phentolamine, propranolol, methysergide, atropine, diphenhydramine, cimetidine, naloxone) did not modify any of the cerebral vascular effects produced by the opiates. These results suggest: (1) specific benzomorphan-kappa opiate receptors which subserve relaxation exist in cerebral blood vessels; (2) some kappa agonists appear to produce, primarily, contraction in cerebral vessels via PCP or sigma-opiate receptors: and cerebral vascular muscle may provide a useful tool to analyse the molecular constitution of these two distinct and opposite-acting opiate receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Cerebral Arteries; Cyclazocine; Dinoprost; Dogs; Drug Interactions; Ethylketocyclazocine; Female; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Phencyclidine; Prostaglandins F; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa