STEREOSELECTIVE AND CALCIUM-DEPENDENT CONTRACTILE EFFECTS OF NARCOTIC-ANTAGONIST ANALGESICS IN VASCULAR SMOOTH-MUSCLE OF RAT

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Abstract
In patients pentazocine administered i.v. can have an unusual action for a strong analgesic, an elevation of blood pressure. The objective of this study in rats was to better quantify and explain the molecular mechanism for the vascular action of l-pentazocine and compare it with other analgesics and narcotic antagonists. In anesthetized rats l-pentazocine (0.3-3 mg/kg i.v.) elevated blood pressure, and this effect was potentiated in pithed rats. The contraction appeared to be nonadrenergic as it was not blocked by the .alpha.-blocked, phenoxybenzamine. In vitro morphine (ED50 = 4 .times. 10-5 M) and the l-isomers of pentazocine (ED50 = 2 .times. 10-6 M), cyclazocine (ED50 = 6 .times. 10-6 M) and levallorphan (ED50 = 8 .times. 10-6 M) contracted the spirally cut aortic strip. The l-isomers were approximately 5 times more potent than their d-enantiomers. Contraction of the aorta by l-pentazocine was not inhibited by dibenamine, atropine, diphenhydramine, pyrilamine or indomethacin nor potentiated by propranolol. Not only was the contraction highly dependent on the concentration of Ca in the bath, but it was also blocked by verapamil and SKF-525A [proadifen hydrochloride] drugs known to inhibit transmembrane Ca influx. Naloxone (3 .times. 10-4-1 .times. 10-3 M), which produced no contractile effect by itself, reduced aortic contraction of l-pentazocine to the greatest extent, that of K moderately and that of norepinephrine only slightly. The naloxone blockade of l-pentazocine vascular contraction was reversed by increasing Ca2+ concentration in the media, suggesting the action of naloxone may resemble a Ca blocker. A direct, stereoselective and Ca dependent vascular action of l-pentazocine probably contributes to its ability to raise blood pressure. The possibility that in high doses narcotic antagonists may decrease Ca influx should be considered.