Stereoselective and calcium-dependent contractile effects of narcotic antagonist analgesics in the vascular smooth muscle of the rat

CH Lee and BA Berkowitz

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 blocker, phenoxybenzamine. In vitro, morphine (ED50 = 4 X 10(-5) M) and the l- isomers of pentazocine (ED50 = 8 X 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. On the other hand, not only was the contraction highly dependent on the concentration of calcium in the bath but it was also blocked by verapamil and SKF-525A, drugs known to inhibit transmembrane calcium influx. Naloxone (3 X 10(- 4) to 1 X 10(-3) M), which produced no contractile effect by itself, reduced aortic contraction of l-pentazocine to the greatest extent, that of potassium moderately and that of norepinephrine only slightly. The naloxone blockade of l-pentazocine vascular contraction was reversed by increasing Ca++ concentration in the media, suggesting the action of naloxone may resemble a calcium blocker. It is proposed that a direct, stereoselective and calcium dependent vascular action of l- pentazocine contributes to its ability to raise blood pressure. The possibility that in high doses narcotic antagonists may decrease calcium influx should also be considered.

Volume 198, Issue 2, pp. 347-356, 08/01/1976
Copyright © 1976 by American Society for Pharmacology and Experimental Therapeutics