MECHANISM OF PINDOLOL-INDUCED VASOCONSTRICTION IN ISOLATED AND PERFUSED DOG CORONARY-ARTERIES

The mechanism of pindolol-induced vasoconstriction in isolated and perfused dog coronary arteries was studied. Single injections of pindolol (I - 100 mug), propranolol (I - 30 mug), and 5-hydroxytryptamine (5-HT, 0.001 - 1 mug) produced a dose-related vasoconstriction in dog coronary arteries which were dilated by acetylcholine. l-Pindolol constricted coronary arteries, but d-pindolol did not. The responses to pindolol and propranolol were not affected by any of the following compounds (100 mug): bunazosin (a selective alpha1-adrenergic antagonist), DG 5128 (a selective alpha2-adrenergic antagonist), atropine (a muscarinic antagonist), chlorpheniramine (a selective H-1-antagonist), cimetidine (a selective H-2-antagonist), and ketanserin (a selective 5-HT2 antagonist). Methysergide (10 mug, a 5-HT1 and 5-HT2 antagonist) significantly reduced pindolol- and propranolol-induced vasoconstrictions, although it did not reduce norepinephrine-induced vasoconstriction in the presence of 5 muM propranolol. Methysergide (10 mug) and ketanserin (100 mug) significantly suppressed 5-HT-induced vasoconstriction. Diltiazem (100 mug, a calcium antagonist) and the incubation in Ca2+-free solution containing 1 mM EGTA for 1 hr significantly reduced the vasoconstrictions induced by pindolol and propranolol. The Ca2+ -free solution containing 1 mM EGTA abolished the vasoconstriction induced by 5-HT in the presence of 1 muM ketanserine. In a solution containing 20 mM KCl, the vasoconstrictions caused by pindolol and propranolol were enhanced in dog coronary arteries. These results indicate that the direct contractile effects of pindolol on dog coronary arteries are mediated, at least partly, through 5-HT1-like receptors, but not through alpha-adrenergic receptors. The vasoconstriction induced by pindolol appears to be associated with an increase of Ca2+ influx in the smooth muscle cell membrane.