Selectivity of Phenytoin and Dihydropyridine Calcium Channel Blockers for Relaxation of the Basilar Artery

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Abstract
We addressed the questions of whether or not phenytoin is a direct vasodilator and if it is selective for brain blood vessels, by studying the relaxant effects of phenytoin on isolated segments of canine basilar, femoral, and brachial arteries. Two dihydropyridine calcium channel blockers, nifedipine and PY 108-068, were also studied for comparison with phenytoin and to test for cerebral selectivity. Blood vessels were contracted with K+, prostaglandin F2.alpha., or serotonin. Phenytoin relaxed the basilar artery with low potency (pD2, 4.71 .+-. 0.14) and moderate selectivity. Phenytoin also antagonized Bay K 8644 contractions of basilar artery in a noncompetitive manner. Basilar arteries contracted with 60 mM K+ were the most sensitive to nifedipine (pD2, 8.72 .+-. 0.18), followed by the mesenteric (pD2, 8.24 .+-. 0.07), femoral (pD2 8.04 .+-. 0.18), and brachial (pD2, 7.66 .+-. 0.23) arteries. A similar pattern was observed in potassium-depolarized arteries relaxed by PY 108-068. The calcium dependence of contraction was studied using intact muscles depolarized in 60 mM K+ as well as chemically skinned basilar artery. Mean pD2 values for Ca2+-induced contractions of intact, depolarized arteries were not different (basilar, 4.15 .+-. 0.13; mesenteric, 4.04 .+-. 0.07; femoral, 4.24 .+-. 0.11). The mean Ca2+ EC50 of chemically skinned basilar arteries was 8.7 .times. 10-7 M, which is similar to the Ca2+ sensitivity of other skinned smooth muscles. The beneficial effect of phenytoin in treating cerebral ischemia may be due in part to relaxation of vascular smooth muscle. The dihydropyridines were potent smooth muscle muscle relaxants with selectivity for the basilar artery. Differences in sensitivity of canine arteries to calcium channel blockers appears not to correspond to any difference in sensitivity of the contractile element to Ca2+.