In vitro effects of calcium antagonists PN 200-110, nifedipine, and nimodipine on human and canine cerebral arteries.

PN 200-110 [4-(2,1,3-benzoxadiazol-4-)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid methyl 1-methylethyl ester], a new dihydropyridine derivative, was investigated by recording isometric tension on spiral strips from human and canine arteries in tissue baths at 37 degrees C. Responses to increasing concentrations of CaCl2 were investigated in calcium-free depolarizing solution (60 mmol/L KCl in equimolar replacement for NaCl, 50 mmol/L TRIZMA buffer, pH 7.4). Comparison of those concentrations that reduced the vasoconstrictor response to 1.6 mmol/L CaCl2 by 50% revealed the following order of potencies on both human and canine arteries: PN 200-110 greater than nimodipine greater than nifedipine. Responses to 5-hydroxytryptamine (5-HT) and blood were investigated in Krebs-Henseleit solution (NaHCO3 buffer). On canine arteries, PN 200-110 antagonized responses to 5-HT when used at 10-30 pmol/L; it was approximately 70 times more potent on basilar than on mesenteric arteries, whereas both nifedipine and nimodipine were, respectively, approximately 10 and 6 times more potent on basilar than on mesenteric arteries. When canine basilar arteries were constricted by the addition of blood to the organ bath, each of the investigated dihydropyridine derivatives elicited concentration-dependent relaxation, producing the following order of potencies: PN 200-110 greater than nifedipine = nimodipine. On human anterior cerebral arteries, the blood-induced contractions were counteracted in the following rank order: PN 200-110 = nimodipine greater than nifedipine. The results suggest that due to its potent calcium-blocking activity on cerebral arteries, PN 200-110 might be of value for the prevention and treatment of cerebrovascular spasms following subarachnoid hemorrhage.