PY 108-068, a new, potent, and selective inhibitor of calcium-induced contraction of rabbit aortic rings.

Abstract

PY 108-068 (PY) is a new benzoxadiazolyle dihydropyridine derivative. It potently antagonizes calcium-induced contractions of rabbit aorta in depolarizing solution (PD'2:8.8). This antagonism is selective, since no relevant antagonistic effects against noradrenaline (NA)-, serotonin (5-HT)-, and angiotensin II (AII)-induced contractions are found at the highest concentration of PY (10(-5) M). Verapamil (V), examined for comparison, was less selective with respect to its antagonism: pA2 value against calcium-induced contractions in depolarizing solution: 7.6, pA2 against serotonin-induced contractions: 6.9. In calcium-free Krebs--Henseleit solution tachyphylaxis occurred after three to four administrations of NA, 5-HT, or AII. When calcium was added in the presence of one of these agonists, the slow phase of concentration, which depends on extracellular calcium, developed. This slow phase of contraction was not inhibited to a relevant extent by a 10(-5) M concentration of PY. Verapamil inhibited the tonic contraction induced by serotonin (pD'2: 5.5) but not to a relevant extent the contractions induced by the two other agonists. PY therefore, inhibits calcium-induced contractions of rabbit aorta in depolarizing solution very selectively, and shows hardly any effects on receptor-operated channels.