Cardiovascular Effects of LAS 30538, a New Vascular Selective Ca2+-Channel Blocker

Abstract

Abstract A new compound, 1-[2-(2,6-dimethylphenoxy)ethyl]-α,α-bis-(p-fluorphenyl)-4-piperidine methanol (LAS 30538), was found to have potent vasodilator effects. Its vasorelaxant activity was demonstrated in rat perfused hindlimbs contracted with 80 Mm K+, having an IC50 value of 40 Nm. In conscious spontaneously hypertensive rats, LAS 30538 administered orally, caused dose-dependent sustained falls in systolic blood pressure with an ED30 value of 11 mg kg−1. In pithed rats, LAS 30538, strongly inhibited vasoconstriction induced by the α2-adrenoceptor agonist B-HT 933 and the calcium agonist compound Bay K8644 with ED50 values of 4 mg kg−1 p.o. and 1·3 mg kg−1 i.v., respectively. Results from electrophysiological studies carried out using guinea-pig papillary muscles partially depolarized by 22 Mm K+ are consistent with LAS 30538 acting as a Ca2+-channel blocker. When compared with verapamil, in guinea-pig and rabbit isolated heart preparations, LAS 30538 caused less cardiodepression and bradycardia. The results suggest that LAS 30538 may have some advantages over other Ca2+-channel blockers such as verapamil in causing less myocardial depression for a given level of vasodilatation.