Abstract
In smooth muscles of the rabbit coronary artery, nisoldipine inhibited the phasic and tonic responses of the contraction induced by 128 mM K (the IC50 values were 4 X 10(-8) M and 1 X 10(-13) M, respectively). This agent also inhibited the tonic response of the acetylcholine (ACh) (10(-5) M)-induced contraction (the IC50 value was 3 X 10(-10) M), but only slightly inhibited the phasic response (in 10(-7) M, 0.86 times the control). Nisoldipine (less than 10(-7) M) had no effect on the K-induced depolarization of the membrane at any given concentration. This drug (5 X 10(-8) M) did inhibit the oscillatory potential changes and spike potential evoked on the ACh-induced slow depolarization. After depletion of stored Ca from the polarized muscles (5.9 mM K), muscle cells accumulated Ca by application of 2.6 mM Ca without generation of contraction, i.e. a subsequently applied 20 mM caffeine produced the contraction in Ca-free solution. Nisoldipine (less than 10(-7) M) had little effect on this accumulation of Ca. The rate of rise and time to reach the maximum amplitude of the 128 mM K- or ACh-induced contraction (in 2.6 mM Ca) depended on the amount of stored Ca in cells. Nisoldipine (10(-8) M) consistently inhibited the Ca-induced contraction evoked in depolarized muscles (128 mM K), regardless of the amount of stored Ca. However, this agent (10(-8) M) did not inhibit the Ca release from storage sites evoked by activation of the muscarinic receptor. After prolonged superfusion (over 120 min) with Na- and Ca-free solution (guanethidine and atropine were present), application of 2.6 mM Ca produced contraction which was inhibited by 10(-8) M nisoldipine, while the depolarization induced by application of these solutions was not inhibited by nisoldipine. In saponin-skinned muscles, nisoldipine had no effect on the contractile proteins, as estimated from the pCa-tension relationship, or on the Ca accumulation into the Ca release from the Ca storage sites, as estimated from the caffeine-induced contraction. It is concluded that nisoldipine possesses a selective inhibitory action on voltage-dependent Ca influx, when the Ca channel is activated by depolarization.