Differential effects of calcium channel antagonists in rat normal and skinned fundus.

CaCl2 (0.1-25 mM, in K(+)-depolarized tissues), KCl (10-112 mM) and acetylcholine (1 nM-1 mM) produced concentration-dependent contractions of rat isolated fundus. Nifedipine (0.01-500 mcM), diltiazem (0.01-100 mcM) and flunarizine (10-500 mcM) each produced a concentration-related inhibition of the log concentration-effect curve for CaCl2. The rank order of potencies of these antagonists, measured as the IC50 against Ca2+ (25 mM)-induced contraction of depolarized fundus, was nifedipine (1.9 mcM) = diltiazem (2.5 mcM) >> flunarizine (660 mcM). Diltiazem depressed KCl-induced contraction with an effectiveness and potency similar to that displayed against CaCl2 but nifedipine and flunarizine were less effective against contractions to KCl compared to CaCl2. Flunarizine (500 mc), but not the other antagonists tested, depressed Ca2+ (20 mc)-evoked contraction of skinned rat fundus preparations. It is concluded that distinct differences exist between the Ca2+ channel antagonists examined. The action of nifedipine and diltiazem is restricted to the plasmalemma, whereas flunarizine also acts on the intracellular contractile apparatus.