Effects of Ca2+ channel antagonists in guinea-pig normal and skinned gall bladder

CaCl2 (0.01-50 mM, in K(+)-depolarized tissues), KCl (0.1-100 mM) and acetylcholine (1 nM-10 mM) produced concentration-dependent contractions of guinea-pig isolated gall bladder. Nifedipine (1-100 microM), verapamil (1-100 microM), diltiazem (1-100 microM), cinnarizine (1-100 microM), and flunarizine (1-100 microM) 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+ (50 mM)-induced contraction of depolarized gall bladder, was diltiazem (0.25 microM) > or = verapamil (0.8 microM) approximately nifedipine (1.2 microM) >> cinnarizine (25 microM) approximately flunarizine (80 microM). Verapamil and diltiazem depressed KCl-induced contraction with an effectiveness and potency similar to those displayed against CaCl2 but nifedipine, cinnarizine and flunarizine were less effective against contractions in response to KCl compared to CaCl2. Verapamil and diltiazem, but not the other Ca2+ channel antagonists tested, had a specific inhibitory effect on the contractions due to KCl when compared to acetylcholine-induced contractions. Cinnarizine (10-100 microM) and flunarizine (10-100 microM), but not the other antagonists tested, depressed Ca2+ (20 microM)-evoked contraction of skinned guinea-pig gall bladder preparations. It is concluded that distinct differences exist between the Ca2+ channel antagonists examined. The action of nifedipine, verapamil and diltiazem is restricted to the plasmalemma whereas cinnarizine and flunarizine also act on the intracellular contractile apparatus.