DIFFERENTIAL-EFFECTS OF CALCIUM-CHANNEL ANTAGONISTS IN RAT NORMAL ANDSKINNED FUNDUS

CaCl2 (0.1-25 mM, in K+-depolarized tissues), KCl(10-112 mM) and acety lcholine (1 nM-1 mM) produced concentration-dependent contractions of rat isolated fundus. Nifedipine (0.01-500 mcM), diltiazem (0.01-100 mc M) and flunarizine (10-500 mcM) each produced a concentration-related inhibition of the log concentration-effect curve for CaCl2. The rank o rder of potencies of these antagonists, measured as the IC50 against C a2+ (25 mM)-induced contraction of depolarized fundus, was nifedipine (1.9 mcM) = diltiazem (2.5 mcM) >> flunarizine (660 mcM). Diltiazem de pressed KCl-induced contraction with an effectiveness and potency simi lar to that displayed against CaCl2 but nifedipine and flunarizine wer e less effective against contractions to KCl compared to CaCl2. Flunar izine (500 mc), but not the other antagonists tested, depressed Ca2+ ( 20 mc)-evoked contraction of skinned rat fundus preparations. It is co ncluded that distinct differences exist between the Ca2+ channel antag onists examined. The action of nifedipine and diltiazem is restricted to the plasmalemma, whereas flunarizine also acts on the intracellular contractile apparatus.