EFFECTS OF CALCIUM-ANTAGONISTS ON RAT NORMAL AND SKINNED FUNDUS

Calcium chloride (CaCl2) (0.1-25 mM, in K+-depolarized tissue), KCl (10-112 mM) and acetylcholine (1 x 10(-9) M-1 mM) produced concentration-dependent contractions of rat isolated fundus. Verapamil (0.01-100-mu-M), cinnarizine (1-100-mu-M), trifluoperazine (10-500-mu-M) and dantrolene (50-250-mu-M) each produced a concentration-related rightward and downward shift 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 verapamil (2.5-mu-M) > cinnarizine (8.7-mu-M) > trifluoperazine (85.1-mu-M) > dantrolene (> 250-mu-M). Cinnarizine (0.5 mM) and trifluoperazine (0.5 mM), but neither verapamil nor dantrolene depressed Ca2+ (20-mu-M)-evoked contraction of rat skinned fundus preparations. In intact preparations of rat fundus, verapamil had greater inhibitory effects on contractions produced by KCl than against those elicited by acetylcholine while trifluoperazine depressed to the same extent the responses to these two spasmogens. Dantrolene was without effect on contractions elicited by KCl or acetylcholine. Cinnarizine inhibited acetylcholine-induced responses but enhanced contractions to KCl. Augmentation of KCl-induced responses by cinnarizine is resistant to verapamil (1-mu-M). This enhancing effect of cinnarizine was not observed for KCl-induced contraction of guinea-pig fundus or rat gastro-oesophageal sphincter. In the rat fundus, cinnarizine (1-100-mu-M) produced an additional and concentration-related contraction when added on the plateau contraction to KCl (100 mM). The enhancing effect and the direct contraction produced by cinnarizine are at least partly dependent on extracellular Ca2+. It is concluded that distinct differences exist between the calcium antagonists examined. The action of verapamil is restricted to the plasmalemma whereas cinnarizine and trifluoperazine also act on the intracellular contractile machinery. Dantrolene is scarcely effective as a calcium antagonist in rat fundus.