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 microM), cinnarizine (1-100 microM), trifluoperazine (10-500 microM) and dantrolene (50-250 microM) 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 microM) greater than cinnarizine (8.7 microM) greater than trifluoperazine (85.1 microM) greater than dantrolene (greater than 250 microM). Cinnarizine (0.5 mM) and trifluoperazine (0.5 mM), but neither verapamil nor dantrolene depressed Ca2+ (20 microM)-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 microM). 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 microM) 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+.(ABSTRACT TRUNCATED AT 250 WORDS)
Burchés
E
E
Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain.
Cortijo
J
J
Orón
J D
JD
Ortiz
J L
JL
Morcillo
E J
EJ
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002936:Cinnarizine / Q000494:pharmacology; D003620:Dantrolene / Q000494:pharmacology; D005260:Female; D005748:Gastric Fundus / Q000187:drug effects*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014268:Trifluoperazine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D014268:Trifluoperazine; D002936:Cinnarizine; D014700:Verapamil; D003620:Dantrolene