Calcium antagonist properties of cinnarizine, trifluoperazine and verapamil in guinea-pig normal and skinned trachealis muscle.
In guinea-pig trachealis, depolarized by a K(+)-rich medium, Ca2+ (0.01-10 mM) caused concentration-related spasm. Verapamil (0.5-5 microM), cinnarizine (10-100 microM) and trifluoperazine (16-160 microM) each produced concentration-dependent antagonism of Ca2+ characterized by a rightward and downward displacement of the log concentration-effect curve for Ca2+. The rank order of potencies of these antagonists, measured as the IC75 against Ca2+ (10 mM)-induced contraction of depolarized trachea, was verapamil (5.6 microM) greater than cinnarizine (59 microM) greater than trifluoperazine (91 microM). In skinned trachea, verapamil in concentrations up to 100 microM did not modify the concentration-effect curve for Ca2+. In contrast, cinnarizine (59-177 microM) diminished the sensitivity and trifluoperazine (273 microM) decreased the responsiveness of the tissue to Ca2+. In skinned trachea, trifluoperazine (91 microM) produced greater inhibition of Ca2+ (10 microM)-induced contraction after 120 min than after 30 min of incubation. Verapamil (100 microM) and cinnarizine (177 microM) were devoid of inhibitory effect against the 10 microM Ca2+ standard. In skinned trachea, changes in the Ca2+ concentration-effect curve produced by cinnarizine (177 microM) were reversed after washout whilst those induced by trifluoperazine (273 microM) persisted. It is concluded that distinct differences exist between the three calcium antagonists examined. The action of verapamil is restricted to the plasmalemma. That of cinnarizine and trifluoperazine is exerted both on the plasma membrane and upon the intracellular contractile machinery.
Cortijo
J
J
Departamento de Farmacologia y Farmacotecnia, Facultat de Medicina, Universitat de València, Spain.
Foster
R W
RW
Small
R C
RC
Morcillo
E J
EJ
D000818:Animals; D002121:Calcium Channel Blockers; D002936:Cinnarizine / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects; D014268:Trifluoperazine / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D014268:Trifluoperazine; D002936:Cinnarizine; D014700:Verapamil