KETAMINE-INHIBITION OF CALCIUM-INDUCED CONTRACTIONS IN DEPOLARIZED RAT UTERUS - A COMPARISON WITH OTHER CALCIUM-ANTAGONISTS

The inhibitory effect of the i.v. anesthetic ketamine on CaCl2-induced contractions in the isolated K+-depolarized uterus of the rat in Ca2+-free medium was compared with that produced by papaverine, theophylline and the Ca entry blocker verapamil. Pre-incubation for 20 min with either ketamine (0.3-3 mM), papaverine (3-30 .mu.M), theophylline (0.1-1 mM) or verapamil (3-30 nM) induced parallel, concentration-dependent rightward displacements of the dose-response curves to Ca2+ (0.04-22 mM). The antagonism was competitive, except that due to verapamil, the Schild plot for which yielded a slope which differed significantly from unity. The calculated pA2 [effective concentration of agonist to antagonist] values (.+-. SE mean) were: ketamine 3.90 .+-. 0.07; papaverine 5.55 .+-. 0.05; theophylline 3.99 .+-. 0.1 and verapamil 9.54 .+-. 0.24. These drugs differed in their ability to relax the sustained contraction induced by Ca2+ (1 mM) in K+-depolarizing solution. Ketamine and verapamil relaxed the preparation in a concentration-dependent manner whereas theophylline and especially papaverine were less potent and induced only partial maximal relaxation. The t1/2 [half-time] of the relaxant effect was significantly less for ketamine than for verapamil (5 and 22 min, respectively). Only ketamine produced a relaxation comparable to that obtained by washing the preparation with Ca2+-free solution (t1/2 = .apprx. 0.5 min). Prior exposure of the depolarized uterine strip to a low concentration of Ca2+ (0.22 mM) increased the potency of ketamine, but decreased that of papaverine and theophylline, in antagonizing Ca2+-induced contractions. In contrast, this procedure did not affect the potency of verapamil. The inhibitory effects of these drugs, excluding those of verapamil, were completely reversed after washing the preparations with a high-K Ca2+-free solution, 3-5 times for about 30-60 min. The relaxant effect produced by ketamine on the rat isolated uterus is due to its ability to antagonize Ca2+ movements competitively. There are marked differences between the nature of the relaxant effects of ketamine and those of papaverine, theophylline and verapamil.