MECHANISMS OF THE INHIBITORY EFFECT OF KETAMINE ON GUINEA-PIG ISOLATED MAIN PULMONARY-ARTERY

Although ketamine increases pulmonary vascular resistance of patients, an occasional decrease of resistance in animals and humans has been r eported. In addition, ketamine has a direct relaxant effect on isolate d smooth muscle. The effects of ketamine on the main pulmonary artery rings isolated from the guinea pig were studied to elucidate the under lying mechanism of the reported relaxant effect of this anesthetic on smooth muscle. Ketamine (10-250 mu g/mL) caused a concentration-depend ent shift to the right of CaCl2 concentration-effect curves on artery rings, suggesting an interference with Ca2+ metabolism. In Ca2+-free b uffer, ketamine (10-250 mu g/mL) did not affect the magnitude of epine phrine-induced contractions but inhibited dose-dependent BaCl2 induced contractions. These observations suggest that ketamine inhibits trans membrane Ca2+ influx but does not affect its release from intracellula r stores or its binding to intracellular receptor sites on the contrac tile system. Ketamine (25-500 mu g/mL) also caused equipotent concentr ation-dependent relaxation of epinephrine-induced contractions in the absence and the presence of monensin, a Na+-ionophore that dissipates the Na+ gradient across the cell membrane, and in Na+-free, sucrose-su bstituted buffer. Ketamine (25-500 mu g/mL) also relaxed ouabain-induc ed contractions to the baseline, an effect that was significantly atte nuated in the presence of ruthenium red, a Ca2+ adenosine triphosphata se (ATPase) inhibitor. The relaxant effect of ketamine (250-750 mu g/m L) of epinephrine-induced contraction also was attenuated in the prese nce of 0.1 mM lanthanum chloride (La3+), an inhibitor of adenosine 5'- triphosphate (ATP)dependent Ca2+ extrusion, and completely inhibited i n the presence of 10 mM La3+. These data suggest that ketamine-induced relaxation is attributed mainly to the stimulation of Ca2+-ATPase and that Nac-dependent, Ca2+ efflux participates only minimally to this r elaxation. We, therefore, conclude that ketamine has two effects on Ca 2+ transport in isolated pulmonary artery smooth muscle: 1) it inhibit s Ca2+ influx, and 2) it stimulates Ca2+-ATPase to cause efflux.