Mechanisms of Direct Inhibitory Action of Ketamine on Vascular Smooth Muscle in Mesenteric Resistance Arteries

Background: Ketamine was previously suggested to relax vascular smooth muscle by reducing the intracellular Ca2+ concentration (Ca2+]i). However, no direct evidence is available to indicate that ketamine reduces the Ca2+]i in vascular smooth muscle of systemic resistance arteries.

Methods: Endothelium-intact or -denuded smooth muscle strips were prepared from rat small mesenteric arteries. Isometric force and Ca2+]i were measured simultaneously in the fura-2-loaded, endothelium-denuded strips. In some experiments, only isometric force was measured in either the endothelium-intact or beta]-escin-treated, endothelium-denuded strips.

Results: In the endothelium-intact strips, lower concentrations (<= 30 mu]m) of ketamine slightly enhanced norepine-phrine-induced contraction, whereas higher concentrations (>= 100 mu]m) of ketamine inhibited both norepinephrine- and KCl-induced contractions. In the fura-2-loaded strips, ketamine (>= 100 mu]m) inhibited the increases in both Ca2+]i and force induced by either norepinephrine or KCl. Ketamine also inhibited the norepinephrine-induced increase in Ca2+]i after treatment with ryanodine. In the absence of extracellular Ca2+, ketamine notably inhibited the norepinephrine-induced increase in Ca2+]i, whereas it only minimally inhibited caffeine-induced increase in Ca2+]i. Ketamine had little influence on the Ca2+]i-force relation during force development to stepwise increment of extracellular Ca2+ concentration during either KCl depolarization or norepinephrine stimulation. Ketamine did not affect Ca2+-activated contractions in the beta]-escin membrane-permeabilized strips.