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 Ca(2+) concentration ([Ca(2+)]i). However, no direct evidence is available to indicate. that ketamine reduces the [Ca(2+)]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 [Ca(2+)]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 (less than or equal to 30 muM) of ketamine slightly enhanced norepinephrine-induced contraction, whereas higher concentrations (greater than or equal to 100 muM) of ketamine inhibited both norepinephrine- and KCI-induced contractions. in the fura-2-loaded strips, ketamine (greater than or equal to 100 muM) inhibited the increases in both [Ca(2+)]i and force induced by either norepinephrine or KCl. Ketamine also inhibited the norepinephrine-induced increase in [Ca(2+)]i after treatment with ryanodine. in the absence of extracellular Ca(2+), ketamine notably inhibited the norepinephrine-induced increase in [Ca(2+)]i, whereas it only minimally inhibited caffeine-induced increase in [Ca(2+)]i. Ketamine had little influence on the [Ca(2+)]i-force relation during force development to stepwise increment of extracellular Ca(2+) concentration during either KCI depolarization or norepinephrine stimulation. Ketamine did not affect Ca(2+)-activated contractions in the beta -escin membrane-permeabilized strips. Conclusions. The action of ketamine on contractile response to norepinephrine consists of endothelium-dependent vasoconstricting and endothelium-independent vasodilating components. The direct vasorelaxation is largely a result of reduction, of [Ca(2+)]i in vascular smooth muscle cells. The [Ca(2+)]i-reducing effects are caused by inhibitions of both voltage-gated Ca(2+) influx and norepinephrine-induced Ca(2+) release from the intracellular stores.