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

Abstract

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[Ca2+]i in vascular smooth muscle cells. The [Ca2+]i-reducing effects are caused by inhibitions of both voltage-gated Ca2+ influx and norepinephrine-induced Ca2+ release from the intracellular stores.

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

“…The suppressive effects of ketamine on intracellular calcium have been reported in a variety of cells and are known to sequentially affect cell activities. In resistant mesenteric arteries, ketamine can decrease voltage-gated calcium influx and norepinephrine-induced calcium release and causes a contractile response in smooth muscle cells (Akata et al, 2001). A decrease in intracellular levels of calcium can be associated with reduced nitric-oxide synthesis in endothelial cells (Fleming and Busse, 1999).…”

Ketamine blocks voltage-gated K+ channels and causes membrane depolarization in rat mesenteric artery myocytes

“…9) exceeded the values usually expected with K V current-inhibiting agents, such as 4-AP. We considered the following possible reasons: (1) Ketamine activates some inward current. (2) The K V current is so important in E m regulation in rat mesenteric artery myocytes that simple blockade of the K V channel can produce large E m depolarizations.…”

“…Interestingly, several in vitro studies have reported vasodilatory effects of ketamine under certain experimental conditions [2,16]. Recently, Akata et al [1] reported a vasodilatory effect of ketamine on mesenteric resistance arteries that were precontracted with norepinephrine. They showed that the relaxing effects of ketamine were largely a result of reductions in the intracellular Ca 2+ concentration in vascular myocytes, and the reduction in [Ca 2+ ] i was due, in turn, to reductions in both the voltage-dependent Ca 2+ influx and norepinephrine-induced Ca 2+ release from the intracellular stores.…”

“…Although these studies suggest that ketamine causes the relaxation of arteries that are precontracted or depolarized with vasoactive agonists by inhibiting ion channels other than K V channels, an exact assessment of the direct effects of ketamine on arteries in their basal or physiological state might require a more systemic study of the multiple targets of ketamine. For example, studies on the effects of ketamine on voltage-gated Ca 2+ channels and other Ca 2+ -permeable channels, such as ryanodine receptors and receptor-operated and store-operated Ca 2+ channels [1,5,22,25] in vascular myocytes, and comparison of the potency or mechanism of action of ketamine on these targets warrant further study.…”

Cellular and molecular mechanisms regulating vascular tone. Part 1: basic mechanisms controlling cytosolic Ca2+ concentration and the Ca2+-dependent regulation of vascular tone

“…Previous studies with Ca 2+ -sensitive indicators have shown that the force-[Ca 2+ ]c ratio or MLC 20 phosphorylation-[Ca 2+ ]c ratio can be variable during contractile response to receptor agonists, proposing the existence of secondary mechanisms that regulate the Ca 2+ sensitivity of contractile myofi laments or MLC 20 phosphorylation [4,[9][10][11][12][13]. In addition, previous studies have reported dissociation between force and MLC 20 phosphorylation levels during the maintenance of contraction, suggesting the existence of a regulatory mechanism(s) that maintains high contractile force at low energy (ATP) cost (i.e., low levels of MLC 20 phosphorylation) [14,15].…”