Facilitation of serotonin-induced contraction of rat mesenteric artery by ketamine

Abstract

Ketamine is an anesthetic with hypertensive effects, which make it useful for patients at risk of shock. However, previous ex vivo studies reported vasodilatory actions of ketamine in isolated arteries. In this study, we reexamined the effects of ketamine on arterial tones in the presence and absence of physiological concentrations of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) by measuring the isometric tension of endothelium-denuded rat mesenteric arterial rings. Ketamine little affected the resting tone of control mesenteric arterial rings, but, in the presence of 5-HT (100~200 nM), ketamine (10~100 µM) markedly contracted the arterial rings. Ketamine did not contract arterial rings in the presence of NE (10 nM), indicating that the vasoconstrictive action of ketamine is 5-HT-dependent. The concentration-response curves (CRCs) of 5-HT were clearly shifted to the left in the presence of ketamine (30 µM), whereas the CRCs of NE were little affected by ketamine. The left shift of the 5-HT CRCs caused by ketamine was reversed with ketanserin, a competitive 5-HT2A receptor inhibitor, indicating that ketamine facilitated the activation of 5-HT2A receptors. Anpirtoline and BW723C86, selective agonists of 5-HT1B and 5-HT2B receptors, respectively, did not contract arterial rings in the absence or presence of ketamine. These results indicate that ketamine specifically enhances 5-HT2A receptor-mediated vasoconstriction and that it is vasoconstrictive in a clinical setting. The facilitative action of ketamine on 5-HT2A receptors should be considered in ketamine-induced hypertension as well as in the pathogenesis of diseases such as schizophrenia, wherein experimental animal models are frequently generated using ketamine.

Enhancement of 5-HT2A receptor function and blockade of Kv1.5 by MK801 and ketamine: implications for PCP derivative-induced disease models

“…The direct effects of ketamine and PCP on dopamine D 2 and serotonin 5-hydroxytryptamine (HT) 2 receptors have been suggested to be implicated in the pathogenesis of schizophrenia 8 – 11 . In agreement with this, a previous study showed that 5-HT 2A receptor (5-HT 2A R)-mediated arterial contraction was facilitated by ketamine 12 , which was suggested to be the mechanism underlying ketamine-induced hypertension. In addition, NMDAr antagonists, including MK801 and ketamine, enhanced the head-twitch response, a 5-HT2R-mediated behavior, in reserpine-treated mice 13 .…”

“…1d ). Similarly, the facilitating effect of ketamine 12 was not observed when the E m -dependent 5-HT response was excluded (Fig. 1e ).…”

“…1b ) in a concentration-dependent manner. However, MK801 alone, similar to ketamine 12 , had a negligible effect on arterial contraction in the control condition without 5-HT (Fig. 1f ).…”

“…In our previous study, we reported that ketamine facilitated 5-HT 2A R-mediated arterial contraction 12 . The findings of this study further demonstrated that MK801, another PCP derivative NMDAr antagonist, also similarly facilitated 5-HT 2A R-mediated arterial contraction.…”

“…5-HT 2A Rs have been previously reported to mediate the effect of 5-HT in rat mesenteric arteries 17 , and ketamine has been shown to facilitate 5-HT 2A R-mediated contraction without unmasking other subtypes of 5-HT receptors, such as 5-HT1B or 5-HT2B receptors 12 . In this study, we examined whether MK801, another PCP derivative, also has similar effects on 5-HT 2A R-mediated arterial contraction.…”