Modification of Endothelium-Dependent Relaxation by Propofol, Ketamine, and Midazolam

Abstract

Since volatile anesthetics, barbiturates, and local anesthetics have been reported to inhibit endothelium-dependent relaxation, we hypothesized that any drug with anesthetic action would suppress this relaxation. In the present study, using rat thoracic aortae, we attempted to determine whether nonbarbiturate intravenous anesthetics, including midazolam, propofol, and ketamine, suppress endothelium-dependent relaxation, and to clarify the mechanism(s) involved. Acetylcholine-induced, endothelium-dependent relaxation was significantly attenuated by propofol and ketamine, but was unaffected by midazolam. Sodium nitroprusside (SNP)-induced relaxation was attenuated by propofol, but not by midazolam or ketamine. The acetylcholine-stimulated 3',5'-cyclic guanosine monophosphate (cGMP) level was reduced by pretreatment with propofol and ketamine but not by midazolam, and that stimulated by SNP was reduced by propofol but not by ketamine or midazolam. We conclude that propofol and ketamine suppress endothelium-dependent relaxation, whereas midazolam has no influence. Moreover, the suppressive effect of ketamine on endothelium-dependent relaxation is mediated by suppression of nitrous oxide (NO) formation, whereas that of propofol may be mediated at least partly by suppression of NO function.

Effects of propofol on substance P-induced relaxation in isolated human omental arteries and veins

“…In the presence of KCl (3 Â 10 À2 M), propofol at 10 À5 ±10 À4 M reduced the maximum response to substance P in the artery segments, but not in the vein segments. This indicates that propofol at these concentrations may reduce synthesis and/or smooth muscle effects of nitric oxide in human arteries as previously suggested in rabbit and rat arteries [7,12]. It could also be due to a reduction of the relaxant properties of the smooth muscle since the relaxant potency of GTN was smaller in the presence of propofol at 10 À5 M and 10 À4 M. However, the reduction only reached statistical signi®cance in the vein segments.…”

Differential effects of chloral hydrate- and ketamine/xylazine-induced anesthesia by the s.c. route

“…The effect is caused mainly by the reduction of calcium entry by the inhibition of voltage dependent L-type calcium channels (Yamazaki et al, 1992). Besides the effect of ketamine diminishing endothelial release of nitric oxide (NO), (Miyawaki et al, 1995), an important mediator of vasodilation, that would enhance the vasoconstrictor effect of noradrenaline, xylazine is also able to reduce the vasoconstriction by blocking alpha 1-adrenoceptors, in an endothelium-independent manner (Skrbic and Chiba, 1993). Thus, the reduction in the vasoconstriction to noradrenaline in ketamine/xylazine-anesthetized rats may occur independently of the reduction of NO release promoted by ketamine.…”

“…This may be due to ketamine action diminishing the endothelial release of NO (Miyawaki et al, 1995) and as a consequence interfering mainly with the vascular relaxation mediated by NO. Interestingly, we did not observe reduction in the vasodilatation promoted by acetylcholine after ketamine/xylazine anesthesia in relation to chloral hydrate.…”

Anesthesia and the Microcirculation

“…There is increasing evidence that anesthetic agents may differentially alter the response of the microcirculation to hemorrhage. 59 During hemorrhage or hemorrhagic shock, altered pharmacokinetics and pharmacodynamics of anesthetics must be considered. After hemorrhage, the highest degree of constriction of mesenteric arterioles, capillaries, and venules was observed under propofol/fentanyl anesthesia, compared with thiopental and ketamine anesthesia.…”