Inhibition of Nitric Oxide-Dependent Vasodilation by Halogenated Anesthetics

Abstract

Publisher Summary In this chapter, the inhibitory effects of halothane, enflurane, and isoflurane on acetylcholine (ACh)–, nitric oxide (NO)–, and carbon monoxide (CO)–induced relaxations in vascular smooth muscle has been reported. This inhibition is the result of competition between NO and the anesthetics for the heme moiety on the soluble guanylate cyclase. It has been suggested that halothane and, to a lesser extent, enflurane and isoflurane have an inhibitory effect on soluble guanylate cyclase (sGC) in the smooth muscle cell. It has been also reported that in endothelial-denuded vessels halothane significantly suppressed relaxation induced by exogenous NO. Like NO, carbon monoxide activates GC by binding to the heme group in the enzyme. Relaxation induced by CO is also inhibited by halothane. This provides further support for an interaction between the anesthetic and GC. In addition, studies using hepatic tissue provide direct evidence that halothane and isoflurane inhibit NO activation of this enzyme. As halothane contains bromine, in addition to chlorine and fluorine, it has the greatest affinity for ferrous heme proteins. Halothane is attracted to and reduced by cytochrome P-450 as is evidenced by its extensive metabolism. In contrast, isoflurane and enflurane contain chlorine and fluorine but not bromine. They do not show the same affinity for ferrous heme proteins, and this is supported by their more limited metabolism. Halothane at both 1 and 2 minimal alveolar concentrations (MAC) inhibits NO-induced relaxation and decreases NO stimulation of cGMP. In contrast, 1 MAC isoflurane is without effect, but 2 MAC isoflurane significantly inhibit those responses. These observations suggest that isoflurane has a lower affinity than halothane for the ferrous heme of sGC; thus, a higher concentration of isoflurane is required to achieve the same inhibition.