Visualization of gaseous monoxide reception by soluble guanylate cyclase in the rat retina

Abstract

Immunohistochemistry using novel monoclonal antibodies (mAbs) allowed us to uncover tissue activities of soluble guanylate cyclase (sGC) fine tuned by NO and CO. Upon NO and CO applications in vitro, purified sGC increased the affinity to mAb3221 by 100- and 10-fold, respectively, but not to mAb28131. Immunohistochemistry for gas-generating enzymes revealed that NO occurred in amacrine, bipolar, and Müller's glia cells (MGCs), whereas CO was derived mostly from heme oxygenase (HO)-2 in MGCs. Basal sGC immunoreactivities in vivo to mAb3221 but not to mAb28131 were enhanced by injecting L-arginine and attenuated by blocking NO synthases, suggesting the ability of the former mAb to sense NO. Comparison of mAb-assisted immunohistochemistry suggested that sGC activities were enhanced by zinc protoporphyrin-IX, an HO inhibitor, and repressed completely by blocking NO. However, suggested roles of CO played in situ varied among different retinal layers. In inner plexiform and inner nuclear layers located in the proximity of the cellular NO sources, CO serves as a simple inhibitor of local sGC, while playing roles in housekeeping sGC activation in external limiting membrane standing far from them. These results suggest that CO generated in MGCs is a diffusible gas mediator regulating sGC in both autocrine and paracrine manners.

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

“…2C), confirming that CO is a tonic vasoconstrictor under basal conditions. This action of CO cannot be readily explained by previously identified CO receptors, such as soluble guanylyl cyclase (6)(7)(8)(9)(10)(11)(12)15) or potassium channels (13,16), both of which mediate vasodilation. Based on previous studies indicating that physiological concentrations of CO can inhibit the ability of CBS to generate vasodilatory H 2 S (17-21, 26, 27, 38), we hypothesize that endogenous CO serves as a tonic vasoconstrictor by inhibiting CBS, thus preventing the H 2 S-mediated vasodilatory response.…”

“…Thus, HO inhibitors cause cerebral vasodilation, an effect reversed by CO (14). This action of CO cannot be readily explained by previously identified CO receptors, such as soluble guanylyl cyclase (6)(7)(8)(9)(10)(11)(12)15) or potassium channels (13,16), both of which mediate vasodilation. The CO and NO systems interface; thus, the vasodilatory actions of HO inhibitors are partially reversed by inhibitors of NOS (14).…”

Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways

“…Regarding the relationship between CO and NO, Suematsu et al reported that micromolar CO increases the basal activity of soluble guanylate cyclase if local concentration of NO is low, 27 whereas CO can serve as a partial antagonist of NO-induced activation of the soluble guanylate cyclase. 28 From these studies, endogenous CO seems to compete with NO in activating soluble guanylate cyclase. However, the results of these previous studies do not necessarily contradict our results because NO and CO may play a role as signaling molecules to protect tissues from injury.…”

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

“…In fact, CO itself modestly activates sGC, by which hepatic sinusoids are constitutively dilated. 2,20,39 By contrast, in vascular smooth muscle cells in which NO is sufficiently supplied from arteriolar endothelium (for example, brain microcirculation), the inducible CO inhibits NO-elicited sGC activation. 40,41 Besides these observations suggesting physiologic actions of CO occurring dependently of local NO levels, the current study provided evidence for a novel mechanism functioning irrespective of the NO effects.…”