Different mechanisms underlying the stimulation of KCa channels by nitric oxide and carbon monoxide

Abstract

IntroductionNitric oxide (NO) is an endogenous vasorelaxant gas that is synthesized from the terminal guanidino nitrogen atoms of L-arginine by NO synthase (1). Carbon monoxide (CO) is another endogenously generated biological gas. The major route for the endogenous generation of CO involves heme oxygenase (HO), which works in concert with NADPH-cytochrome P450 reductase to cleave the heme ring in hemoproteins into biliverdin, CO, and iron (2). Results from our laboratory (3) and others (4-7) have demonstrated that endogenously generated CO can effectively relax vascular tissues. The physiological role of endogenous CO is thus indicated. NO and CO are not redundant messenger molecules. For instance, NO potently dilated hepatic artery, but only slightly dilated the portal venous vascular bed. In contrast, CO had no effect on the hepatic artery, but relaxed the portal venous vascular bed (8). In some cases, NO and CO may even have opposite effects. CO inhibited, but NO increased, the release of IL-1β from rat hypothalamus stimulated by high K + concentrations (9). NO and CO do have at least two common targets in vascular smooth muscle cells (SMCs), i.e., soluble guanylyl cyclase (sGC) and large-conductance calciumactivated K + (K Ca ) channels (10)(11)(12)(13)(14). Although the debate has not been settled on whether NO and CO directly act on K Ca channels or indirectly by altering intracellular second messengers, many single channel studies on the cell-free membrane patches have been supportive for a direct interaction of NO and CO with K Ca channel proteins. Even for these single channel studies different mechanisms for the effects of NO and CO on K Ca channels have been presented. The NO effect on K Ca channels in rabbit aortic SMCs was related to the changes in sulfhydryl groups (10). Our previous study showed that CO acted on the histidine residue of K Ca channel proteins in rat tail artery SMCs (13).Large-conductance K Ca channels are stimulated by increased intracellular calcium concentration and by membrane depolarization. These K Ca channels are composed of two noncovalently linked subunits: the poreforming α subunit and the accessory β subunit, which affects the electrophysiological and pharmacological properties of K Ca channel complexes (15). The interactions of NO and CO with α and β subunits of K Ca channels may be the determining factor for the selective modulation of K Ca channels, which has not been addressed.The interaction between NO and CO on the regulation of vascular contractility is another important but still largely uncharted issue. The activation of largeconductance K Ca channels in SMCs accounts for a significant part of the relaxation induced by NO (16) The molecular mechanisms underlying the effects of nitric oxide (NO) and carbon monoxide (CO), individually and collectively, on large-conductance calcium-activated K + (K Ca ) channels were investigated in rat vascular smooth muscle cells (SMCs). Both NO and CO increased the activity of native K Ca channels. Dehydrosoyasaponin-I, a spe...

Dependency of Cortical Functional Hyperemia to Forepaw Stimulation on Epoxygenase and Nitric Oxide Synthase Activities in Rats

“…Part of the vasodilation resulting from an increase in cyclic guanosine monophosphate can be mediated by opening of K Ca channels (Paterno et al, 1996). In addition, NO may exert a direct effect on the ␤-subunit of the K Ca channel (Wu et al, 2002). Vasodilation by EETs is also mediated by activation of K Ca channels (Alkayed et al, 1996b;Gebremedhin et al, 1992).…”

NO counterbalances HO-1 overexpression-induced acceleration of hepatocyte proliferation in mice

“…This might be explained by the desensitization of sGC for NO through CO by overexpression of HO-1, as this has been described for HO-1 transgenic mice 17 as well as the abolishment of NO-mediated attenuation of CO-mediated stimulatory effects on vascular smooth muscle Ca 2 þ -activated K þ channels. 49 In conclusion, our model provides evidence that NO plays a major role in adjusting vascular tone in HO-1 overexpressing animals. This is important in order to maintain adequate perfusion and salutary effect on shear force within the hepatic microvasculature upon liver resection to assure a physiological regeneration process.…”

Vascular CO Counterbalances the Sensitizing Influence of 20-HETE on Agonist-Induced Vasoconstriction

“…12 Previous studies established that the activity of K Ca channels in small arterial vessels is reduced by exogenous 20-HETE 5,8 and increased by exogenous CO. 1,6,7 20-HETE and CO manufactured by vascular smooth muscle cells also are believed to decrease and increase the activity of K Ca channels, respectively, because the open state probability of the channel(s) was shown to increase 8 and decrease 1,7 during treatment with a CYP4A inhibitor and a HO inhibitor, respectively. According to the present study, in renal interlobar arteries smooth muscle cells undergoing inhibition of 20-HETE synthesis with DDMS, treatment with exogenous 20-HETE suppressed K ϩ channel activity; this effect was offset by concurrent exposure of the cells to exogenous CO.…”

“…4 The reciprocal modulatory actions of CO and 20-HETE on vascular reactivity to phenylephrine are linked, respectively, to stimulation and inhibition of large conductance calcium-activated potassium (K Ca ) channels in vascular smooth muscle. 1,[5][6][7][8] In view of the aforementioned observations, it is conceivable that the sensitivity of arterial vessels to constrictor agonists is determined, at least in part, by the interplay between CO and 20-HETE manufactured by the vessels. One possibility is that the modulatory interplay simply results from the balance between regulatory substances with opposite actions on vascular reactivity.…”