Carbon Monoxide-Mediated Activation of Large-Conductance Calcium-Activated Potassium Channels Contributes to Mesenteric Vasodilatation in Cirrhotic Rats

Abstract

Large-conductance calcium-activated potassium channels (BK Ca s) are important regulators of arterial tone and represent a mediator of the endogenous vasodilator carbon monoxide (CO). Because an up-regulation of the heme oxygenase (HO)/CO system has been associated with mesenteric vasodilatation of cirrhosis, we analyzed the interactions of BK Ca and of HO/CO in the endothelium-dependent dilatation of mesenteric arteries in ascitic cirrhotic rats. In pressurized mesenteric arteries (diameter, 170 -350 m) of ascitic cirrhotic rats, we evaluated the effect of inhibition of BK Ca , HO, and guanylylcyclase on dilatation induced by acetylcholine and by exogenous CO; and HO-1 and BK Ca subunit protein expression. Inhibition of HO and of BK Ca reduced acetylcholine-induced vasodilatation more in cirrhotic rats than in control rats, whereas inhibition of guanylyl-cyclase had a similar effect in the two groups. CO was more effective in cirrhotic rats than in control rats, and the effect was hindered by BK Ca inhibition. The expression of HO-1 and of BK Ca ␣-subunit was higher in mesenteric arteries of cirrhotic rats compared with that of control animals, whereas the expression of the BK Ca ␤1-subunit was lower. In conclusion, an overexpression of BK Ca ␣-subunits, possibly due to HO up-regulation with increased CO production, participates in the endothelium-dependent alterations and mesenteric arterial vasodilatation of ascitic cirrhotic rats.Mesenteric arterial vasodilation is a key mechanism in the pathophysiology of the hyperdynamic circulatory syndrome of cirrhosis. This syndrome is responsible for serious complications, such as ascites, hepatorenal syndrome, and gastrointestinal hemorrhage. The pathophysiological mechanism that supports the vasodilation of mesenteric arteries in cirrhosis is a decrease in the response of the arteries to vasoconstricting agents (Sieber et al., 1993), caused by an increase in vasodilating substances of endothelial origin, such as nitric oxide (NO), prostacyclin, and, as recently demonstrated, carbon monoxide (CO) (Wiest and Groszmann, 1999;Fernandez et al., 2001;Gonzales-Abraldes et al., 2002).We have recently shown that an increased action of the heme oxygenase (HO)/CO system plays a role in the hyporesponsiveness of small resistance mesenteric arteries to phenylephrine (PE) only in the advanced stage of experimental cirrhosis (Bolognesi et al., 2005). Therefore, the increased activity of the HO/CO system may participate in the evolution of cirrhosis from compensated to decompensated.HO is a microsomal enzyme with two main distinct isoforms: the inducible isoenzyme HO-1 and the constitutive one HO-2 (Zhang et al., 2001;Johnson et al., 2003a). It is the rate-limiting enzyme in the degradation of heme to biliverdin, CO, and free iron (Motterlini et al., 1998). CO, generated by HO in endothelial and smooth muscle layers of arterial vessels, modulates vascular tone by inducing relaxation of vascular smooth muscle cells through stimulation on soluble guanylyl cyclase (sGC) and ope...

The RCK1 high-affinity Ca 2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels

“…However, the results of the experiments using HMOX-2 null mice show that other hypoxia sensing mechanisms exist (38). Although the exact role of modulation of Slo1 BK channels by CO in acute oxygen sensing remains uncertain (38), it is clear that CO does activate Slo1 BK channels and contributes to many other physiological processes, including vasodilation (9,11,(13)(14)(15). The ability of the Slo1 BK channel to directly respond to CO at physiological voltages at low to moderate [Ca 2ϩ ] i via the high-affinity RCK1 Ca 2ϩ sensor further illustrates the channel's remarkable modulatory repertoire.…”

“…The modulation of Slo1 BK channels by CO is physiologically and pathophysiologically important. For example, the stimulatory effect of CO on Slo1 BK channels underlies its well documented vasodilatory effect (9,11,(13)(14)(15), and the use of CO has been suggested as a potential therapeutic strategy against pulmonary hypertension (11). Production of CO by HMOXs requires oxygen (1), and this oxygen dependence raises the possibility that changes in cellular oxygen tension regulate the Slo1 BK channel activity indirectly by regulating the availability of CO (16).…”

Cirrhotic Cardiomyopathy

“…In contrast, there is an increased NO drive in the peripheral arterial circulation, especially in the splanchnic bed, that causes vasodilation. Other mediators implicated in the splanchnic arterial vasodilation seen in cirrhosis include carbon monoxide (CO) and endogenous cannabinoids (14,15).…”

Natural heme oxygenase-1 inducers in hepatobiliary function

“…Hyper-expression of HO-1 is particularly relevant in cirrhotic rats with ascites and its function is mediated by large-conductance calcium-activated potassium channels [67] . The alpha subunits of these channels, in particular, are increased in cirrhotic animals and their increase may be mediated by the increased HO-1 [68] . In experimental pre-hepatic portal hypertension, obtained by partial portal vein ligation in rats, Fernandez et al [69] have shown that HO activity is increased in the liver.…”