Evidence that potassium channels make a major contribution to SIN‐1‐evoked relaxation of rat isolated mesenteric artery

Abstract

Infirmary, Bristol BS2 8HW1 The NO donor 3-morpholino-sydnonimine (SIN-1; 0.01-1O UM) evoked concentration-dependent relaxation of rat isolated mesenteric arteries pre-constricted with phenylephrine (1-3 uM). The relaxation to SIN-i 5 Exposure of intact arterial segments to charybdotoxin and apamin, in the presence of NO synthase blockers, also significantly inhibited SIN-i-evoked relaxation, reducing the maximum response by around 80% (n=4; P<0.01). 6 Addition of superoxide dismutase (SOD; 30 u ml-1), potentiated relaxations to SIN-i in all tissues, but did not alter the effects of charybdotoxin and ODQ on SIN-i-evoked relaxation. 7 These data show that although relaxation to the NO-donor SIN-1 is not significantly different between endothelium-intact and denuded arterial segments, the mechanisms which mediate SIN-1-evoked relaxation in the rat isolated mesenteric artery appear to be modulated by the basal release of endothelium-derived NO. In the presence of an intact endothelial cell layer, the major mechanism for SIN-i-evoked relaxation appears to be the activation of charybdotoxin-sensitive potassium channels. In contrast, when basal NO synthesis is inhibited, SIN-1 appears to cause full relaxation by both the activation of a charybdotoxin-sensitive pathway and the stimulation of soluble guanylyl cyclase.

Involvement of cyclic GMP and potassium channels in relaxation evoked by the nitric oxide donor, diethylamine NONOate, in the rat small isolated mesenteric artery

“…The inhibition of smooth muscle relaxation in the mesenteric artery correlates with the block of cGMP accumulation, and indicates an important contribution by cGMP to the arterial relaxations evoked by DEA NONOate, an observation which has also been reported in the canine middle cerebral artery (Onoue and Katusic 1998). The contribution made by ODQ-sensitive, cGMP-dependent signalling pathways to NO donor relaxation of this artery has been shown to vary with the particular NO donor utilised: S-nitroso-N-acetylpenicillamine (White and Hiley 1998) > DEA NONOate (this study) > SIN-1 (Plane et al 1996). The reason for these apparent differences in sensitivity to ODQ remains uncertain.…”

“…However, more recently several authors have presented evidence which suggests that vascular relaxation to nitric oxide may occur through a cGMP-independent stimulation of smooth muscle potassium channels (Bolotina et al 1994;Plane et al 1996Plane et al , 1998Mistry and Garland 1998;Homer and Wanstall 2000).…”

“…Previously, we have shown that the nitric oxide donor, 3-morpholinylsydnoneimine chloride (SIN-1), can activate large conductance, calcium-activated potassium channels (BK Ca ) present in the smooth muscle of the rat small mesenteric artery, through a mechanism independent of the cGMP-dependent signalling pathway (Plane et al 1996;Mistry and Garland 1998). In the present study, we have extended these observations by investigating the relative contribution made by cGMP and potassium channels to the relaxation evoked by the novel nitric oxide donor, DEA NONOate (Maragos et al 1991).…”

Molecular mechanism of cGMP-mediated smooth muscle relaxation

“…This led to the assumption that NO and cGMP actions were synonymous in smooth muscle. However, it is now known from work with several models, including the canine middle cerebral artery (Onoue and Katusic, 1998); rat aorta (Kanagy et al, 1996) and mesenteric artery (Plane et al, 1996); guinea pig bronchial smooth muscle (Wong et al, 1995); and porcine tracheal smooth muscle (Stuart-Smith et al, 1998), that at least part of NO-induced SM relaxation is cGMP independent. CO also generates cGMP by activating s-GC.…”

Mechanism of a Nitric Oxide Donor NOR 1-Induced Relaxation in Longitudinal Muscle of Rat Proximal Colon

“…These results suggest that NO induces the relaxation of smooth muscle by increasing the cyclic GMP content. On the contrary, an inhibitor of soluble guanylate cyclase inhibited the NO-mediated increase in cyclic GMP content, whereas it did not affect NOmediated relaxation in the guinea pig and porcine trachea (10,11), rat mesenteric artery (12) and canine aorta (13). Cyclic GMP-independent NO-mediated relaxation was also suggested in the gastrointestinal tract such as the rat duodenum (14) and proximal colon (15).…”