Effects of nicorandil as compared to mixtures of sodium nitroprusside and levcromakalim in isolated rat aorta

Abstract

1 The contribution of the relaxant mechanisms of nicorandil (NIC) were analysed by comparing its eects with those of sodium nitroprusside (SNP), levcromakalim (LEM) and mixtures (1:10, 1:30 and 1:100) of SNP:LEM in isolated endothelium-denuded rat aorta. 2 In rings precontracted with KCl (25 mM), the relative inhibitory potency of the soluble guanylate cyclase inhibitor ODQ and the K ATP channel inhibitor glibenclamide (GLI) on SNP:LEM mixtures showed a good correlation with the relative proportion of SNP and LEM in the mixtures. Furthermore, the degree of the inhibition by ODQ and GLI of the eects of the 1:30 SNP:LEM mixture varied as a function of the relative potency of SNP and LEM in KCl-, noradrenaline-(NA) or NA plus nifedipine-treated arteries. 3 The inhibitory eects of ODQ, GLI and ODQ plus GLI on NIC-induced relaxation was similar to that for the 1:30 SNP:LEM mixture in NA plus nifedipine-contracted arteries, but the inhibition of GLI or ODQ plus GLI was smaller in KCl-contracted arteries. 4 In conclusion, the relative importance of activation of the cyclic GMP pathway and K ATP channel opening in mixtures of SNP and LEM could be predicted by the proportion of the drugs in the mixtures and by the relative potency of SNP vs LEM in dierent experimental conditions. Furthermore, the present results suggest that besides these two mechanisms, a third ODQ-and GLIinsensitive mechanism, possibly involving Ca 2+ channel blockade, also participates in the relaxant eects of NIC in KCl-induced contractions.

NO donors-relaxation is impaired in aorta from hypertensive rats due to a reduced involvement of K+ channels and sarcoplasmic reticulum Ca2+-ATPase

“…The inhibition of smooth muscle relaxation in rat aorta from normotensive and hypertensive rats correlates with the blockade of cGMP accumulation, which indicates an important contribution of cGMP to the arterial relaxation evoked by [Ru(terpy)(bdq)NO] 3+ and SNP. The relevance of sGC activation to NO donor-induced relaxation was reported in other studies (Bonaventura et al, 2005;Soloviev et al, 2004;Keeble et al, 2001;Sathishkumar et al, 2005;Cogolludo et al, 1999;Tseng et al, 2000). In the present study, the inhibitory effect of ODQ on the relaxation induced by [Ru(terpy)(bdq)NO] 3+ was higher in hypertensive rat aorta, since the relaxation was almost blocked when compared to normotensive rats.…”

Different K+ Channels Are Involved in Relaxation of Arterial and Venous Graft Induced by Nicorandil

“…In the present study, glibenclamide partly inhibited the relaxation of HSV induced by nicorandil at higher concentrations. Previously, Cogolludo et al 28 suggested that in rat aorta, the contribution of the K ATP channel opening to the vasorelaxation is more important at high concentrations of nicorandil. Also, this result is in agreement with those in human umbilical arteries 29 and rabbit femoral artery, 30 which demonstrates that glibenclamide partially antagonized the relaxation induced by nicorandil.…”

The Relaxant Action of Nicorandil in Bovine Tracheal Smooth Muscle

“…The relative contribution of these 2 mechanisms to nicorandil-induced relaxation varies depending on the experimental protocol and preparations studied. For example, in the femoral and pulmonary arteries and the aorta, the activation of guanylyl cyclase plays a major role [6,11,26,27], whereas nicorandil exerts its effects on the coronary circulation mainly as a K ATP channel opener [28]. On the other hand, in the mesenteric arteries, both mechanisms contribute to the relaxant effects of nicorandil [8,10,11].…”

“…It produces relaxation in various smooth muscle preparations through 2 main mechanisms: (1) an increase in membrane K + conductance through the opening of ATP-sensitive K + (K ATP ) channels, leading to hyperpolarization, and (2) release of nitric oxide (NO), leading to elevated cyclic guanosine monophosphate (cGMP) levels by stimulation of soluble guanylyl cyclase [3,4,5,6,7]. The relative contribution of these 2 mechanisms to nicorandil-induced relaxation depends on the tissue and experimental conditions [8,9,10,11].…”