Involvement of endothelium in relaxant action of glibenclamide on the rat mesenteric artery

The present report describes the complex effect of glibenclamide, an antidiabetic sulfonylurea agent, on the rat isolated mesenteric artery. Although glibenclamide concentration dependently reversed the relaxant effect of pinacidil, an activator of ATP-sensitive K⁺ channels (the concentration for half-maximum reversal effect was 0.56 μM with endothelium and 0.17 μM without endothelium), in the artery precontracted with phenylephrine (1 μM), it relaxed phenylephrine-induced sustained contraction at higher concentrations (IC₅₀: 4.4 ± 1.1 μM with endothelium and 226.1 ± 44.2 μM without endothelium). The relaxant effect of glibenclamide was partially inhibited by pretreatment of the artery with either N(G)-nitro-L-arginine (10-100 μM) or methylene blue (1 μM). Indomethacin (10 μM) had no effect. Moreover, glibenclamide also concentration dependently (3-500 μM) reduced the sustained contraction induced by 60 mM K⁺ (IC₅₀: 99.5 ± 16.1 μM). The relaxation induced by glibenclamide was not affected by various putative K⁺ channel blockers such as charybdotoxin (100 nM), tetraethylammonium ions (1 mM), apamin (100 nM) and 4-aminopyridine (1 mM). The results indicate an involvement of the endothelium, probably of nitric oxide, in the relaxation induced by glibenclamide in the endothelium-intact rat mesenteric arteries. The inhibitory effect of glibenclamide on the high-K⁺-induced contraction suggests that glibenclamide may interfere with Ca²⁺ influx, which in turn affects intracellular Ca²⁺ levels in arterial smooth muscle, leading to reduction of muscle contractility. It is suggested that two distinct pharmacological effects induced by glibenclamide may be mediated through different glibenclamide binding sites, however, the data show an overlap of concentrations of glibenclamide for producing the two effects in rat isolated mesenteric arteries.