Vasorelaxant and antiproliferative effects of berberine

The present study was intended to examine the relaxant effects of berberine in rat isolated mesenteric arteries. Berberine produced a rightward shift of the concentration-response curve to phenylephrine and significantly reduced the maximal contractile response to phenylephrine. Berberine (10^-7-3x10^-5 M) also relaxed the phenylephrine- and 9,11-dideoxy-11α,9α-epoxy-methanoprostaglandin F(2α)-precontracted arteries with respective IC₅₀ values of 1.48±0.16x10^-6 and 2.23±0.22x10^-6 M. Removal of a functional endothelium significantly attenuated the berberine-induced relaxation (IC₅₀: 4.73±0.32x10^-6 M) without affecting the maximum relaxant response. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) or methylene blue reduced the relaxant effect of berberine, and L-arginine (10^-3 M) partially antagonized the effect of L-NAME. In contrast, pretreatment with 10^-6 M glibenclamide or 10^-5 M indomethacin had no effect. Berberine (10^-5 M) reduced over by 50% the transient contraction induced by caffeine or phenylephrine in endothelium-denuded rings bathed in Ca²⁺-free Krebs solution. Pretreatment with putative K⁺ channel blockers, such as tetrapentylammonium ions (1-3x10^-6 M), 4-aminopyridine (10^-3 M), or Ba²⁺ (3x10^-4 M), significantly attenuated the berberine-induced relaxation in endothelium-denuded arteries. In contrast, tetraethylammonium ions (3x10^-3 M), charybdotoxin (10^-7 M) or glibenclamide (10^-6 M) were without effect. Berberine reduced the high-K⁺-induced sustained contraction and the relaxant response to berberine was greater in rings with endothelium (IC₅₀: 4.41±0.47x10^-6 M) than in those without endothelium (IC₅₀: 8.73±0.74x10^-6 M). However, berberine (10^-6-10^-4 M) did not affect the high-K⁺-induced increase of intracellular [Ca²⁺] in cultured aortic smooth muscle cells. Berberine did not affect active phorbol ester-induced contraction in Ca²⁺-free Krebs solution. In addition, berberine inhibited proliferation of cultured rat aortic smooth muscle cells with an IC₅₀ of 2.3±0.43x10^-5 M. These findings suggest that berberine could act at both endothelium and the underlying vascular smooth muscle to induce relaxation. Nitric oxide from endothelium may account primarily for the berberine-induced endothelium-dependent relaxation, while activation of tetrapentylammonium-, 4-aminopyridine- and Ba²⁺-sensitive K⁺ channels, inhibition of intracellular Ca²⁺ release from caffeine-sensitive pools, or a direct relaxant effect, is likely responsible for the berberine-induced endothelium-independent relaxation. Mechanisms related to either Ca²⁺ influx or protein kinase C activation may not be involved. Both vasorelaxant and antiproliferative effects may contribute to a long-term benefit of berberine in the vascular system. Copyright (C) 2000 Elsevier Science B.V.