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)-3 x 10(-5) M) also relaxed the phenylephrine- and 9,11-dideoxy-11 alpha,9 alpha-epoxy-methanoprostaglandin F-2 alpha-precontracted arteries with respective IC50 values of 1.48 +/- 0.16 x 10(-6) and 2.23 +/- 0.22 x 10(-6) M. Removal of a functional endothelium significantly attenuated the berberine-induced relaxation (IC50: 4.73 +/- 0.32 x 10(-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 (1-3 x 10(-6) M), 4-aminopyridine (10(-3) M), or Ba2+ (3 x 10(-4) M), significantly attenuated the berberine-induced relaxation in endothelium-denuded arteries. In contrast, tetraethylammonium ions (3 x 10(-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 +/- 0.47 x 10(-6) M) than in those without endothelium (IC50: 8.73 +/- 0.74 x 10(-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 +/- 0.43 x 10(-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. (C) 2000 Elsevier Science B.V. All rights reserved.