Vasorelaxant and antiproliferative effects of berberine

Abstract

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 −7–3×10 −5 M) also relaxed the phenylephrine- and 9,11-dideoxy-11α,9α-epoxy-methanoprostaglandin F 2α-precontracted arteries with respective IC 50 values of 1.48±0.16×10 −6 and 2.23±0.22×10 −6 M. Removal of a functional endothelium significantly attenuated the berberine-induced relaxation (IC 50: 4.73±0.32×10 −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 Ca 2+-free Krebs solution. Pretreatment with putative K + channel blockers, such as tetrapentylammonium ions (1–3×10 −6 M), 4-aminopyridine (10 −3 M), or Ba 2+ (3×10 −4 M), significantly attenuated the berberine-induced relaxation in endothelium-denuded arteries. In contrast, tetraethylammonium ions (3×10 −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 (IC 50: 4.41±0.47×10 −6 M) than in those without endothelium (IC 50: 8.73±0.74×10 −6 M). However, berberine (10 −6–10 −4 M) did not affect the high-K +-induced increase of intracellular [Ca 2+] in cultured aortic smooth muscle cells. Berberine did not affect active phorbol ester-induced contraction in Ca 2+-free Krebs solution. In addition, berberine inhibited proliferation of cultured rat aortic smooth muscle cells with an IC 50 of 2.3±0.43×10 −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 Ba 2+-sensitive K + channels, inhibition of intracellular Ca 2+ release from caffeine-sensitive pools, or a direct relaxant effect, is likely responsible for the berberine-induced endothelium-independent relaxation. Mechanisms related to either Ca 2+ 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.