Vasorelaxant and antiproliferative effects of berberine
Introduction
Berberine, an isoquinoline alkaloid, derived from the Chinese herb Huanglian and many other plants, such as the Berberidaceae family, has a varied pharmacology, including antibiotic activity (Hahn and Cuak, 1975), antitumor action (Nishino et al., 1986) and antimotility properties (Yamamoto et al., 1993). Extracts of berberine-containing plants have been used for many centuries in the treatment of diarrhea Dutta et al., 1972, Sack and Froehlich, 1982, Chang and But, 1987, probably through inhibition of mucosal Cl− secretion (Taylor et al., 1999). Several studies indicate important cardiovascular effects of berberine. Berberine exerts both positive ionotropic and negative chronotropic effects in isolated guinea-pig atria (Shaffer, 1985), and an antifibrillatory effect (Pang et al., 1986). Berberine was also used in the treatment of congestive heart failure (Martin-Neto et al., 1988). In vivo, berberine lowers blood pressure in mammals Sabir and Bhide, 1971, Chun et al., 1979. In isolated vascular preparations, berberine causes relaxation (Chiou et al., 1991). More recently, Chiou et al. (1998) have reported that berberine possessed a relaxant effect on rabbit corpus cavernosal tissues. Activation of some K+ channels may contribute to the endothelium-independent relaxation induced by berberine (Chiou et al., 1998). Besides, a phospholipase C-mediated contractile mechanism may be partially involved in the berberine-induced vascular response (Bova et al., 1992). Nevertheless, the vascular sites for a hypotensive activity of berberine are not clear. It is possible that berberine acts on both endothelium and the underlying vascular smooth muscle to induce vasorelaxation via multiple cellular mechanisms. In this study, we attempted to examine the roles of endothelium-derived vasoactive factors, K+ channel activation, Ca2+ influx, intracellular Ca2+ release and protein kinase C-mediated pathway in the berberine-induced relaxation of rat isolated mesenteric artery, and to examine a possible antiproliferative effect of berberine on cultured aortic smooth muscle cells, which could account for its long-term beneficial effect in the cardiovascular system.
Section snippets
Tissue preparation
Male Sprague–Dawley rats (supplied by Animal Services Center, Chinese University of Hong Kong, Hong Kong) weighing ∼250–300 g were killed by cervical dislocation and bled. The main branch of the superior mesenteric artery was dissected out and cut into three 3-mm wide ring segments. The ring was mounted between two stainless wire hooks in a 10-ml organ bath filled with Krebs solution. The upper wire was connected to a force-displacement transducer (Grass Instruments, USA) and the lower one
Vasorelaxant effect of berberine
Phenylephrine contracted the rat isolated mesenteric artery rings with an EC50 of 6.0±0.07×10−7 M and a maximum increase in tension of 10.1×0.6 mN (n=5). After a control curve for the phenylephrine-induced contractile response, the rings were incubated for 30 min with different concentrations of berberine and a concentration–response curve for phenylephrine was again obtained. A low concentration of berberine (10−7 M) caused an approximately parallel shift of the phenylephrine
Discussion
Berberine was found to exert a hypotensive action in rats (Chun et al., 1979) and to raise intracavernous pressure in rabbits (Chiou et al., 1998), however, the mechanism responsible for its vasodilator effect is not clear. The present study showed a relaxant action of berberine in rat isolated mesenteric arteries. Berberine at concentrations higher than 10−7 M showed a non-competitive antagonism against the phenylephrine-induced contraction. It was reported before that berberine derivatives
Acknowledgements
This work was supported by a grant from Hong Kong Research Grants Council (CUHK 4217/97M) and an UPGC Direct Grant (A/C 2040705).
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