Systemic administration of AM elicits a potent hypotensive effect due to its vasodilatory action. The hemodynamic effects of human AM were initially investigated in anesthetized rats (Kitamura et al., 1993). Intravenous bolus injection of AM caused a rapid, remarkable, and long-lasting reduction in blood pressure in a dose-dependent manner. The maximum decrease in mean blood pressure after injection of a high dose (3 nmol/kg) of AM was approximately 50 mmHg, and the significant hypotensive effect lasted for 30-60 minutes. The reduction in blood pressure was closely associated with the decrease in total peripheral resistance, and this was concomitant with increases in cardiac output and stroke volume, probably secondary to reduced afterload (Ishimaya et al., 1993). In their study using anesthetized rats, heart rate was not significantly altered by AM injection. However, many other studies showed that reflex tachycardia in response to blood pressure fall was observed. The hypotensive effect of AM was also seen in both conscious and hypertensive rats. In addition, a significant decrease in systemic blood pressure induced by acute or chronic administration of AM
has been observed in rabbit, sheep, and human. Furthermore, vasodilatory actions of AM have been studied in not only the systemic vasculature but also regional vascular beds including renal (Hirata et al, 1995), pulmonary (Lippton et al., 1994), cerebral (Lang et al, 1997), and coronary circulation (Yoshimoto et al, 1998).
Many studies have addressed the mechanism of vasodilatory effect of AM and the results differ depending on animal species and vascular preparation. Most observations indicate that AM may induce endothelium-independent relaxation by acting on calcitonin gene-related peptide (CGRP) receptors and elevating cAMP level in vascular smooth muscle cells (Eguchi et al, 1994). For example, in perfused rat mesenteric vascular beds, administration of AM induced endothelium-independent vasodilation. This vasodilator response was not affected by atropine or propranolol, but was clearly inhibited by CGRP(8-37), an antagonist for CGRP1 receptor, suggesting that AM induced nonadrenergic and noncholinergic vasodilation in which CGRP receptors might be involved (Nuki et al, 1993). On the other hand, AM binds to specific receptors in endothelial cells and elicits endothelium-dependent vasorelaxation mediated by nitric oxide. Shimekake et al. (1995) minutely investigated the biological action of AM on cultured bovine aortic endothelial cells. According to their study, the specific binding of AM to endothelial cells was observed, and AM induced intracellular cAMP accumulation in a dose-dependent manner. AM also induced an increase in intracellular free Ca in endothelial cells in a dose-dependent manner. This intracellular free Ca increase resulted from phospholipase C activation and inositol 1,4,5-trisphosphate formation, and seemed to cause nitric oxide synthase activation by monitoring intracellular cGMP accumulation. As another mechanism of endothelial nitric oxide synthase activation by AM, Nishimatsu et al. (2001) showed that phosphatidylinositol 3-kinase/Akt pathway was involved. In addition, endothelium-derived hyperpolarizing factor, vasodilatory prostanoids, and suppressed production of endothelin-1 may be implicated in AM-induced endothelium-dependent vasorelaxation. Taken together, it is proper that the vasodilatory effect of AM is mediated by at least two mechanisms, a direct action on vascular smooth muscle cells and an indirect effect through primary actions on endothelial cells. AM clearly inhibits platelet-derived growth factor- or angiotensin II-induced migration of vascular smooth muscle cells (Horio et al, 1995). In addition to the antimigratory effect, AM also inhibits vascular smooth muscle cell proliferation stimulated by serum or platelet-derived growth factor (Kano et al., 1996). In quiescent cells, however, AM has been shown to elicit a growth-promoting effect (Iwasaki et al., 1998). Therefore, AM may bidirectionally regulate the proliferation of vascular smooth muscle cells. As for other direct effects on those cells, AM inhibits endothelin-1 production and stimulates inducible nitric oxide synthase in cultured rat aortic smooth muscle cells.
AM inhibits serum deprivation-induced endothelial cell apoptosis via a cAMP-independent mechanism (Kato et al., 1997). In addition, AM has been recently shown to promote endothelial regeneration and angiogenesis through Akt activation (Miyashita et al., 2003; Kim et al., 2003). Taken together with several recent findings concerning protective roles of AM against acute ischemia and vascular injury (Abe et al., 2003; Kawai et al., 2004), there may be a possibility that AM is useful as a novel therapeutic strategy for some kinds of vascular disease.
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