CARVEDILO 단독 혹은 CYCLOSPORINE과의 혼합투여가백서대동맥 평활근 배양세포의 증식에 미치는 영향

Abstract

Background: Typical pathologic lesions of chronic allograft rejection or transplant vascular sclerosis are similar to arteriosclerotic vascular lesion of non-transplant patients or vascular remodeling process after vascular injury. Abnormal and excess proliferation of vascular smooth muscle cells (VSMC) which are triggered by endothelium-derived cytokines or growth factors, plays a major role during these process. Effective prophylactic or therapeutic strategies against chronic rejection or transplant vasculopathy are not yet clearly established. Recent in vitro cell culture study showed that carvedilol, a novel antihypertensive agent, has the significant inhibitory activities against the proliferation of VSMC. Materials and methods: Using in vitro cultured VSMC, we measured the anti-proliferative activity of carvedilol alone, or in combination with cyclosporine. Growth-arrested cultured VSMC (5-9 passage) from the aorta of rat (Sprague-Dawley) were exposed to platelet derived growth factor (PDGP), endothelin-1, or angiotensin-II. Carvedilol and/or cyclosporine were added as inhibitors. Proliferation was assessed by incorporated [^(3)H]-thymidine activity. Results: PDGF stimulated mitogenesis most effectively. Carvedilol inhibited mitogenesis in a dose-dependent manner in the presence of PDGF (10 ng/ml). Compared to control, proliferation was significantly decreased to 60.3(±10.4)% and 18.3(±5.9)% in the presence of 10μ M and 100μ M of carvedilol, respectively (p<0.05, each). Carvedilol also produced significant concentration -dependent inhibitory activities against VSMC proliferation induced by endothelin-1 (10 nM) and angiotensin-II (100 nM). The IC_(50) of carvedilol in PDGP-, endothelin-1 and angiotensin-11-stimulated VSMC were I ~ 10μ M. Cyclosporine (100 nM) did not show significant inhibition of VSMC proliferation regardless of the kinds of cytokines. However, combined addition of carvedilol and cyclosporine inhibited significantly VSMC proliferation. The pattern of inhibition in combined group was very similar with that of carvedilol alone group regardless of the kind of cytokines. Conclusions: The present study demonstrated that carvedilol significantly inhibited the proliferation of VSMCs regardless of the kind of cytokines, and even under the presence of cyclosporine in cultured VSMC. These indicate that carvedilol has the unique potential to reduce the development of transplant vasculopathy in hyperten sive renal transplant recipients under cyclosporine-based hnmunosuppression.