Ginsenoside-Rb1 Prevents HIV protease inhibitor ritonavir-induced vasomotor dysfunction

Abstract

Introduction. We previously reported that ritonavir (RTV), one of the clinically used HIV protease inhibitors, can cause endothelial injury by increasing oxidative stress. The objective of this study was to determine whether an active ingredient of Panax ginseng, Ginsenoside-Rb1 (Rb1), could prevent coronary arteries from RTV-induced vasomotor dysfunction. Methods. Porcine coronary arteries were cut into 5-mm rings and incubated with RTV (15 μM) or/and Rb1 (1 or 10 mg/L) for 24 h. Vasomotor function was studied with a myograph tension system in response to U46619 (contraction) and bradykinin (relaxation). The mRNA and protein levels of endothelial nitric oxide synthase (eNOS) were determined by real-time PCR and Western blot, respectively. Superoxide anion levels were determined by lucigenin-enhanced chemiluminescence. Results. In response to U46619, the control vessels showed a vessel tension of 168 mN, while RTV-treated vessels had 41 mN, showing a 76% reduction ( P < 0.001, n = 8). The combination of RTV and Rb1 (1 or 10 mg/L) showed a vessel tension of 76 or 90 mN, respectively. In response to bradykinin, the control vessel rings relaxed by 70%, while RTV-treated vessels only relaxed by 29%, which showed a 59% reduction ( P < 0.001). Rb1 (1 or 10 mg/L) plus RTV showed 46 or 58% of vasorelaxation, respectively. The eNOS mRNA expression was decreased by 77% in RTV-treated vessels over controls ( P < 0.05). Western blot and immunohistochemistry also showed a decrease of eNOS protein levels in RTV-treated vessels. Superoxide anion levels in the RTV-treated group was increased by 47% over controls ( P < 0.05). Rb1 treatment (1 and 10 mg/L) significantly inhibited RTV-induced down regulation of eNOS and overproduction of superoxide anion. Conclusions. HIV protease inhibitor RTV significantly decreases vessel contractivity and endothelium-dependent vasorelaxation in porcine coronary arteries. It also decreases eNOS and increases superoxide anion production. Ginsenoside-Rb1 effectively inhibited RTV-induced endothelial dysfunction and oxidative stress in this model.