Effects of HIV protease inhibitor ritonavir on vasomotor function and endothelial nitric oxide synthase expression.

The use of HIV protease inhibitors (PIs) may be associated with cardiovascular diseases in HIV-infected patients. The objective of this study was to determine the effects of the HIV PI ritonavir on vasomotor function and endothelial nitric oxide synthase (eNOS) expression. Porcine coronary artery rings were incubated with ritonavir for 24 hours. Vasomotor function was studied with a myograph tension system in response to U46619 (contraction), bradykinin (endothelium-dependent relaxation), and sodium nitroprusside (SNP) (endothelium-independent relaxation). The vessel tension contraction after challenge with U46619 showed a significant decrease in 15- and 30-microM ritonavir-treated rings (P < 0.05). In response to bradykinin at 10 M, ritonavir (15 and 30 microM) reduced the relaxation by 27% and 78%, respectively, as compared with controls (P < 0.05). No alterations in the relaxation response were observed in the presence of SNP (10 M). The mRNA and protein levels of eNOS of the artery rings were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. The eNOS mRNA showed a 54% and 65% reduction for 15- and 30-microM ritonavir-treated rings, respectively (P < 0.05). The eNOS protein levels were also substantially decreased in these groups. In parallel, human coronary artery endothelial cells (HCAECs) were studied. HCAECs treated with ritonavir showed significant reductions in mRNA and protein levels of eNOS (P < 0.05). Thus, ritonavir significantly impairs vasomotor function and reduces eNOS expression in porcine coronary artery endothelial cells as well as HCAECs. This study suggests that ritonavir may contribute to coronary artery disease formation in antiviral therapy for HIV-infected patients.