Vascular effects of protease inhibitors and non-nucleoside reverse transcriptase inhibitors, the major components of highly active antiretroviral therapy [HAART]

Abstract

The number of patients with human immunodeficiency virus (HIV) infection increase every year worldwide. Highly active antiretroviral therapy (HAART), including protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), has shown promise for the treatment of HIV. However, previous experimental studies suggest that certain PIs affect vascular regulation, leading to the development of cardiovascular disease (CVD), which becomes one of the major causes of morbidity and mortality in HIV-infected patients. Therefore, it is possible that HAART imposes adverse effects on vascular reactivity. The present study was designed to study the acute effects of various clinically used PIs (indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir) and NNRTIs (efavirenz and nevirapine) on isolated rat mesenteric arteries suspended in organ chambers for the measurement of isometric force. Among the antiretroviral drugs tested, all PIs and NNRTIs, except nevirapine, caused full relaxation of mesenteric arteries during contractions to phenylephrine. These relaxations were not affected by the presence of nitro-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthases. The present data suggested that most clinically used PIs and NNRTIs relax mesenteric arteries by activating a signalling pathway that is independent of the release of nitric oxide. Since the relaxation occurred when the antiretroviral drugs are present at high concentrations, care should be taken with the prescription of high doses of these drugs to avoid unwanted vasodilatation.