Background:  Protease inhibitors (PI) have been associated with endothelial function and possibly early atherosclerosis, however the mechanism is not known. In order to isolate the effects of these drugs on the endothelium and nitric oxide (NO) bioavailability and production from secondary effects on insulin resistance and dyslipidemia and also from potential direct HIV viral effects or host immunological responses; we studied a common protease inhibitor’s effect on endothelium of non-HIV-infected subjects.

Methods:  We prospectively treated 6 non-HIV infected, healthy volunteers (mean age 25) with open-label lopinavir-ritonavir (LPVr), 3 tablets twice daily for 4 weeks. Pre- and post-therapy, forearm blood flow was used to measure intra-arterial responses to acetylcholine (Ach), sodium nitroprusside (SNP), and N^G-monomethyl-L-arginine (L-NMMA). Wilcoxon signed-rank test on area under the curve was used.

Results:  Absolute forearm blood flow responses to Ach infusions increased significantly after treatment with LPVr for 4 weeks, consistent with increasing endothelium-dependent vasodilation (p = 0.03). This effect was also significant after Bonferroni post-test for 15 µg/min (p <0.05) and 30 µg/min (p <0.01). Absolute forearm blood flow in response to endothelium independent vasodilator SNP infusion was non-significantly increased after treatment with LPVr (p = 0.06). L-NMMA, a NO-synthase inhibitor, reduced basal blood flow by 13±12% pre-LPVr but by 45.5±4% post-LPVr during 8 µmol/min L-NMMA infusion (p = 0.03), consistent with increased NO bioavailability. Co-infusion of Ach and L-NMMA prior to LPVr reduced Ach-dependent blood flow from 794±98% to 632±195% (p = 0.45) but after 4 weeks of LPVr, co-infusion of L-NMMA significantly reduced ACh stimulated blood flow from 852±148% to 485±84% (p <0.05), also consistent with increased NO bioavailability. No significant changes in insulin sensitivity or cholesterol was found.

Conclusions:  Forearm blood flow responses with multiple pharmacological agonists and inhibitors were consistent for these 6 non-HIV-infected subjects. All blood flow responses supported a global effect on increased NO bioavailability (i.e. increase in flow during Ach and SNP infusions and decrease in flow during L-NMMA infusion). These results indicate that the accelerated rate of cardiovascular events in HIV infected patients treated with LPV/r is unlikely to be due to a direct toxic effect of the drug on endothelial cell function.