Indinavir impairs endothelial function in healthy HIV-negative men.
BACKGROUND
Potent antiretroviral treatment has drastically reduced mortality in HIV-infected patients but may accelerate atherosclerotic disease, which could be partially mediated via endothelial dysfunction.


METHODS
In 8 HIV-negative healthy males, leg blood flow responses to intraartery infusions of methacholine chloride (Mch), sodium nitroprusside, and NG-mono-methyl-L-arginine (L-NMMA) were measured before and after 4 weeks of daily oral indinavir. In the same subjects, we also assessed the effect of indinavir on lipids, insulin sensitivity, markers of inflammation, as well as oxidative stress.


RESULTS
After 4 weeks of indinavir, the endothelium-dependent response to methacholine chloride was impaired (195% +/- 38% vs 83% +/- 13%, P < .05), the response to NG-mono-methyl-L-arginine (nitric oxide-dependent tone) was nearly abrogated (-30% +/- 4% vs -1% +/- 11%, P < .05), whereas the endothelium-independent response to sodium nitroprusside remained unchanged. Fasting insulin levels increased from 5.8 +/- 1.2 to 7.0 +/- 1.4 microU/mL (P < .05), and HOMA-IR scores increased from 1.3 +/- 0.3 to 1.6 +/- 0.3 U (P < .05). There were no changes in blood pressure, lipids, markers of inflammation, or oxidative stress.


CONCLUSIONS
Four weeks of the HIV-1 protease inhibitor indinavir, in the absence of HIV-1 infection, causes vascular dysfunction most likely at the level of endothelial nitric oxide production. The vascular dysfunction may be mediated partially by the concomitant induction of insulin resistance but other mechanisms cannot be ruled out.
Shankar
Sudha S
SS
Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Dubé
Michael P
MP
Gorski
J Christopher
JC
Klaunig
James E
JE
Steinberg
Helmut O
HO
D000328:Adult; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D018023:HIV Seronegativity; D006801:Humans; D019469:Indinavir / Q000494:pharmacology*; D008297:Male; D014664:Vasodilation / Q000187:drug effects
D017320:HIV Protease Inhibitors; D019469:Indinavir