5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 8–11 July 2003, Le Meridien Montparnasse, Paris, France

INDINAVIR-ASSOCIATED ENDOTHELIAL DYSFUNCTION IS ASSOCIATED WITH INCREASED PLASMA ADIPONECTIN LEVELS

Antiviral Therapy 2003; 8:L5 (abstract 1)

SS Shankar, M Degawa-Yamauchi, RV Considine, HO Steinberg and MP Dubé
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

We have demonstrated that the HIV-1 protease inhibitor indinavir (IDV) induces endothelial dysfunction in normal volunteers. Recent data from in vitro and animal studies suggest that the adipocytokine adiponectin reduces the neo-intimal thickening and vascular smooth muscle proliferation that occur in response to vascular damage, possibly as a part of an adipo-vascular axis. Plasma adiponectin levels have also been found to be elevated in subjects with essential hypertension, possibly as a counter-regulatory response to mitigate the endothelial damage associated with high arterial pressure. We therefore explored the possibility that IDV-induced endothelial dysfunction leads to a compensatory increase in plasma adiponectin levels.

METHODS: Eleven HIV-negative healthy, non-obese, normotensive subjects were studied before and after 4 weeks of IDV (800 mg orally thrice daily). Endothelial function was evaluated by measuring the leg blood flow (LBF) responses to graded intra-arterial infusions of the endothelium-dependent vasodilator methacholine chloride (Mch; 5, 10, 15 µg/min) and the endothelium-independent vasodilator sodium nitroprusside (SNP; 1.75, 3.5, 7 µg/min). Plasma adiponectin levels were measured by radioimmunoassay (RIA). Results are expressed as mean ±standard error of measurement (SEM), pre-IDV vs 4 weeks post-IDV, and compared using a paired t-test.

RESULTS: IDV did not induce significant changes in weight, lipid profile or blood pressure at 4 weeks. Maximal increments in LBF in response to intra-arterial Mch, expressed as a percentage of baseline, were significantly impaired after IDV (195±38 pre vs 83±13% post, P<0.05). There was no significant difference in the response to SNP. A significant 23% increase in plasma adiponectin levels occurred after 4 weeks of IDV treatment (16.2 ±2.3 pre vs 19.3 ±2.4 µg/ml post, P<0.05). The degree of endothelial dysfunction correlated positively with the increase in adiponectin levels (R²=0.585; P<0.05).

CONCLUSIONS: In healthy non-obese HIV-negative volunteers, 4 weeks of daily IDV impairs endothelial function and is associated with increased plasma adiponectin levels. The correlation between these variables suggests that the IDV-induced elevation in adiponectin levels may be occurring as a protective response to damage initiated by the IDV-induced endothelial dysfunction.

Acknowledgements: This work was supported by grants from the NIH - K23 AI052852, R01 HL72711, and the Indiana University General Clinical Research Center M01 RR00750.

Presenting author: SS Shankar

2003-07-08
1

Copyright © 2003 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.