Dube MP, Shankar S, Vanderluitgaren JM, Leffler CM, Baron AD, Steinberg HO; Conference on Retroviruses and Opportunistic Infections.
9th Conf Retrovir Oppor Infect Feb 24 28 2002 Wash State Conv Trade Cent Seattle Wash Conf Retrovir Oppor Infect 9th 2002 Seattle Wash. 2002 Feb 24-28; 9: abstract no. LB10.
Indiana Univ., Indianapolis
BACKGROUND: Protease inhibitor-based regimens have been associated with endothelial dysfunction, an early step in atherogenesis that predicts cardiovascular events. Possible mediators of endothelial dysfunction include dyslipidemia, insulin resistance, hypertension, or direct drug effects.METHODS: 6 healthy, non-obese, normotensive, HIV-seronegative men with mean age 41 years were evaluated before and after 4 weeks of IDV 800 mg TID. Subjects did not change diet or exercise habits during study. Hyperglycemic clamps (plasma glucose levels ~200 mg/dL for 240 minutes) and direct, invasive measurements of leg blood-flow were performed in basal conditions and during intra-arterial infusion of vasoactive compounds.RESULTS: Mean (+/-SEM) BMI was 23.8+/-1.3 kg/m2. Subjects lost a mean of 0.7 kg (p = 0.3, paired t-test) over 4 weeks. The increase in leg blood-flow (LBF) during femoral artery infusion of the endothelium-dependent vasodilator methacholine (Mch) at maximal doses (15 ?g/minute), expressed as percentage of change from pre-Mch basal values, were markedly impaired after 4 weeks ofIDV: +227+/-45 pre-IDV, +82+/-18 post-IDV, p = 0.003. The response to the endothelium-independent vasodilator nitroprusside, an exogenous source of nitric oxide (NO), did not change. The expected reduction in LBF after infusion of the NO synthase antagonist L-NMMA, expressed as the percentage of change from pre-LNMMA values, was abolished withIDV: -30.4+/-8.9 pre-IDV vs +7.2+/-9.2 post-IDV, p = 0.03. HOMA-IR increased significantly: 1.15+/-0.23 pre-IDV, 1.52+/-0.34 post-IDV, p = 0.03. During hyperglycemic clamp, steady-state plasma glucose was similar: 201+/-1 mg/dL pre-IDV, 196+/-3 mg/dL post-IDV, as were glucose infusion rates: 16.1+/-1.5 pre-IDV, 15.4+/-2.2 mg/kg/minute post-IDV. Steady-state insulin concentrations during hyperglycemia were increased during treatment: 43.3+/-9.3 muU/mL pre-IDV, 54.4+/-7.5 muU/mL post-IDV, p = 0.06. Mean blood pressure, cholesterol, and triglycerides did not change.CONCLUSIONS: IDV induces endothelial dysfunction when administered as monotherapy for 4 weeks to healthy, HIV seronegative men. This does not appear to be mediated by dyslipidemia or changes in blood pressure. Endogenous NO-mediated vasodilation appears to be impaired, although other mechanisms may also be involved. Insulin resistance, and perhaps other drug-related effects, may contribute to endothelial dysfunction from IDV.
Publication Types:
Keywords:
- Acquired Immunodeficiency Syndrome
- HIV Infections
- Humans
- Indinavir
- Insulin Resistance
- Male
- Nitric Oxide
- Nitric Oxide Synthase
- Nitroprusside
- Vasodilation
- physiology
Other ID:
UI: 102264331
From Meeting Abstracts