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Inhibition of bilirubin metabolism attenuates angiotensin‐II dependent hypertension in mice
Author(s) -
Vera Trinity,
Stec David E.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.183
Subject(s) - bilirubin , medicine , endocrinology , indinavir , angiotensin ii , metabolism , population , chemistry , blood pressure , immunology , sida , environmental health , viral disease , virus
Population and experimental studies indicate that elevated plasma bilirubin levels are associated with reduced incidence of hypertension. Despite these observations few studies have attempted to moderately raise plasma bilirubin levels for cardiovascular benefit. We tested the hypothesis that induction of moderate hyperbilirubinemia by treatment with Indinavir, a drug known to compete with bilirubin for metabolism by UDP‐Glucuronosyltransferase 1A1, can attenuate Ang‐II dependent hypertension. Treatment of mice with Indinavir (500mg/kg/day, gavage) increased serum unconjugated bilirubin by 87% (n=4) while decreasing serum conjugated bilirubin from 70% to 20% (n=4). This treatment was not associated with hepatic toxicity. Next, we examined the effect of this increase in bilirubin on the development of Ang II dependent hypertension. Mice were treated with Indinavir or Vehicle 3 days prior to the implantation of an osmotic minipump to delivered Ang II at a rate of 1 μg/kg/min. Mean arterial pressure (MAP) was measured in conscious, unrestrained mice for 3 consecutive days starting 7 days after the implantation of the Ang II minipumps. MAP averaged 138 ± 4 and 127 ± 12 mmHg in Ang II and Indinavir + Ang II treated mice respectively (n=3). These results indicate that treatment with Indinavir induces moderate hyperbilirubinemia and prevents Ang II dependent hypertension in mice without hepatotoxic effects.