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1Division of Pulmonary and Critical Care Medicine, Department of Medicine, 2Department of Anesthesiology, and 3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Submitted 19 December 2002 ; accepted in final form 9 May 2003
The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to improve multiple normal endothelial cell functions and inhibit vascular wall cell proliferation. We hypothesized that one such agent, simvastatin, would attenuate chronic hypoxic pulmonary hypertension. Male adult Sprague-Dawley rats were exposed (14 days) to normoxia (N), normoxia plus once-a-day administered simvastatin (20 mg/kg ip) (NS), hypoxia (10% inspired O2 fraction) (H), or hypoxia plus simvastatin (HS). Mean pulmonary artery pressure, measured in anesthetized, ventilated rats with an open-chest method, was reduced from 25 ± 2 mmHg in H to 18 ± 1 in HS (P < 0.001) but did not reach normoxic values (12 ± 1 mmHg). Similarly, right ventricular/left ventricular plus interventricular septal weight was reduced from 0.53 ± 0.02 in the H group to 0.36 ± 0.02 in the HS group (P < 0.001). The increased hematocrit in H (0.65 ± 0.02) was prevented by simvastatin treatment (0.51 ± 0.01, P < 0.001). Hematocrit was similar in N versus NS. Alveolar vessel muscularization and medial thickening of vessels 50–200 µM in diameter induced by hypoxia were also significantly attenuated in the HS animals. Lung endothelial nitric oxide synthase (eNOS) protein expression in the HS group was less than H (P < 0.01) but was similar in N versus NS. We conclude that simvastatin treatment potently attenuates chronic hypoxic pulmonary hypertension and polycythemia in rats and inhibits vascular remodeling. Enhancement of lung eNOS expression does not appear to be involved in mediating this effect.
pulmonary vascular remodeling; 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition; nitric oxide; polycythemia; small G proteins
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