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1 Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
2 Department of Anesthesiology, Johns Hopkins University, Baltimore, MD, USA
3 Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: rgirgis{at}jhmi.edu.
The 3-hydoxy-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 d) to normoxia (N), normoxia plus once daily simvastatin (20 mg/kg IP) (NS), hypoxia (10% FiO2) (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 group H to 0.36 ± 0.02 in HS (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 vs. NS. Alveolar vessel muscularization and medial thickening of vessels 50-200 µM in diameter induced by hypoxia were also significantly attenuated in HS animals. Lung endothelial nitric oxide protein (eNOS) expression in the HS group was less than H (P < 0.01), but was similar in N vs. 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.
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