Mitsutoshi Satoh1, Akira Satoh. 1. Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba, 274-8510, Japan.
Abstract
PURPOSE: We examined the inhibitory effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors and a phosphodiesterase type V inhibitor on hemodynamic function and cardiac remodeling in rats with monocrotaline-induced pulmonary hypertension. METHODS: The rat model of pulmonary hypertension was created by administration of monocrotaline (70 mg/kg, s.c.) to male Wistar rats. A polyethylene tube was introduced into a femoral artery for measurement of mean arterial pressure, another into the right ventricle via the right jugular vein for measurement of right ventricular systolic pressure (RVSP), and another into a femoral vein for administration of test drugs. RESULTS: Repeated administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) and simvastatin (2 mg/kg/day, p.o. 0 - 28 days) significantly reduced RVSP and right ventricular weight (RV)/left ventricular + septum weight (LV + S) without a change in heart rate. However, repeated administration of pravastatin (4 mg/kg/day, p.o. 0 - 28 days) did not reduce the monocrotaline-induced elevation of RVSP and RV/(LV + S) significantly. The reduction of RVSP and RV/(LV + S)) induced by a combination of a prostacyclin analogue, beraprost (100 mg/kg/day, 0 - 28 days) and simvastatin (2 mg/kg/day, 0 - 28 days), was more potent than the effect induced by each drug alone. Sildenafil (5 mg/kg/day, 0 - 28 days) tended to reduce RVSP and RV/(LV + S). Repeated combined administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) + sildenafil (5 mg/kg/day, p.o. 0 - 28 days) significantly reduced Lung/BW. CONCLUSION: Our present results suggest that repeated administration of the lipophilic HMG-CoA reductase inhibitors, atorvastatin and simbastatin, selectively attenuates the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension, and that a combination of HMG-CoA reductase inhibitor and beraprost has a more potent effect than each agent alone.
PURPOSE: We examined the inhibitory effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors and a phosphodiesterase type V inhibitor on hemodynamic function and cardiac remodeling in rats with monocrotaline-induced pulmonary hypertension. METHODS: The rat model of pulmonary hypertension was created by administration of monocrotaline (70 mg/kg, s.c.) to male Wistar rats. A polyethylene tube was introduced into a femoral artery for measurement of mean arterial pressure, another into the right ventricle via the right jugular vein for measurement of right ventricular systolic pressure (RVSP), and another into a femoral vein for administration of test drugs. RESULTS: Repeated administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) and simvastatin (2 mg/kg/day, p.o. 0 - 28 days) significantly reduced RVSP and right ventricular weight (RV)/left ventricular + septum weight (LV + S) without a change in heart rate. However, repeated administration of pravastatin (4 mg/kg/day, p.o. 0 - 28 days) did not reduce the monocrotaline-induced elevation of RVSP and RV/(LV + S) significantly. The reduction of RVSP and RV/(LV + S)) induced by a combination of a prostacyclin analogue, beraprost (100 mg/kg/day, 0 - 28 days) and simvastatin (2 mg/kg/day, 0 - 28 days), was more potent than the effect induced by each drug alone. Sildenafil (5 mg/kg/day, 0 - 28 days) tended to reduce RVSP and RV/(LV + S). Repeated combined administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) + sildenafil (5 mg/kg/day, p.o. 0 - 28 days) significantly reduced Lung/BW. CONCLUSION: Our present results suggest that repeated administration of the lipophilic HMG-CoA reductase inhibitors, atorvastatin and simbastatin, selectively attenuates the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension, and that a combination of HMG-CoA reductase inhibitor and beraprost has a more potent effect than each agent alone.
Authors: Martin R Wilkins; Omar Ali; William Bradlow; John Wharton; Anne Taegtmeyer; Christopher J Rhodes; Hossein A Ghofrani; Luke Howard; Petros Nihoyannopoulos; Raad H Mohiaddin; J Simon R Gibbs Journal: Am J Respir Crit Care Med Date: 2010-05-15 Impact factor: 21.405