Satoh Mitsutoshi, Satoh Akira
Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba, 274-8510, Japan.
J Pharm Pharm Sci. 2009 Feb 4;11(2):118s-130s. doi: 10.18433/j34k5z.
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.
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.
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.
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.
我们研究了3-羟基-3-甲基戊二酰辅酶A（HMG）-辅酶A还原酶抑制剂和5型磷酸二酯酶抑制剂对野百合碱诱导的肺动脉高压大鼠血流动力学功能和心脏重塑的抑制作用。
通过给雄性Wistar大鼠皮下注射野百合碱（70mg/kg）建立肺动脉高压大鼠模型。将一根聚乙烯管插入股动脉以测量平均动脉压，另一根通过右颈静脉插入右心室以测量右心室收缩压（RVSP），还有一根插入股静脉用于给药。
重复给予阿托伐他汀（2mg/kg/天，口服，0 - 28天）和辛伐他汀（2mg/kg/天，口服，0 - 28天）可显著降低RVSP和右心室重量（RV）/左心室+室间隔重量（LV + S），心率无变化。然而，重复给予普伐他汀（4mg/kg/天，口服，0 - 28天）并未显著降低野百合碱诱导的RVSP升高和RV/（LV + S）。前列环素类似物贝拉普罗斯（100mg/kg/天，0 - 28天）和辛伐他汀（2mg/kg/天，0 - 28天）联合使用诱导的RVSP和RV/（LV + S）降低比单独使用每种药物的效果更强。西地那非（5mg/kg/天，0 - 28天）倾向于降低RVSP和RV/（LV + S）。重复联合给予阿托伐他汀（2mg/kg/天，口服，0 - 28天）+西地那非（5mg/kg/天，口服，0 - 28天）可显著降低肺/体重。
我们目前的结果表明，重复给予亲脂性HMG-辅酶A还原酶抑制剂阿托伐他汀和辛伐他汀可选择性减轻野百合碱诱导的肺动脉高压大鼠的RVSP升高、肺动脉高压发展和右心室重塑，并且HMG-辅酶A还原酶抑制剂与贝拉普罗斯联合使用比单独使用每种药物具有更强的效果。
