Effects Of Atorvastatin On Monocrotaline-induced Pulmonary Arterial Remodelling In Rats

PartⅠPulmonary Arteriolar Remodelling in the Pulmonary Arterial hypertension in RatsObjectiveTo eveluate the relationship between the remodelling of pulmonary arteriolar structure induced by monocrotaline and the increase of pulmonary arterial pressure in rats.MethodsThirty-two Sprague-Dawley rats were randomly divided into two groups: normal control (Ctr group) and pulmonary arterial hypertension (PAH group). The pulmonary arterial hypertension was induced by an injection of 40mg/Kg monocrotaline intraperitoneally. After 2 and 4 weeks, mean of Pulmonary Arterial Pressure (MPAP) and Right Ventricular Hypertrophy Index(RVHI)were measured,and WT% and WA% of pulmonary arterioles were evaluated by ipp6.0 Image Analysis Software.ResultsAfter 2 weeks, no significant difference was found between PAH and Ctr group in MPAP and RVHI[(23.6±2.1)vs(26.0±2.8)mmHg,(23.4±4.6)vs(24.7±3.9)%, P >0.05]. However, in comparison with Ctr guoup, WT% and WA% of pulmonary arterioles in PAH group were significantly increased[WT:(39.1±2.8)vs(50.8±3.1)%, WA:( 51.2±3.0)vs(74.5±2.9)%, P <0.05]. Afer 4 weeks, compared with Ctr group, MPAP,RVHI,WT% and WA% in PAH group were significantly increased [MPAP:(24.0±3.0)vs(35.7±3.1)mmHg, RVHI:(24.2±3.7)vs(44.6±4.3)%, P<0.01; WT:(40.1±3.1)vs(57.5±2.0)%, WA:(51.1±2.0)vs(78.3±2.0)%, P <0.05].ConclusionsMonocrotaline-induced pulmonary arteriolar remodelling is prior to the increase of pulmonary arterial pressure in rats.PartⅡEffects of Atorvastatin on Monocrotaline-induced Pulmonary Arterial Remodelling in RatsObjectiveTo investigate the effects of atorvastatin, losartan, diltiazem and benazepril on monocrotaline-induced pulmonary arterial remodelling in rats.MethodsSixty Sprague-Dawley rats were randomly assigned to six groups:normal control (Ctr), pulmonary arterial hypertension (PAH), losartan (Los), atorvastatin (Ato), diltiazem (Dil) and benazepril (Ben) treated groups. The rats were given a dose of 40mg/Kg monocrotaline intraperitoneally in PAH, losartan, atorvastatin, diltiazem and benazepril treated groups and untreated rats were given 1ml normal saline intraperitoneally as control. After 4 weeks, the rats were given 50mg/Kg/d of losartan, 5mg/Kg/d of atorvastatin, 25mg/Kg/d of diltiazem and 10mg/Kg/d of benazepril by gavage respectively in losartan, atorvastatin, diltiazem and benazepril treated groups for 4 weeks. 4 weeks after medication, mean of pulmonary arterial pressure and right ventricular hypertrophy index were measured, and WT% and WA% of pulmonary arterioles were evaluated. The pulmonary arterial trunks from each group were collected. The protein expression for Cavα1c, SERCA-2a, IP3R-1, RyR-3 in pulmonary artery was determined by Western-Blot and densitometry.Results(1) MPAP and RVHI were significantly higher in PAH, as compared with Ctr group. MPAP and RVHI were significantly decreased after treatment of atorvastatin, losartan, diltiazem and benazepril. [MPAP: Ctr(23.22±3.27), PAH(36.12±4.17), Los(29.80±4.76), Ato(27.57±4.07), Dil(25.27±6.18) vs Ben(28.11±6.02)mmHg; RVHI: Ctr(25.58±2.94), PAH(45.60±3.81), Los(38.53±6.40), Ato(37.72±5.96), Dil(39.96±2.61) vs Ben(39.50±4.90)%, P <0.05 respectively](2) WT% and WA% were significantly increased in PAH, in comparison with Ctr group. Administration of atorvastatin, losartan, diltiazem and benazepril, they were significantly reduced. WT% and WA% in benazepril treated group was lower than that in losartan and diltiazem treated groups. [WT: Ctr(37.63±3.63), PAH(58.48±4.59), Los(44.89±5.69), Ato(42.76±2.87), Dil(43.04±4.96) vs Ben(37.41±4.35)%; WA: Ctr(51.37±6.40), PAH(76.84±7.04), Los(61.27±5.46), Ato(59.27±3.36), Dil(61.74±4.90) vs Ben(53.86±5.53)%, P <0.05 respectively](3) In comparison with PAH, Cavα1c and RyR-3 expression was obviously decreased after treatment of atorvastatin, losartan, diltiazem and benazepril. And RyR-3 expression in atorvastatin treated group was lower than that in other medicine treated groups [Cavα1c: Ctr(0.071±0.023), PAH(0.295±0.046), Los(0.117±0.025), Ato(0.109±0.037), Dil(0.125±0.012) vs Ben(0.134±0.034); RyR-3: Ctr(0.711±0.016), PAH(0.757±0.023), Los(0.532±0.017), Ato(0.441±0.027), Dil(0.474±0.021) vs Ben(0.488±0.023), P <0.05 respectively]. There was an significant increase in the expression of SERCA-2a after treatment of atorvastatin and losartan [SERCA-2a: Ctr(0.369±0.014), PAH(0.137±0.028), Los(0.289±0.013), Ato(0.285±0.019), Dil(0.122±0.030) vs Ben(0.107±0.032), P<0.05 respectively]. IP3R-1 was upregulated after treatment of atorvastatin and losartan and downregulated after treatment of diltiazem and benazepril [IP3R-1: Ctr(0.402±0.021), PAH(0.315±0.033), Los(0.360±0.023), Ato(0.371±0.020), Dil(0.083±0.016) vs Ben(0.074±0.022), P<0.05 respectively].Conclusions(1) Pulmonary arterial pressure was reduced and right ventricular hypertrophy and pulmonary arterioles remodelling were attenuated by atorvastatin, losartan, diltiazem and benazepril in monocrotaline-induced pulmonary hypertensive rats. (2) The expression of calcium channel proteins such as Cavα1c, SERCA-2a, IP3R-1, RyR-3 was markedly changed in pulmonary artery in monocrotaline-induced pulmonary hypertensive rats.(3) Atorvastatin, losartan, diltiazem and benazepril could regulate the expression of Cavα1c, SERCA-2a, IP3R-1, RyR-3 differently in pulmonary artery.