| Part 1 Effects of S(-)-amiodipine on left ventricular hypertrophy and expression of Endothelin-1 in spontaneously hypertensive ratsBackground:Left ventricular hypertrophy(LVH) becomes a preclinical disease and an independent risk factor for congestive heart failure,ischemic heart disease,arrhythmia,sudden death,and stroke. Hemodynamic factors and neurohormones derived mainly from the renin-angiotensin system (RAS) may modulate both the extent of cardiac hypertrophy and fibrosis.In addition to appropriate management of additional risk factors and associated clinical conditions,early, intensive and effective BP control is required in the prevention and management of hypertension.Objective:in this study,we measured blood pressure,morphology of LV,cardiac function in SHR.we evaluated the expression of preproET-1 in hypertrophied LV myocardium of SHR.To investigate the effect of S(-)-amlodipine on blood pressure,LV morphology,cardic faunction and expression of preproET-1 in LV of SHR.Method and Results:1.Research on blood pressure of SHR and effect of S(-)-amlodipineTwenty male SHR were randomly grouped to receive either S(-)-amlodipine(2mg/kg·d) or vehicle.Age-matched Wistar-Kyoto(WKY) rats served as controls.Systolic blood pressure (SBP) was measured at the beginning,4,8,and 12 weeks of the experiment by tail cuff method.The results showed that blood pressure of S(-)-amlodipine group was significantly lower than untreatment group(154.23±7.99 mmHg vs 201.41±5.01 mmHg,P＜0.01).2.The LV function of SHR and effect of S(-)-amlodipineRats were anaesthetized with intraperitoneal injection of urethane 1.0g/kg,then the right carotid artery was cannulated with a transducer-tipped catheter,the catheter was advanced further into LV.The recorded or calculated parameters were left ventricle systolic pressure (LVSP),left ventricle end diastolic pressure(LVEDP),the maximal rise rate of left ventricle pressure(+dp/dtmax),the maximal decline rate of left ventricle pressure(-dp/dtmax) and heart rate(HR).The results indicated that,S(-)-amlodipine 2mg/kg·d increased the left ventricular +dp/dtmax/LVSP(55.37±7.96 l/s vs 61.98±5.43 l/s,P＜0.05),-dp/dtmax/LVSP(39.81±5.21 1/s vs 46.74±4.79 l/s,P＜0.05).3.The LVW/BW in SHR and effect of S(-)-amlodipineThe left ventricle(including interventricular septum) samples were weighed after the right and left atria,right ventricular flee wall were dissected.The LV mass index was calculated by dividing the LV weight by the body weight in each animal.By the end of the experiment,the LVW/body weight ratio(LVW/BW) in SHR-C were significantly greater than that in WKY(2.94±0.11 mg/g vs 2.40±0.17 mg/g,P＜0.01), Compared with SHR-C,after 12 weeks treatment with S(-)-amlodipine,the LVW/BW in SHR-A decreased significantly(2.94±0.11 mg/g vs 2.61±0.13 mg/g,P＜0.01).4.Pathological analysis of LV in SHR and effect of S(-)-amlodipineTissue sections were stained with the hematoxylin-eosin(HE) and Massom stain.The average cardiomyocite diameter and interstitial collagen volume fraction(ICVF) was calculated with the aid of an image analyzer(Image ProPlus 5.0).ICVF=collagen areas/total areas×100%.The cardiomyocite diameter of SHR-C was significantly larger than that of WKY(16.13±2.79μm 12.57±3.16μm,P＜0.05).Compared with SHR-C,the cardiomyocite diameter in SHR-A decreased significantly(14.3±2.85μm vs 16.13±2.79μm,P＜0.05).ICVF of SHR-C was higher than WKY(12.38%vs 4.62%,P＜0.01),S(-)-amlodipine treatment decreased ICVF of SHR-A(7.36%vs 12.38%,P＜0.01).5.Endothelin-1 of LV in SHR and effect of S(-)-amlodipinEndothelin-1(ET-1) concentrations of left ventricular was measured.Left ventricular preproET-1 mRNA expression was measured by real-time PCR.The results showed that the expression of preproET-1 mRNA of S(-)-amlodipine treated group decreased 20%compared with hypertension group(P＜0.01),and the ET-1 level in the left ventricular were markedly lower in the SHR treated with S(-)-amlodipine than in the hypertension group(184.43±16.78 pg/g vs 207.69±16.09 pg/g,P＜0.05).Conclusion: 1.In this study,LVH was prominent in SHR.2.The results of this study confirmed that SHR significantly impaired LV function associated with increased arterial pressure and LVH.3.The ET-1 level and expression of preproET-1 mRNA in LV of SHR was increased.4.S(-)-amlodipine could preserve cardiac systolic and diastolic function and inhibit left ventricular hypertrophy in SHR.These effects may partially associate with the decreased ET-1 level of heart. Part 2 Protective effects of S(-)-amlodipine on endothelial function in spontaneously hypertensive ratsBackground:Hypertension is accompanied and influenced by significant changes in arterial function. Although changes in endothelial and smooth muscle cell function are important in acute control of total peripheral resistance and blood pressure,changes in blood vessel structure also contribute to long-term alterations in arterial function.Vascular remodeling and dysfunction play important role in the pathophysiology of hypertension.Objective:In this study,we observed the morphology and of endothelial function of thoracic aortic in SHR,and investigated whether S(-)-amlodipine can improve vascular remodeling and vascular endothelial relaxation of spontaneously hypertensive rats(SHR).Method and Results:1.Research on structure of thoracic aortic in SHR and effect of S(-)-amlodipinThoracic aortic sections were stained with the hematoxylin-eosin(HE) and Massom stain. The average media thickness(MT) and cross--sectional area(CSA) were calculated with the aid of an image analyzer(Image ProPlus 5.0).The MT of SHR-C was significantly larger than that of WKY(97±5μm vs 84±4μm, P＜0.05).Compared with SHR-C,MT in SHR-A decreased significantly(91±3μm vs 97±5μm, P＜0.05).CSA of SHR-C was larger than WKY(0.65±0.02 mm2 vs 0.58±0.03 mm2,P＜0.05), S(-)-amlodipine treatment decreased CSA of SHR-A(0.62±0.02 mm2 vs 0.65±0.02 mm2, P＜0.01).2.The endothelium function in SHR and effect of S(-)-amlodipinRats were studied to observe the endothelium dependent relaxation of thoracic aorta to acetylcholine(ACh) and sodium nitmpruside(SNP).The maximal endothelium dependent relaxation to ACh was enhanced markedly after treatment with S(-)-amlodipine(48.39±14.86%vs 34.71±9.23%,P＜0.05).The difference of endothelium dependent relaxations between control group and S(-)-amlodipine group was eliminated by L-Nω-Nitro-arginine(L-NAME).The thoracic aorta respons to SNP was no different in all groups(P＞0.05).3.The oxidation stress in SHR and effect of S(-)-amlodipinSerum NO,ET and SOD levels of all groups were assahed.The results showed that the NO level of SHR-C was significantly lower than that of WKY (27.98±4.53μmol/L vs 48.59±7.12μmol/,P＜0.01),and Serum ET levels of SHR-C was higher than WKY(207.69±16.81 ng/L vs 151.32±27.89 ng/L,P＜0.01).Serum NO and SOD concentration were increased in SHR-A group(NO:36.66±7.52μmol/L vs 27.98±4.53μmol/L, P＜0.05;SOD:229.22±20.38×103 U/L vs 200.13±6.85×103 U/L,P＜0.01).On the other hand,plasma ET level decreased in SHR-A group(184.43±16.78 ng/L vs 207.69±16.81 ng/L, P＜0.05).Conclusion:1.The MT and CSA of SHR were significantly larger than thats of WKY,vascular remodeling was observed in thoracic aorta of SHR.2.The endothelium-dependent vasodilation function was weakened in SHR,the damaged endothelial function was exised in SHR.3.S(-)-amlodipine couldl improve endothelial relaxation and vascular remodeling in SHR.This effect may be related to an decreased oxidation stress.
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