Effect Of Benazepril And Candesartan On Expressions Of SMADs During Myocardial Remodeling In Spontaneous Hypertensive Rats

Objective To observe the effects of benazepril and candesartan on the myocardial remodeling. And to investigate the expressions of transforming growth factorβ₁ (TGF-β₁), Smad3 and Smad7 proteins in spontaneous hypertensive rat (SHR) and related mechanisms.Methods Male SHRs of 12 weeks old were given benazepril(10mg·kg^-1·d^-1), candesartan(4mg·kg^-1·d^-1) alone or given benazepril(5mg·kg^-1·d^-1) and candesartan(2mg·kg^-1·d^-1) for 12 weeks. Male WKY rats of 12 weeks old are the non-hypertensive control. The arterial systolic pressure was measured using the tail-cuff method every two weeks. After 12weeks'treatment, cardiac geometry and function was evaluated and ultrasonic integrated backscatter was acquired at interventricular septum (IVS) and left ventricular posterior wall (LVPW) with the echocardiographic system. Left ventricular catheter was placed via right common carotid artery and hemodynamics parameters were determined. Then, Rats were sacrificed and hearts were harvested. Heart weight index, area of cadiocytes and total protein levels of the left ventricle were examined to compare the effects on myocardial hypertrophy. Meanwhile, the content of myocardial hydroxyproline was measured. The collagen volume fraction (CVF) and perivascular collagen area (PVCA) were assessed by collagne-specific Picro-sirius red staining with computerized video processing. Collagen type I and type III were determined with polarization microscopy on Picro-sirius red staining tissue slices. The amount of cross-linked collagen in the myocardium was determined using the limited pepsin degradation properties. Besides, concentration of Angâ…¡in plasma and myocardium was measured by radioimmunity method, expressions of TGF-β₁, Smad3 and Smad7 proteins were detected using immunohistochemistry and western-blot analysis respectively.Results The arterial systolic pressure, heart weight index, thickness of IVS and LVPW, area of cardiocyte and total proteins of left ventricle were increased in SHRs but attenuated significantly after the treatment of benazepril or candesartan. The combined treatment had the synergic effects except arterial systolic pressure. Meanwhile, the corrected ultrasonic integrated backscatter, the content of myocardial hydroxyproline, CVF, PVCA and the amount of cross-linked collagen were reduced after treatment in each group. The combined treatment can enhance the amount of collagen type III and had the synergic effects on total proteins of left ventricle. Otherwise, concentration of Angâ…¡in plasma and myocardium was down-regulated after the treatment of benazepril, and that was also diminished equally after the combined treatment, but augmented after the treatment of candesartan. Moreover, the expressions of TGF-β₁, Smad3 proteins were raised in SHRs but blunted significantly after the treatment of benazepril or candesartan. The expressions of Smad7 were up-regulated after the treatment of benazepril or candesartan, while that were stable after the combined treatment.Conclusion There is a synergistic effect of attenuating myocardial hypertrophy and improving the quantity and quality of myocardial collagen in SHRs by combined use of benazepril and candesartan. It may be related to the regulation of angiotensinâ…¡and the expressions of TGF-β₁, Smad3 and Smad7 proteins.