Brown L, Duce B, Miric G, Sernia C
Department of Physiology and Pharmacology, The University of Queensland, Australia.
J Am Soc Nephrol. 1999 Jan;10 Suppl 11:S143-8.
Fibrosis impairs cardiac function. This project has determined the expression and deposition of collagens and fibronectin and cardiac function in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat after inhibition of the renin-angiotensin system. DOCA-salt hypertension was induced in 8-wk-old male Wistar rats by uninephrectomy and administration of DOCA (25 mg every fourth day, subcutaneously) and 1% NaCl in the drinking water for 4 wk. Starting 2 wk after surgery, rats were given either oral captopril (100 mg/kg), oral candesartan cilexetil (2 mg/kg), or subcutaneous spironolactone (50 mg/kg) daily for 2 wk (reversal protocol). DOCA-salt rats failed to gain weight with markedly increased water intake and decreased food intake; drug treatment did not alter these parameters. Systolic BP increased from 116+/-5 mmHg in uninephrectomized rats to 179+/-7 mmHg in DOCA-salt rats and was not decreased by treatment (captopril 172+/-1 mmHg; candesartan 187+/-2 mmHg; spironolactone 178+/-3 mmHg). Captopril, candesartan, and spironolactone reversed the increased collagen I mRNA in DOCA-salt rats; only candesartan reversed the increased collagen III mRNA. Collagen IV mRNA was unchanged in DOCA-salt rats and following treatment. Total fibronectin mRNA increased without changing the proportion of fibronectin mRNA as the fetal isoforms EIIIA and EIIIB. Captopril, candesartan, and spironolactone reversed the increased deposition of perivascular and interstitial collagen in DOCA-salt rats; the increased cardiac fibronectin deposition was reversed by candesartan and spironolactone. Captopril, candesartan, and spironolactone also attenuated or reversed the increased diastolic stiffness and the increased dP/dt but not the increased rate-pressure products in DOCA-salt rat hearts. Thus, inhibition of the renin-angiotensin system reverses cardiac fibrosis in DOCA-salt rats and returns some indices of myocardial function to normal.
纤维化会损害心脏功能。本项目已确定在抑制肾素 - 血管紧张素系统后，醋酸脱氧皮质酮（DOCA）-盐高血压大鼠体内胶原蛋白、纤连蛋白的表达与沉积以及心脏功能的情况。通过单侧肾切除并皮下注射DOCA（每四天25mg）以及给予1%氯化钠饮用水4周，在8周龄雄性Wistar大鼠中诱导DOCA-盐高血压。手术后2周开始，大鼠每天分别给予口服卡托普利（100mg/kg）、口服坎地沙坦酯（2mg/kg）或皮下注射螺内酯（50mg/kg），持续2周（逆转方案）。DOCA-盐大鼠体重未增加，饮水量显著增加而食物摄入量减少；药物治疗未改变这些参数。收缩压从单侧肾切除大鼠的116±5mmHg升高至DOCA-盐大鼠的179±7mmHg，且治疗后未降低（卡托普利172±1mmHg；坎地沙坦187±2mmHg；螺内酯178±3mmHg）。卡托普利、坎地沙坦和螺内酯使DOCA-盐大鼠中增加的I型胶原蛋白mRNA水平逆转；只有坎地沙坦使增加的III型胶原蛋白mRNA水平逆转。DOCA-盐大鼠及治疗后IV型胶原蛋白mRNA未改变。总纤连蛋白mRNA增加，但其作为胎儿异构体EIIIA和EIIIB的纤连蛋白mRNA比例未改变。卡托普利、坎地沙坦和螺内酯使DOCA-盐大鼠中血管周围和间质胶原蛋白沉积增加的情况逆转；坎地沙坦和螺内酯使心脏纤连蛋白沉积增加的情况逆转。卡托普利、坎地沙坦和螺内酯还减弱或逆转了DOCA-盐大鼠心脏中增加的舒张硬度和增加的dP/dt，但未逆转增加的速率-压力乘积。因此，抑制肾素-血管紧张素系统可逆转DOCA-盐大鼠的心脏纤维化，并使一些心肌功能指标恢复正常。
