Brilla C G, Matsubara L S, Weber K T
Division of Cardiology, University of Missouri-Columbia 65212.
J Mol Cell Cardiol. 1993 May;25(5):563-75. doi: 10.1006/jmcc.1993.1066.
In arterial hypertension associated with primary or secondary hyperaldosteronism myocardial fibrosis is an important determinant of pathologic hypertrophy. To further examine the relationship between elevations in plasma aldosterone (ALDO) and myocardial fibrosis, we analysed perivascular collagen area (PVCA) and interstitial collagen volume fraction (CVF) by videodensitometry and hydroxyproline concentration (HPro) by high-performance liquid chromatography. We examined both the left (LV) and right (RV) ventricles in the following rats models of primary or secondary hyperaldosteronism of eight weeks duration: unilateral renal ischemia (RHT); continuous ALDO administration via osmotic minipumps (0.75 microgram/h s.c.) and enhanced dietary sodium following uninephrectomy (AL); in RHT and AL after pre- and continuous treatment with either 20 (S) or 200 (SS) mg/kg/day s.c. of the aldosterone receptor antagonist, spironolactone; in AL after pre- and continuous treatment with 50 mg/kg/day oral captopril (AL + CAP); as well as in age and sex matched controls (C). Systolic arterial pressure was comparably elevated in RHT and AL (202 +/- 12 and 193 +/- 7 mmHg, respectively; P < 0.0005 vs C); it remained elevated with low dose spironolactone in either model of arterial hypertension, but was normalized with high dose spironolactone or captopril in AL. Left ventricular hypertrophy (LVH), expressed as significantly elevated LV/RV weight or LV/BW ratios, was present in all experimental groups, excluding AL + SS and AL + CAP, when compared with C (P < 0.005). In each ventricle, CVF and PVCA were increased (P < 0.005) in either model of hypertension and in AL + CAP, but were no different from C in all groups receiving either dose of spironolactone. Similar findings were observed for HPro. Thus, myocardial fibrosis was comparable in primary or secondary hyperaldosteronism, wherein elevations in plasma aldosterone, relative to increased sodium intake, are associated with arterial hypertension. The competitive ALDO receptor antagonist, spironolactone, was able to prevent fibrosis in either model irrespective of the development of LVH and the presence of hypertension. Captopril prevented hypertension and LVH, but not unexpectedly it did not prevent myocardial fibrosis in primary hyperaldosteronism. These findings provide further evidence that in these rat models increased plasma ALDO, relative to dietary sodium, plays a major role in the adverse accumulation of collagen that appears in the myocardium.
在与原发性或继发性醛固酮增多症相关的动脉高血压中，心肌纤维化是病理性肥大的一个重要决定因素。为了进一步研究血浆醛固酮（ALDO）升高与心肌纤维化之间的关系，我们通过视频密度测定法分析了血管周围胶原面积（PVCA）和间质胶原体积分数（CVF），并通过高效液相色谱法分析了羟脯氨酸浓度（HPro）。我们在以下为期八周的原发性或继发性醛固酮增多症大鼠模型中检查了左心室（LV）和右心室（RV）：单侧肾缺血（RHT）；通过渗透微型泵持续给予ALDO（0.75微克/小时，皮下注射）并在单侧肾切除术后增加饮食中的钠含量（AL）；在RHT和AL中，在预先和持续给予20（S）或200（SS）毫克/千克/天皮下注射醛固酮受体拮抗剂螺内酯后；在AL中，在预先和持续给予50毫克/千克/天口服卡托普利后（AL + CAP）；以及年龄和性别匹配的对照组（C）。RHT和AL中的收缩期动脉压均显著升高（分别为202±12和193±7毫米汞柱；与C组相比，P < 0.0005）；在任何一种动脉高血压模型中，低剂量螺内酯治疗后收缩期动脉压仍保持升高，但在AL组中，高剂量螺内酯或卡托普利可使其恢复正常。与C组相比（P < 0.005），除AL + SS和AL + CAP外，所有实验组均出现左心室肥厚（LVH），表现为LV/RV重量或LV/BW比值显著升高。在每个心室中，CVF和PVCA在任何一种高血压模型以及AL + CAP组中均增加（P < 0.005），但在接受任何一种剂量螺内酯的所有组中与C组无差异。HPro也观察到类似的结果。因此，原发性或继发性醛固酮增多症中的心肌纤维化相当，其中相对于钠摄入量增加，血浆醛固酮升高与动脉高血压相关。竞争性ALDO受体拮抗剂螺内酯能够在任何一种模型中预防纤维化，而与LVH的发展和高血压的存在无关。卡托普利可预防高血压和LVH，但不出所料，它不能预防原发性醛固酮增多症中的心肌纤维化。这些发现进一步证明，在这些大鼠模型中，相对于饮食中的钠，血浆ALDO升高在心肌中出现的胶原不良积累中起主要作用。
