Karam H, Heudes D, Hess P, Gonzales M F, Löffler B M, Clozel M, Clozel J P
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Cardiovasc Res. 1996 Feb;31(2):287-95.
Recent studies have shown that beside elevated arterial blood pressure, humoral factors such as angiotensin II, aldosterone, endothelin or bradykinin might play a role in the cardiac hypertrophy and fibrosis secondary to hypertension. In addition, it seems that perivascular fibrosis and interstitial fibrosis are controlled by independent mechanisms. Therefore, the goal of our study was to evaluate the respective role of the increased arterial pressure and of humoral factors on cardiac remodeling in an experimental hypertension model.
Uninephrectomized rats received DOCA, a high salt diet, and when hypertension was installed, they were treated for 6 weeks with either a long-acting calcium antagonist, mibefradil (30 mg/kg day-1), an ACE inhibitor, enalapril (3 mg/kg day-1), or a mixed ETA-ETB endothelin receptor antagonist, bosentan (100 mg/kg day-1). A group of hypertensive rats was left untreated and a sham-operated group of normotensive rats was used for control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and interstitial as well as perivascular fibrosis were evaluated by quantitative morphometry.
DOCA-salt hypertensive rats exhibited a marked cardiac hypertrophy associated with a decrease of maximal coronary blood flow and interstitial and perivascular fibrosis. The calcium antagonist nearly normalized arterial pressure and suppressed all these changes. Enalapril had no effect on arterial pressure and perivascular fibrosis but decreased subendocardial fibrosis. Bosentan had a very small effect on arterial pressure but decreased cardiac hypertrophy and both perivascular and subendocardial fibrosis.
We conclude that in DOCA salt hypertension, humoral factors such as endothelin may play a role beside high blood pressure in cardiac remodeling. In addition, the different components of this remodeling (decrease of vascular reserve, cardiac hypertrophy and cardiac fibrosis) are controlled independently.
近期研究表明，除动脉血压升高外，血管紧张素II、醛固酮、内皮素或缓激肽等体液因子可能在高血压继发的心脏肥大和纤维化中起作用。此外，血管周围纤维化和间质纤维化似乎受独立机制控制。因此，我们研究的目的是在实验性高血压模型中评估动脉压升高和体液因子对心脏重塑的各自作用。
单侧肾切除的大鼠接受去氧皮质酮（DOCA）和高盐饮食，当出现高血压时，用长效钙拮抗剂米贝拉地尔（30mg/kg/天）、血管紧张素转换酶（ACE）抑制剂依那普利（3mg/kg/天）或ETA-ETB内皮素受体混合拮抗剂波生坦（100mg/kg/天）治疗6周。一组高血压大鼠不接受治疗，另一组假手术的正常血压大鼠用作对照。治疗结束时，在离体灌注心脏中测量最大冠状动脉血流量。通过定量形态学评估心脏肥大、间质纤维化和血管周围纤维化。
DOCA-盐性高血压大鼠表现出明显的心脏肥大，伴有最大冠状动脉血流量减少以及间质和血管周围纤维化。钙拮抗剂使动脉压几乎恢复正常，并抑制了所有这些变化。依那普利对动脉压和血管周围纤维化无影响，但减少了心内膜下纤维化。波生坦对动脉压影响很小，但减轻了心脏肥大以及血管周围和心内膜下纤维化。
我们得出结论，在DOCA盐性高血压中，除高血压外，内皮素等体液因子可能在心脏重塑中起作用。此外，这种重塑的不同组成部分（血管储备减少、心脏肥大和心脏纤维化）受独立控制。
