Nunes V W, Fortes Z B, Nigro D, Carvalho M H, Zorn T M, Scivoletto R
Department of Pharmacology, Laboratory of Hypertension, SP, São Paulo, Brazil.
Gen Pharmacol. 2000 Feb;34(2):117-25. doi: 10.1016/s0306-3623(00)00053-7.
In the present study, we investigated whether the correction of endothelial dysfunction can be independent of the normalization of high blood pressure levels by enalapril in deoxycorticosterone (DOCA-salt) hypertensive rats. Aorta morphology and the response of aortas with (E+) and without (E-) endothelium to noradrenaline, acetylcholine, and sodium nitroprusside were studied. DOCA-salt hypertensive and normotensive (control) rats were or were not treated with enalapril (5 mg/day/rat in the drinking fluid) for 1, 7, or 15 days. Blood pressure was measured before and after 1, 3, 7, and 15 days of enalapril treatment. Enalapril normalized the high blood pressure levels in 50% (responders) of the hypertensive rats after 3 to as many as 15 days but not after 1 day of treatment. Initial blood pressure levels were not different between responders and nonresponders. Blood pressure levels of normotensive control rats were not altered by enalapril treatment. The tunica media of aortas of DOCA-salt hypertensive rats treated or not treated with enalapril for 15 days was thicker than aortas from normotensive rats. Enalapril corrected the reduced response to acetylcholine observed in aorta from hypertensive rats from the first day of treatment. This treatment rendered aortas from normotensive control rats more sensitive (lower EC(50)) to acetylcholine without a change in the maximal responses. The responses to sodium nitroprusside, a nitric oxide donor, were unaltered in aorta E+ or E- from control and hypertensive rats before and after enalapril treatment. Enalapril did not correct the increased responses to noradrenaline observed in aorta E+ of hypertensive rats. These results suggest that the high blood pressure in DOCA-salt hypertension is not correlated with the altered response to endothelium-dependent agents (either dilator or constrictors). The endothelium-dependent vasodilation by antihypertensive agents can be corrected independently of normalization of blood pressure levels or the vascular morphology.
在本研究中，我们调查了依那普利能否在不使高血压水平恢复正常的情况下，独立纠正脱氧皮质酮（DOCA-盐）高血压大鼠的内皮功能障碍。研究了主动脉形态以及有（E+）和无（E-）内皮的主动脉对去甲肾上腺素、乙酰胆碱和硝普钠的反应。DOCA-盐高血压大鼠和正常血压（对照）大鼠接受或不接受依那普利（饮水中5mg/天/只大鼠）治疗1、7或15天。在依那普利治疗1、3、7和15天前后测量血压。依那普利在治疗3至多达15天后使50%的高血压大鼠（反应者）的高血压水平恢复正常，但治疗1天后未恢复。反应者和无反应者的初始血压水平无差异。依那普利治疗未改变正常血压对照大鼠的血压水平。接受或未接受依那普利治疗15天的DOCA-盐高血压大鼠主动脉的中膜比正常血压大鼠的主动脉厚。从治疗第一天起，依那普利就纠正了高血压大鼠主动脉中观察到的对乙酰胆碱反应降低的情况。这种治疗使正常血压对照大鼠的主动脉对乙酰胆碱更敏感（较低的半数有效浓度（EC50）），而最大反应无变化。在依那普利治疗前后，对照和高血压大鼠的E+或E-主动脉中对一氧化氮供体硝普钠的反应未改变。依那普利未纠正高血压大鼠E+主动脉中观察到的对去甲肾上腺素反应增加的情况。这些结果表明，DOCA-盐高血压中的高血压与对内皮依赖性药物（扩张剂或收缩剂）反应改变无关。抗高血压药物引起的内皮依赖性血管舒张可在血压水平或血管形态未恢复正常的情况下独立得到纠正。
