Mäkynen H, Kähönen M, Wu X, Hutri-Kähönen N, Tolvanen J P, Pörsti I
Medical School, University of Tampere, Finland.
Pharmacol Toxicol. 1997 Oct;81(4):180-9. doi: 10.1111/j.1600-0773.1997.tb02066.x.
Angiotensin-converting enzyme inhibitors have been suggested to improve the function of arterial endothelium and smooth muscle not only through inhibition of angiotensin II formation and reduction of blood pressure, but also via additional pathways, e.g. potentiation of endogenous kinins and enhancement of endothelial autacoid formation. Therefore, we investigated whether 10-week-long quinapril therapy (10 mg kg-1 day-1) could beneficially influence the function of mesenteric arterial rings in vitro in deoxycorticosterone-NaCl-treated Wistar-Kyoto rats, a model of hypertension which is known to be resistant to angiotensin-converting enzyme inhibition. The quinapril treatment had no long-term blood pressure-lowering effect nor did it reduce the associated cardiac hypertrophy in deoxycorticosterone-NaCl hypertension. In noradrenaline-precontracted arterial rings the endothelium-dependent relaxations to acetylcholine and adenosine 5'-diphosphate as well as the endothelium-independent relaxations to nitroprusside and isoprenaline were clearly attenuated in the deoxycorticosterone-NaCl-treated rats. However, the quinapril therapy was without significant effect on any of these dilatory responses. In the presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, the relaxations to acetylcholine in untreated and quinapril-treated hypertensive animals were practically absent, whereas in normotensive rats distinct relaxations to higher concentrations of acetylcholine were still present. Interestingly, when endothelium-dependent hyperpolarization was prevented by precontracting the preparations with potassium chloride, no differences were found in relaxations to acetylcholine and adenosine 5'-diphosphate between the study groups. Exogenous bradykinin induced small comparable contractions in endothelium-intact mesenteric arterial rings from all study groups. In conclusion, the 10-week-long quinapril therapy did not have any significant effects on arterial function in deoxycorticosterone-NaCl hypertensive rats. Therefore, the present results stress the roles of reduced blood pressure and diminished angiotensin II formation in the beneficial vascular effects of long-term angiotensin-converting enzyme inhibition in the present model of hypertension. Furthermore, since the relaxations to acetylcholine and adenosine 5'-diphosphate in the deoxycorticosterone-NaCl-treated rats were attenuated in the absence and presence of nitric oxide synthase inhibition but not under conditions which prevented hyperpolarization, impaired endothelium-dependent relaxation to agonists can be attributed to diminished endothelium-dependent hyperpolarization in this model of hypertension.
血管紧张素转换酶抑制剂已被认为不仅可通过抑制血管紧张素II的形成和降低血压来改善动脉内皮和平滑肌功能，还可通过其他途径，如增强内源性激肽和增加内皮自分泌物质的形成。因此，我们研究了为期10周的喹那普利治疗（10毫克/千克/天）是否能对脱氧皮质酮-氯化钠处理的Wistar-Kyoto大鼠（一种已知对血管紧张素转换酶抑制有抵抗性的高血压模型）肠系膜动脉环的功能产生有益影响。喹那普利治疗对脱氧皮质酮-氯化钠高血压没有长期的降压作用，也没有减轻相关的心脏肥大。在去甲肾上腺素预收缩的动脉环中，脱氧皮质酮-氯化钠处理的大鼠对乙酰胆碱和腺苷5'-二磷酸的内皮依赖性舒张以及对硝普钠和异丙肾上腺素的非内皮依赖性舒张明显减弱。然而，喹那普利治疗对这些舒张反应均无显著影响。在一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯存在的情况下，未治疗和喹那普利治疗的高血压动物对乙酰胆碱的舒张几乎消失，而在正常血压大鼠中，对较高浓度乙酰胆碱仍有明显的舒张。有趣的是，当用氯化钾预收缩制剂来阻止内皮依赖性超极化时，研究组之间对乙酰胆碱和腺苷5'-二磷酸的舒张没有差异。外源性缓激肽在所有研究组的内皮完整的肠系膜动脉环中引起了类似的小收缩。总之，为期10周的喹那普利治疗对脱氧皮质酮-氯化钠高血压大鼠的动脉功能没有任何显著影响。因此，目前的结果强调了在本高血压模型中，降低血压和减少血管紧张素II形成在长期血管紧张素转换酶抑制的有益血管作用中的作用。此外，由于在一氧化氮合酶抑制存在和不存在的情况下，脱氧皮质酮-氯化钠处理的大鼠对乙酰胆碱和腺苷5'-二磷酸的舒张均减弱，但在阻止超极化的条件下则不然，因此在该高血压模型中，对激动剂的内皮依赖性舒张受损可归因于内皮依赖性超极化减弱。
