Kähönen M, Mäkynen H, Wu X, Arvola P, Pekki A, Pörsti I
Medical School, Department of Pharmacology, Clinical Pharmacology and Toxicology, University of Tampere, Finland.
J Pharmacol Exp Ther. 1996 Jun;277(3):1701-9.
Angiotensin-converting enzyme inhibition has been shown to attenuate arterial contractions, but the underlying mechanisms have not been clarified in detail. Therefore, we investigated the effects of 10-week-long quinapril therapy (10 mg kg-1 day-1) on responses of mesenteric arterial rings in vitro in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats. The hypertrophy of cardiac muscle and mesenteric arterial smooth muscle was effectively reduced in SHR by quinapril treatment. Maximal contractile force generation to 5-hydroxy-tryptamine was reduced in endothelium-intact and -denuded rings of quinapril-treated SHR when compared with untreated SHR. Contractile sensitivity of endothelium-intact rings to 5-hydroxytryptamine was also attenuated in SHR by quinapril, whereas no differences were found between the study groups in sensitivity of endothelium-denuded rings. Inhibition of NO synthesis by NG-nitro-L-arginine methyl ester increased the sensitivity and contractile force generation of endothelium-intact rings to 5-hydroxytryptamine more effectively in quinapril-treated than in untreated SHR, whereas indomethacin had only minor effects on the responses in the study groups. Maximal responses and sensitivity to norepinephrine were also reduced in SHR by quinapril and were more effectively increased by NG-nitro-L-arginine in quinapril-treated than in untreated SHR. In addition, KCI-induced maximal contractions of endothelium-denuded rings were attenuated in quinapril-treated SHR. However, when the release of norepinephrine from vascular adrenergic nerve endings was eliminated by sympathectomy, no differences were found in maximal KCI-induced contractions between the study groups; this suggests that diminished contractions to KCI in quinapril-treated SHR resulted from reduced release of endogenous norepinephrine from vascular nerve endings during depolarization. The inhibitory effects of the calcium channel blocker nifedipine on arterial contractions in the Wistar-Kyoto rat groups and the quinapril-treated SHR were similar and were lower than in untreated SHR. In conclusion, the present findings suggest that effective reversal of cardiovascular hypertrophy, normalization of the function of voltage-dependent calcium channels, sympathoinhibitory action and enhanced endothelium-derived NO release can explain the attenuated arterial constrictor responses that occur after the long-term inhibition of angiotensin-converting enzyme.
血管紧张素转换酶抑制已被证明可减弱动脉收缩，但潜在机制尚未详细阐明。因此，我们研究了为期10周的喹那普利治疗（10毫克/千克/天）对自发性高血压大鼠（SHR）和正常血压的Wistar-Kyoto大鼠肠系膜动脉环体外反应的影响。喹那普利治疗有效减轻了SHR的心肌和肠系膜动脉平滑肌肥大。与未治疗的SHR相比，喹那普利治疗的SHR的内皮完整和去内皮环对5-羟色胺的最大收缩力产生降低。喹那普利也减弱了SHR中内皮完整环对5-羟色胺的收缩敏感性，而在去内皮环的敏感性方面，研究组之间未发现差异。NG-硝基-L-精氨酸甲酯抑制NO合成在喹那普利治疗的SHR中比未治疗的SHR更有效地增加了内皮完整环对5-羟色胺的敏感性和收缩力产生，而吲哚美辛对研究组的反应只有轻微影响。喹那普利也降低了SHR对去甲肾上腺素的最大反应和敏感性，并且在喹那普利治疗的SHR中，NG-硝基-L-精氨酸比未治疗的SHR更有效地增加了这些反应。此外，喹那普利治疗的SHR中KCl诱导的去内皮环最大收缩减弱。然而，当通过交感神经切除术消除血管肾上腺素能神经末梢去甲肾上腺素的释放时，研究组之间在最大KCl诱导的收缩方面未发现差异；这表明喹那普利治疗的SHR中对KCl收缩减弱是由于去极化期间血管神经末梢内源性去甲肾上腺素释放减少。钙通道阻滞剂硝苯地平对Wistar-Kyoto大鼠组和喹那普利治疗的SHR动脉收缩的抑制作用相似，且低于未治疗的SHR。总之，目前的研究结果表明，心血管肥大的有效逆转、电压依赖性钙通道功能的正常化、交感神经抑制作用以及内皮源性NO释放的增强可以解释长期抑制血管紧张素转换酶后发生的动脉收缩反应减弱。
