Haynes W G, Ferro C E, Webb D J
University of Edinburgh, Department of Medicine, Western General Hospital, Scotland.
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S183-5.
The physiologic significance of endothelin-1 (ET-1) generation in human resistance vessels is unknown. We therefore investigated whether endothelin-converting enzyme (ECE) activity could be demonstrated in human vessels, and the effects of inhibition of the generation or actions of ET-1 on vascular tone in healthy men. Brachial artery infusion of local doses of big ET-1 caused a slow-onset, dose-dependent forearm vasoconstriction that was abolished by co-infusion of the ECE inhibitor phosphoramidon. Phosphoramidon did not affect responses to ET-1. Phosphoramidon caused slow-onset vasodilatation when infused alone, with blood flow increasing by 37% (p = 0.03). Vasoconstriction to ET-1 was completely abolished by co-infusion of the ETA receptor antagonist BQ-123 (p = 0.006), with forearm blood flow tending to increase. Infusion of BQ-123 alone resulted in progressive vasodilatation, with blood flow increasing by 64% (p = 0.007). These results suggest that endogenous generation of ET-1 contributes to the maintenance of vascular tone in states of normal and elevated blood pressure. ECE inhibitors and ETA receptor antagonists may have potential as vasodilators in the treatment of diseases associated with vasoconstriction, such as hypertension and chronic heart failure.
内皮素-1（ET-1）在人体阻力血管中的生理意义尚不清楚。因此，我们研究了在人体血管中是否能证明内皮素转化酶（ECE）的活性，以及抑制ET-1的生成或作用对健康男性血管张力的影响。向肱动脉局部注入大剂量ET-1会引起缓慢起效的、剂量依赖性的前臂血管收缩，而同时注入ECE抑制剂磷酰胺素可消除这种收缩。磷酰胺素不影响对ET-1的反应。单独注入磷酰胺素会引起缓慢起效的血管舒张，血流量增加37%（p = 0.03）。同时注入ETA受体拮抗剂BQ-123可完全消除对ET-1的血管收缩作用（p = 0.006），前臂血流量有增加趋势。单独注入BQ-123会导致渐进性血管舒张，血流量增加64%（p = 0.007）。这些结果表明，内源性ET-1的生成有助于维持正常血压和高血压状态下的血管张力。ECE抑制剂和ETA受体拮抗剂可能作为血管舒张剂在治疗与血管收缩相关的疾病（如高血压和慢性心力衰竭）方面具有潜力。
