Taddei S, Virdis A, Ghiadoni L, Salvetti A
Cattedra di Medicina Interna, Department of Internal Medicine, University of Pisa, Italy.
J Cardiovasc Pharmacol. 2000;35(4 Suppl 2):S37-40. doi: 10.1097/00005344-200000002-00009.
Endothelium plays a primary role in the local modulation of vascular function and structure by the production and release of several substances including nitric oxide and endothelins (ET). Nitric oxide is a labile substance produced from the catabolism of L-arginine and not only causes vessel relaxation, but also inhibits platelet aggregation, smooth muscle cell proliferation, monocyte adhesion, adhesion molecules expression and endothelin-1 (ET-1) production. Endothelium-derived ET-1 is a potent vasoconstrictor and has inotropic and mitogenic properties. ET-1 acts through smooth muscle ET(A) and ET(B) receptors, which mainly mediate vasoconstriction, and endothelial ET(B) receptors, which oppose ET(A)- and ET(B)-mediated vasoconstriction by stimulating nitric oxide formation. Both nitric oxide and ET-1 play a crucial role in the cardiovascular physiology and an alteration of these systems can be a promoter of or be associated with most cardiovascular diseases. Essential hypertension is a pathological condition characterized by endothelial dysfunction. In hypertensive patients nitric oxide availability is impaired because of the production of cyclooxygenase-derived vasoconstrictor substances. The latter may also mediate the vasoconstrictor response to exogenous ET-1 because in forearm circulation of essential hypertensives, but not of normotensive controls, the ET-1-induced vasoconstriction is significantly blunted by intrabrachial indomethacin. Therefore, in normotensive subjects and essential hypertensives the vasoconstrictor effect of ET-1 seems to be dependent on different mechanisms. Moreover, in the peripheral circulation of normotensive subjects, where tonic nitric oxide production is preserved, unselective ET(A/B), receptor blockade by TAK-044 causes a very modest degree of vasodilation. In contrast in essential hypertensives, where the tonic nitric oxide production is reduced, the vasodilating effect of TAK-044 is more evident, indicating that the predominant vascular effect of endogenous ET-1 is the vasoconstriction. A possible explanation for this finding, in addition to an increased production of the peptide, could be related to a reduced ET(B) receptor-mediated nitric oxide activation. These peculiar aspects of the role of ET-1 in essential hypertension could have physiopathological relevance.
内皮通过产生和释放包括一氧化氮和内皮素（ET）在内的多种物质，在局部调节血管功能和结构方面发挥着主要作用。一氧化氮是由L-精氨酸分解代谢产生的一种不稳定物质，它不仅能使血管舒张，还能抑制血小板聚集、平滑肌细胞增殖、单核细胞黏附、黏附分子表达以及内皮素-1（ET-1）的产生。内皮源性ET-1是一种强效的血管收缩剂，具有变力性和促有丝分裂特性。ET-1通过平滑肌ET(A)和ET(B)受体发挥作用，这些受体主要介导血管收缩，而内皮ET(B)受体则通过刺激一氧化氮生成来对抗ET(A)和ET(B)介导的血管收缩。一氧化氮和ET-1在心血管生理中都起着关键作用，这些系统的改变可能是大多数心血管疾病的促发因素或与之相关。原发性高血压是一种以内皮功能障碍为特征的病理状态。在高血压患者中，由于环氧化酶衍生的血管收缩物质的产生，一氧化氮的可用性受损。后者也可能介导对外源性ET-1的血管收缩反应，因为在原发性高血压患者的前臂循环中，而不是血压正常的对照组中，臂内注射吲哚美辛可显著减弱ET-1诱导的血管收缩。因此，在血压正常的受试者和原发性高血压患者中，ET-1的血管收缩作用似乎依赖于不同的机制。此外，在血压正常受试者的外周循环中，由于维持了一氧化氮的持续性产生，TAK-044对ET(A/B)受体的非选择性阻断仅引起非常轻微的血管舒张。相比之下，在原发性高血压患者中，由于一氧化氮的持续性产生减少，TAK-044的血管舒张作用更为明显，这表明内源性ET-1的主要血管效应是血管收缩。除了该肽产量增加外，这一发现的一个可能解释可能与ET(B)受体介导的一氧化氮激活减少有关。ET-1在原发性高血压中的这些特殊作用方面可能具有生理病理学意义。
