What turns on the endothelins?

Abstract

Production of the potent vasoconstrictor peptide endothelin-1 (ET-1) within the circulation is increased markedly in a number of pathologies, such as the damage following from ischaemia and reperfusion, vasculitis, congestive heart failure, and systemic inflammatory response (septic shock syndrome) and related pathological states. All these conditions are associated with marked increases in the production of cytokines such as tumour necrosis factor-alpha and interleukin-2. Our experiments indicate that in rats administration of either of these cytokines results in a rapid increase in the circulating levels of ET-1 and a very pronounced ET-1-dependent coronary vasoconstriction. Furthermore, in rats suffering from adjuvant polyarthritis, in which there is marked joint inflammation and associated cytokine production, there are dramatic increases in coronary perfusion pressure which are absent when rats are treated with an endothelin receptor antagonist. This does not imply that inflammation must be associated with coronary vasoconstriction and myocardial dysfunction, but rather that in the rat, where ET-1 is a strong and almost irreversible constrictor of coronary vessels, coronary perfusion pressure serves as a very good bioassay for ET-1 activity. What our results do imply is that the ET-1 system is latent, but that in numerous disease states it can become rapidly upregulated following endothelial activation by cytokines.

Periarticular tissue levels of cytokine- and endothelin-1-like immunoreactivity during the course of antigen-induced arthritis in the rat

“…This is in agreement with the systemic effect found in rats with adjuvant-induced arthritis [5] which indicated that either the local production of ET-1 was so large that the plasma levels became elevated or that there was a general enhancement of ET-1 synthesis. Other explanations are also possible; RA is a highly symmetrical disease and the presence of a, possibly neurogenic, communication pathway between the joints cannot be excluded.…”

“…ET-1 is a powerful vasoconstrictor and in rats with adjuvant-induced arthritis a coronary vasoconstriction has been noted [5]. This condition could be relieved by administration of an ET-antagonist.…”

“…Another possibility that has not yet been investigated, is that vasoactive compounds influence this parameter. One such mediator is endothelin-1 (ET-1) which is a powerful vasoconstrictor and has in rats been shown to be released in levels that give systemical effects during inflammatory arthritis [5].…”

Evaluation of Arterial Endothelin-1 Levels, before and during a Sleep Study, in Patients with Bronchial Asthma and Chronic Obstructive Pulmonary Disease

“…The synthesis of ET-1 is promoted by hypoxia, viruses and several cytokines, including TNF-α, which may act as intermediates in those processes [12, 13, 14, 15, 16]. Ischaemic shock and sepsis induce the synthesis of ET-1 as well [17]. …”

Role of TGF-β in Vascular Development and Vascular Reactivity

“…These data suggest that TGF-ß1 by itself was not promoting an increase in vasoconstrictors (such as ET-1) or a decrease in vasodilators (such as NO from endothelium-derived constitutive (ec)-NOS or NOS III) important for the maintenance of vascular tone. However, production of ET-1 is known to be increased in septic shock [56,57], and we cannot exclude the possibility that TGF-ß1 increased ET-1 levels further during the administration of LPS. In addition, a recent study by Hollenberg et al [58] reported that iNOS inhibition reversed the arteriolar hyporesponsiveness to ET-1 in septic rats.…”