What turns on the endothelins?

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.