The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth

Endothelin-1 (ET-1) is a critical autocrine and paracrine regulator of cardiac physiology and pathology. Produced locally within the myocardium in response to diverse mechanical and neurohormonal stimuli, ET-1 acutely modulates cardiac contractility. During pathological cardiovascular conditions such as ischaemia, left ventricular hypertrophy and heart failure, myocyte expression and activity of the entire ET-1 system is enhanced, allowing the peptide to both initiate and maintain maladaptive cellular responses. Both the acute and chronic effects of ET-1 are dependent on the activation of intracellular signalling pathways, regulated by the inositol-trisphosphate and diacylglycerol produced upon activation of the ETA receptor. Subsequent stimulation of protein kinases C and D, calmodulin-dependent kinase II, calcineurin and MAPKs modifies the systolic calcium transient, myofibril function and the activity of transcription factors that coordinate cellular remodelling. The precise nature of the cellular response to ET-1 is governed by the timing, localization and context of such signals, allowing the peptide to regulate both cardiomyocyte physiology and instigate disease.