The impact of the endothelin type A receptor on regional endothelin-1 turnover, in particular renal endothelin-1 release, in humans

Rullman E, Gustafsson T, Ahlborg G. The impact of the endothelin type A receptor on regional endothelin-1 turnover, in particular renal endothelin-1 release, in humans. J Appl Physiol 108:1625-1630, 2010. First published February 11, 2010; doi: 10.1152/japplphysiol. 00881.2009.-The endothelin type A (ETA) receptor was studied in six healthy subjects on two occasions with or without an ETA receptor (BQ-123) blockade. At 40 min of either BQ-123 or NaCl infusion, a concomitant infusion of the endothelin-1 (ET-1) precursor, big ET-1, was initiated to augment ET-1 formation. Blood samples were taken from catheters in a peripheral artery, the renal and femoral veins, and the pulmonary artery. Forty minutes of infusion with BQ-123 alone increased heart rate (P < 0.001) and cardiac output (CO; P < 0.01) and depressed mean arterial blood pressure (P < 0.001) and systemic vascular resistance (SVR; P < 0.01). During infusion of big ET-1 alone, CO, stroke volume, and renal blood flow decreased ( P < 0.01), whereas SVR and pulmonary and renal vascular resistance increased (P < 0.05). These responses to big ET-1 were abolished or diminished by BQ-123. Renal ET-1 release was threefold higher when big ET-1 infusion was preceded by BQ-123 infusion (P < 0.001). Arterial ET-1 concentrations rose to similar levels after big ET-1 infusion ( P < 0.01) in both trials because of elevated concomitant pulmonary uptake (P < 0.05) after ETA blockade. Although there was no net ET-1 leg exchange, leg ET-1 turnover was higher after big ET-1 was preceded by BQ-123. Gene expression of endothelin-converting enzyme 1 and ET-1 in skeletal muscle remained unaltered on both occasions. Our data demonstrate that the level of circulating ET-1 is regulated by ETA receptor-mediated negative feedback. This mechanism seems to be coupled to increased conversion of big ET-1 and is most potent in the kidneys. This emphasizes the important physiological role of ETA receptors in the kidneys, and the lung seems to be mainly a clearing organ for ET-1.