The impact of the endothelin type A receptor on regional endothelin-1 turnover, in particular renal endothelin-1 release, in humans.
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.
Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska University Hospital, Huddinge 141 86 Stockholm, Sweden.
Eric
E
Rullman
Thomas
T
Gustafsson
Gunvor
G
Ahlborg
D000328:Adult; D019332:Endothelin-1 / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D044022:Receptor, Endothelin A / Q000378:metabolism*; D014666:Vasomotor System / Q000502:physiology*
D019332:Endothelin-1; D044022:Receptor, Endothelin A