Regional hemodynamic effects and clearance of endothelin-1 in humans: renal and peripheral tissues may contribute to the overall disposal of the peptide.
We investigated the regional balance of endothelin-1 across the renal and leg vascular bed as well as the hemodynamic effects of exogenously administered endothelin-1 in six healthy men. Net regional endothelin-1 balance was calculated from the respective arteriovenous differences in plasma concentrations and the corresponding plasma flow, the latter being determined by para-aminohippurate or indocyanine-green dye using appropriate catheter techniques. During constant intravenous (i.v.) infusion of endothelin-1 (0.4 pmol/kg/min), a slight increase in diastolic blood pressure (p less than 0.05) and a decrease in heart rate (p less than 0.01) were observed. In contrast, no significant changes in leg hemodynamics were noted. Renal plasma flow decreased by approximately 30%, and renal vascular resistance increased by 50% as compared with the control (placebo) period (p less than 0.01). Renin plasma concentrations did not change substantially during endothelin-1 infusion. During the control (placebo) period, arterial endothelin-1 plasma concentrations averaged 2.1 +/- 1.0 pM. An equilibrated peptide balance across the leg and a slight renal uptake of endothelin-1 was observed. After endothelin-1 infusion, arterial plasma concentrations of the peptide increased to 4.9 +/- 1.3 pM (p less than 0.01), and a net overall renal and limb uptake of endothelin-1 accounted for approximately 9 and 6% of the infused endothelin-1 amount, respectively. Results showed that at systemic endothelin-1 plasma concentrations, comparable to those which occur in a variety of pathologic conditions such as hypertension or cardiogenic shock, besides pulmonary clearance, renal and limb uptake of the peptide may also contribute to the short half-life (t1/2) of endothelin-1 in humans.
Gasic
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I. Medizinische Universitätsklinik, Division of Clinical Pharmacology, Vienna, Austria.
Wagner
O F
OF
Vierhapper
H
H
Nowotny
P
P
Waldhäusl
W
W
D000328:Adult; D001808:Blood Vessels / Q000378:metabolism; D016232:Endothelins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007208:Indocyanine Green; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism*; D007866:Leg / Q000098:blood supply; D008297:Male; D010130:p-Aminohippuric Acid
D016232:Endothelins; D007208:Indocyanine Green; D010130:p-Aminohippuric Acid