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Department of Medical Physiology, University of Copenhagen, Denmark.

1. Renal, endocrine and haemodynamic responses to separate intravenous infusions of three doses of endothelin-1 (40, 400 and 4000 fmol kg-1 min-1) were investigated in conscious dogs. 2. Administration of 40, 400 and 4000 fmol kg-1 min-1 endothelin-1 for 120 min increased plasma endothelin-1 levels by two-, seven- and 250-fold, respectively. 3. The two low doses did not have measurable effects on mean arterial blood pressure and heart rate but tended to increase glomerular filtration rate. The high dose increased mean arterial blood pressure (MABP; from 104 +/- 4 to 138 +/- 4 mmHg, P < 0.05) and decreased heart rate (from 71 +/- 4 to 46 +/- 3 beats min-1, P < 0.05) as well as glomerular filtration rate (from 47 +/- 3 to 19 +/- 5 ml min-1, P < 0.05). 4. At rates of 40 and 400 fmol kg-1 min-1, endothelin-1 increased sodium excretion about five- and eightfold, respectively. Relative changes in fractional sodium excretion were very similar. The high dose was markedly antinatriuretic (reducing sodium excretion from 8.3 +/- 1.1 to 1.2 +/- 0.2 mumol min-1, P < 0.05). 5. Diuresis increased during the administration of the two lower doses, which did not change plasma atrial natriuretic peptide or vasopressin concentrations. Urine flow increased after termination of the infusion of the pressor dose despite elevated plasma vasopressin and subnormal glomerular filtration rate. 6. Infusion of endothelin-1 at 40 fmol kg-1 min-1 did not change the concentrations of angiotensin II and atrial natriuretic peptide in plasma. Infusion of 400 fmol kg-1 min-1 was associated with a decrease in plasma angiotensin II, while plasma atrial natriuretic peptide was unchanged. The high dose of endothelin-1 markedly increased plasma levels of both hormones. 7. It is concluded that endothelin-1 at low plasma concentrations increases sodium excretion while a higher pressor dose of endothelin-1 is antinatriuretic. However, increases in plasma endothelin-1 seem to elicit diuresis over a wide concentration range, although possibly by different mechanisms.

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