Action of endothelin-1 on glomerular haemodynamics in the dog: lack of direct effects on glomerular ultrafiltration coefficient.

Abstract

1. Although numerous studies have demonstrated the potent vasoconstrictor effect of endothelin-1 on the renal vasculature, it is difficult to differentiate in vivo between indirect and direct actions of endothelin. 2. In the present study we therefore performed micropuncture experiments in 14 anaesthetized dogs after the administration of endothelin-1 into the renal artery (i.r.a.) for 15 min at a dose of 2.78 ng min-1 kg-1 which did not affect blood pressure or contralateral kidney function. 3. In seven dogs on a 'normal' sodium diet (3.5 mmol of NaCl day-1 kg-1) endothelin-1 resulted in decreases in renal blood flow and glomerular filtration rate with a rise in filtration fraction from 0.24 +/- 0.01 to 0.35 +/- 0.01. Similar changes were seen at the single-nephron level. An increase from 0.11 +/- 0.01 to 0.23 +/- 0.02 (+109 +/- 11%) in efferent, and from 0.15 +/- 0.01 to 0.24 +/- 0.02 mmHg min-1 microliter-1 (+58 +/- 4%) in afferent arteriolar resistance was observed. The ultrafiltration coefficient, Kf, decreased from 4.75 +/- 0.14 to 3.67 +/- 0.14 microliter min-1 mmHg-1 (P < 0.01). 4. In another group of seven dogs, the same endothelin-1 infusion was given after an administration into the renal artery of a 'cocktail' designed to block the receptors of alpha- and beta-adrenergic agonists, thromboxane A2, leukotrienes and angiotensin II together with intravenous cyclo-oxygenase inhibition. Under these conditions, the vasoconstrictor action of endothelin-1 was reduced by more than 30%. The increase in vascular resistance was now relatively similar in both arterioles, i.e. +44 +/- 5% in the afferent and 66 +/- 6% in the efferent arterioles (no significant difference). No change in Kf was seen after the 'cocktail'-blockade (9.4 +/- 0.4 versus 10.1 +/- 0.1 microliter min-1 mmHg-1). 5. In conclusion, in anaesthetized dogs on a 'normal' salt diet, the vasoconstrictor effect of endothelin-1 is more pronounced on the efferent than on the afferent arteriole. This is accompanied by decreases in glomerular filtration rate and water, urea and electrolyte excretion. Part of the vasoconstrictor action of endothelin seems to be mediated by other autacoids. Endothelin-1 itself contributes only partly to pre- and post-glomerular vasoconstriction and has no direct effect on the glomerular ultrafiltration coefficient Kf.