Yutaka Yamashita

Renal vasodilating and diuretic actions of a selective endothelin ETB receptor agonist, IRL1620

The effects of a selective agonist for endothelin ETB receptors, Suc-[Glu9,Ala11,15]endothelin-1-(8-21), IRL1620, on renal hemodynamics and urine formation were studied in anesthetized dogs. Intrarenal arterial infusion of IRL1620 at a dose of 50 ng/kg/min increased renal blood flow from 3.37 +/- 0.30 (mean +/- S.E.) to a maximal value of 4.43 +/- 0.45 ml/g kidney weight per min (ml/g/min) at 9.1 +/- 1.0 min after the start of infusion, with no change in systemic blood pressure and heart rate. Urine flow rate increased and urine osmolality, osmolar clearance and free water reabsorption decreased significantly whereas glomerular filtration rate remained unchanged. In dogs given ibuprofen (12.5 mg/kg, i.v.) after the start of infusion of the peptide, renal blood flow increased slightly but significantly from 3.78 +/- 0.82 to 4.17 +/- 0.96 ml/g/min (1.0 +/- 0.1 min), followed by a gradual reduction in renal blood flow. In dogs given L-NG-nitroarginine (75 micrograms/kg/min), the renal blood flow decreased following intrarenal administration of IRL1620 (50 ng/kg/min). It is suggested that IRL1620 enhances the release of nitric oxide and prostaglandins in the kidney and promotes renal vasodilation. The IRL1620-induced reduction of urine osmolality and free water reabsorption was affected by neither ibuprofen nor L-NG-nitroarginine, thereby suggesting that the suppression of urine concentration did not seem to be linked to the enhanced production of nitric oxide or prostaglandins in the kidney.

Endothelin stimulates the renal production of prostaglandin E2 and I2 in anesthetized dogs

The infusion of endothelin into the renal artery of anesthetized dogs (5 ng/kg per min) decreased the renal blood flow without changing the blood pressure, indicating that endothelin caused renal vasoconstriction. The renal secretion rate of prostaglandin E2 and I2 markedly increased and these increases were abolished by pretreatment with aspirin. Furthermore, the renal vasoconstrictor effect of endothelin was potentiated by aspirin, suggesting a role of prostaglandins in the renal action of endothelin.

Effects of NG-nitro-L-arginine on renal hemodynamic responses to endothelin-3 in anesthetized dogs

The effects of NG-nitro-L-arginine (L-NNA), a nitric oxide (NO) synthase inhibitor, on renal vascular response to endothelin-3 (ET-3) were studied in anesthetized dogs. Intrarenal arterial (i.r.a.) infusion of ET-3 (5 and 25 ng/kg/min for 2 min) elicited a dose-dependent increase in renal blood flow (RBF) with no change in the systemic blood pressure (BP). Marked attenuation of the renal vasodilatory response to ET-3 was observed following the administration of L-NNA (75 micrograms/kg/min i.r.a. for 20 min), and there was a partial reversion when L-arginine (100 mg/kg i.v.) was given. Continuous administration of ET-3 at a rate of 5 ng/kg/min i.r.a. for 25 min increased RBF with no change in BP and heart rate (HR). The glomerular filtration rate (GFR) remained unchanged throughout the experiment, the result being a significant decrease in the filtration fraction (FF). The significant increase in urine flow rate (UF) was associated with a marked reduction in urine osmolarity (Uosm) during ET-3 infusion, but urinary excretion of sodium (UNaV) remained unchanged. Pretreatment with L-NNA abolished the ET-3-induced renal vasodilation. RBF decreased immediately after the start of ET-3 infusion into animals treated with L-NNA. Thus, ET-3 is a diuretic and renal vasodilatory peptide, the vascular effects of which may be mediated by production of endothelial NO in the kidney.

Effects of the calcium channel antagonist nicardipine on renal action of endothelin in dogs.

Endothelin is a potent vasoconstrictor peptide isolated from cultured vascular endothelial cells. Interaction between endothelin and calcium channel antagonist on the renal hemodynamics and urine formation was studied in anesthetized dogs. Intrarenal arterial administration of the peptide progressively reduced renal blood flow from 139 +/- 22 to 85 +/- 12 ml/min at 20 min after the start of continuous infusion, with no change in systemic blood pressure. Glomerular filtration rate, urine flow and urinary sodium and calcium excretion decreased significantly by 30-50% from the preinfusion control values. An endothelin-induced reduction in renal blood flow was markedly attenuated by pretreatment with the calcium antagonist nicardipine (100 ng/kg/min intrarenally). Changes in glomerular filtration rate and antinatriuretic and anticalciuretic actions by the peptide was not affected by nicardipine treatment. It is suggested that the renal vasoconstrictor action, but not the tubular action, of endothelin is functionally coupled with the activation of dihydropyridine-sensitive calcium channels.