Renal effects of specific antagonists of arginine vasopressin in dogs.

To investigate the effects on renal hemodynamics of specific antagonists of arginine vasopressin (AVP), CGP 29325 (d(CH2)5-D-Tyr(Et)VAVP), which has both anti-vasopressor and anti-antidiuretic activities against AVP, and CGP 25838E (d(CH2)5-Tyr(Me)AVP), which has only anti-vasopressor activity, were administered to normally hydrated anesthetized dogs, and the effects on renal function were examined. The pressor response and constriction of renal and mesenteric arteries induced by AVP were dose-dependently blocked by intravenous CGP 25838E. Following intrarenal arterial administration (i.r.a.) of CGP 29325 at 3 micrograms/min, water diuresis occurred and urine osmolality (UOsm) decreased to less than 250 mOsm/kg. Renal blood flow (RBF), glomerular filtration rate (GFR), and urinary sodium excretion (UNaV) remained unchanged. A higher dose (10 micrograms/min, i.r.a.) of CGP 29325 further decreased UOsm to about 110 mOsm/kg. Although arterial blood pressure (BP), GFR and UNaV remained unchanged, RBF decreased from the control value 3.7 +/- 0.35 to 2.4 +/- 0.40 ml/g.min. CGP 25838E (10 micrograms/min, i.r.a.) had no effect on renal hemodynamics and urine formation. When administered into the mesenteric artery, CGP 25838E (10 micrograms/min) increased mesenteric blood flow (MBF) from 199 +/- 34 to 240 +/- 40 ml/min without any alteration in blood pressure. We tentatively conclude that CGP 29325, at a lower dose, exerted anti-antidiuretic effects through a specific inhibition of V2 receptors, while the higher dose of CGP 29325 altered RBF, through yet to be determined mechanisms. The vasoconstrictive activity of AVP may contribute to the regulation of mesenteric circulation, but not to renal hemodynamics, in anesthetized dogs.

Small intestine as possible source of increased plasma cGMP after administration of alpha-hANP to dogs.

A synthetic alpha-human atrial natriuretic peptide (alpha-hANP) was infused into the renal artery of anesthetized dogs, and the urine flow, renal hemodynamics, and plasma guanosine 3',5'-cyclic monophosphate (cGMP) were determined. alpha-hANP led to a natriuresis accompanied by an increase in renal blood flow in the infused kidney but not in the contralateral kidney. The systemic blood pressure remained unchanged. The arterial plasma cGMP significantly increased after alpha-hANP administration. The plasma cGMP in the renal vein was significantly lower than that in the aorta throughout the experiment; therefore the elevated circulating cGMP was probably of extrarenal origin. The plasma cGMP in the right ventricle and femoral vein was also increased to the same extent seen in the aorta. On the other hand, plasma cGMP in the superior mesenteric vein was remarkably increased over that in the aorta. After the administration of alpha-hANP, the increased circulating cGMP seems to be the result of an enhancement of production of this nucleotide from the small intestine or organs drained by the superior mesenteric venous circulation.

Possible tubular site of action in anesthetized dogs of a synthetic alpha-human atrial natriuretic polypeptide.

Intrarenal arterial infusion of a synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) in a dose of 5.0 micrograms/min to anesthetized dogs led to a significant increase in urine flow and urinary excretion of electrolytes. Tubular sites of action of alpha-hANP were determined by using free water clearance techniques and in stop-flow experiments. During water diuresis, free water clearance did not increase in proportion to the increase in urine flow rate. Intrarenal administration of the peptide to dehydrated animals resulted in no change in solute-free water reabsorption, notwithstanding a significant increase in osmolar clearance. These data suggest that the peptide acts on the diluting segment of the ascending limb of Henle and also at the distal nephrons, findings which support data obtained in stop-flow experiments. Infusion of the peptide lowered inulin concentration and elevated sodium concentration in the stop-flow urine from the distal tubules and collecting duct. It is tentatively concluded that alpha-hANP produces potent diuretic and natriuretic responses by suppressing water and sodium transport in the distal portion of the nephron.

Renal effects of a synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) in anesthetized dogs.

The effects of a synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) on renal hemodynamics and urine formation were investigated in anesthetized dogs. Intrarenal arterial infusion of the peptide (1.0 microgram/min) increased renal blood flow, glomerular filtration rate and urine flow with no change in systemic blood pressure. A lower dose of alpha-hANP (0.2 micrograms/min) produced a significant diuresis and natriuresis, while renal hemodynamics remained unchanged. The urinary excretion of Na, Cl and Ca was increased in proportion to the urine flow. We propose that alpha-hANP inhibits tubular reabsorption of electrolytes, and in higher dose produces renal vasodilation.