We studied the actions of iv fenoldopam, a selective dopamine-1 (DA-1) receptor agonist, in 10 normal men eating a diet containing 150 meq sodium and 60 meq potassium per day. During DA-1 receptor stimulation systemic hemodynamic function did not change. Fenoldopam resulted in an increase in urine flow rate from 13 +/- 1 (+/- SE) to a peak of 17 +/- 2 mL/min (P less than 0.05) and an increase in renal plasma flow from 344 +/- 39 to 481 +/- 44 mL/min (P less than 0.05). Urinary sodium excretion and fractional excretion of sodium both increased. Urinary sodium excretion rose to a maximum of 0.32 +/- 0.05 compared with a control value of 0.21 +/- 0.03 meq/min (P less than 0.01), while fractional excretion of sodium rose to 2.7 +/- 0.6 compared with a control value of 1.6 +/- 0.1% (P less than 0.05). The glomerular filtration rate did not change. Administration of a predominantly DA-2 antagonist during continuous DA-1 receptor stimulation did not block the fenoldopam-induced natriuresis. The rise in plasma aldosterone concentration after metoclopramide administration was blunted by DA-1 receptor activation [19.2 +/- 2.9 during control compared with 12.7 +/- 1.3 ng/dL (P less than 0.01) during fenoldopam]. No change occurred in serum potassium, plasma cortisol, or PRA. We conclude that selective DA-1 receptor stimulation in man produces sustained natriuresis and inhibition of aldosterone release by direct renal and adrenal effects.
To evaluate the role of renin-angiotensin in the renal vasoconstriction with combined acute hypoxemia and hypercapnic acidosis preceded by acute hypoxemia, we studied eight conscious mongrel uninephrectomized dogs with chronic renal catheters and controlled sodium intake (80 mEq/24 h x 4 days). The animals were studied during combined acute hypoxemia and hypercapnic acidosis (PaO2 34 +/- 1 mm Hg, PaCo2 57 +/- 1 mm Hg, pH 7.20 +/- 0.01) preceded by 80 min of acute hypoxemia (PaO2 34 +/- 1 mm Hg) during: (a) intrarenal infusion of vehicle (n = 8); or (b) intrarenal administration of the angiotensin II antagonist [Sar1,Ala8]-AII, 70 ng kg-1 min-1 (n = 8). The combination of acute hypoxemia and hypercapnic acidosis resulted in diminished effective renal plasma flow and increased renal vascular resistance during intrarenal vehicle infusion. Intrarenal [Sar1,Ala8]-AII did not abolish the renal vasoconstriction in the initial 20 min of this combined blood gas derangement but resulted in a more prompt return of the renal vascular variables toward control levels with continuation of the blood gas derangement for an additional 20 min, suggesting a role for angiotensin in renal vasoconstriction. These observations suggest that while renin-angiotensin may not mediate the initial renal vasoconstriction in the first 20 min of combined acute hypoxemia and hypercapnic acidosis, in uninephrectomized conscious dogs, it attenuates the spontaneous recovery of renal hemodynamic variables to baseline as the blood gas derangement continues.
Amphibian skin has functional characteristics of epithelium in the mammalian distal nephron and plays an important role in sodium and water metabolism in these animals. A peptide extracted from the skin of the Australian frog Crinia georgiana has been purified, has been determined to have the amino acid sequence of [Ala-Pro-Gly-(Ile3-Val5)]angiotensin II, and recently has been synthesized. We studied the renal effect of synthetic frog skin angiotensin II (FSAII) infused via the renal artery in doses that were confined to the kidney. FSAII was infused intrarenally at 0.2, 2, and 4 pmol/kg.min in uninephrectomized conscious dogs (n = 5) in metabolic balance at a sodium intake of 80 meq/day. FSAII was confined to the kidney, as demonstrated by the absence of any systemic pressor response and/or any increase in plasma aldosterone concentrations during intrarenal FSAII infusion at rats of 0.2 and 2 pmol/kg.min. At 4 pmol/kg.min, FSAII traversed the kidney in amounts sufficient to stimulate aldosterone secretion (P less than 0.05). All three doses of FSAII caused significant antidiuresis and antinatriuresis, and decreased fractional excretion of sodium. There were no changes in the glomerular filtration rate (GFR) or renal plasma flow (RPF) during FSAII infusion at 0.2 and 2 pmol/kg.min. At 4 pmol/kg.min, FSAII engendered a significant decrease in GFR and RPF, while the filtration fraction increased. There were no significant changes in arterial blood pressure at any dose of FSAII. When confined to the kidney, FSAII caused antidiuresis and anti-natriuresis in the absence of a change in GFR and RPF. These results provide evidence that angiotensin acts directly at the renal tubular level to alter renal function.
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