The character of the atrial natriuretic response: pressure and volume effects.

Synthetic atrial natriuretic factor (ANF) was compared to the well-characterized diuretics hydrochlorothiazide and furosemide in rats. While ANF was markedly more potent than either agent, its natriuretic potency more closely resembled hydrochlorothiazide. Probenecid, a drug that competes with diuretics such as furosemide for secretion into the renal tubular lumen and thereby decreases diuretic effectiveness, did not interfere with the natriuretic actions of ANF. In rats, continuous infusion of ANF resulted in a bell-shaped dose-response relationship. Above a dose of approximately 100 pmol/kg per min, the response waned and at the highest doses studies, 1-2 nmol/kg per min, urinary sodium excretion fell below control levels. A similar bell-shaped dose-response curve was observed in anaesthetized volume-expanded monkeys. During euvolaemia, conscious monkeys showed a marked fall in blood pressure without concomitant natriuresis. The blood pressure was sustained for the 3-h duration of the ANF infusion. One percent body weight volume expansion blunted the fall in blood pressure in these monkeys and the restored natriuretic response did not wane during 3-h infusion. When the fall in blood pressure was prevented by angiotensin II infusion in conscious euvolaemic monkeys, the natriuretic response to ANF was expressed.

Renal and blood pressure responses to synthetic atrial natriuretic factor in spontaneously hypertensive rats.

Atrial natriuretic factor (ANF) is a potent natriuretic and vasorelaxant agent that also stimulates guanosine 3',5'-cyclic monophosphate (cGMP) excretion in normotensive animals. These properties suggest that ANF may be involved in the regulation of blood pressure. To test a pure preparation of ANF in both normotensive and hypertensive animals, a synthetic 26 amino acid peptide (sANF) contained within endogenous rat ANF was infused intravenously into conscious Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at doses from 12 to 190 pmol/minute. Mean arterial pressure fell progressively as doses of sANF were increased until maximum responses of -41 +/- 5 mm Hg and -29 +/- 5 mm Hg were obtained during infusion of 95 pmol/minute sANF in SHR and WKY, respectively. Heart rate was not significantly affected in either group. At sANF doses of 12 to 50 pmol/minute, urinary electrolyte excretion rose in a dose-related fashion and was similar in WKY and SHR. At infusions of 95 to 190 pmol/minute, the diuretic and saluretic responses were diminished in the hypertensive animals. Only the 190 pmol/minute sANF dose significantly enhanced cGMP excretion in SHR (p less than 0.05); however, in WKY urinary cGMP excretion was elevated in a dose-related fashion. At the highest sANF dose, cGMP excretion was approximately 15 times that observed in the pretreatment urine. The differences in the renal and blood pressure responses to sANF in SHR and WKY suggest that the actions of endogenous ANF may be altered in hypertension.

Renal and systemic effects of synthetic atrial natriuretic factor.

A synthetic peptide corresponding to a sequence of 26 amino acids contained in endogenous rat atrial natriuretic factor (ANF), was infused into one renal artery of anesthetized dogs for a comprehensive in vivo evaluation of the renal and systemic effects of pure ANF. The results proved conclusively that ANF acted directly on the kidney since urine volume and fractional excretion of sodium, potassium, chloride and calcium were elevated in a dose-related manner in the ANF-treated kidney, but were not significantly affected in the contralateral saline-infused organ. The maximum effects achieved with the synthetic ANF were higher than any reported following intravenous administration of crude extracts of rat atria and were similar to those produced by thiazide diuretics. In four of the five dogs studied, renal vascular resistance fell progressively as doses of ANF were increased. Glomerular filtration rate was not significantly elevated during ANF infusion, but was correlated with sodium excretion rates. Even though mean arterial pressure was progressively reduced, there was no significant change in heart rate and no stimulation of renin secretion. Arterial cyclic GMP concentration was higher in the basal state and rose more rapidly than did renal venous levels, indicating that increases in circulating concentrations of arterial cyclic GMP originated from an extrarenal source. Dose-related elevations in urinary cyclic GMP excretion could be explained by increased cyclic GMP filtration, by enhanced production in tubular cells, or by renal tubular secretion. Especially in the saline-infused kidney, there was a clear dissociation between excretion of cyclic GMP and fractional sodium excretion. We conclude that the synthetic ANF increased electrolyte excretion via a direct renal action which was not solely dependent upon changes in renal vasculature, renin secretion or cyclic GMP levels.

Thromboxane B2 and prostaglandin E2 in the rat kidney with unilateral ureteral obstruction.

The production of prostaglandin E2- (PGE2) like and thromboxane A2-(TXA2) like substances is increased after release of unilateral ureteral obstruction (UUO) for 3 days in the isolated perfused rabbit kidney. It has been postulated that this increase in TXA2 biosynthesis might contribute to the development of vasoconstriction in the obstructed kidney. In the present studies, the production of TXA2 and PGE2 in the kidney was further investigated in rats after UUO for 2-18 h. Radioimmunoassay was used to determine thromboxane B2 (TXB2), a chemically stable metabolite of TXA2, and PGE2 production during the incubation of renal slices in vitro. Unlike previous studies, an increase in TXB2 and PGE2 production was demonstrable in the obstructed kidney even in the absence of pharmacological stimulation by bradykinin or angiotensin II. The effect of UUO on prostaglandin production differed in the different anatomical parts of the kidney. In the papilla, production of both TXB2 and PGE2 was increased in the obstructed kidney. In the cortex, however, UUO had a stimulatory effect only on TXB2 production but not on PGE2 production. The increase in TXB2 and PGE2 production was demonstrable as early a 2 h (tested) after ureteral obstruction. Prolongation of ureteral obstruction for 18 h diminished the stimulatory effect of UUO on PGE2 production but not on TXB2 production.

Effect of potassium deficiency on papillary plasma flow in the rat.

Chronic potassium (K+) deficiency has been shown previously to cause a reduction in solute content in the renal papilla, an effect that is potentially important as a contributing factor to the concentrating defect seen in this circumstance. The cause of the decrease in papillary solute content has not been adequately explained. Because alterations in the blood flow rate through the renal papilla may affect the solute content of the papilla, the present experiments examined the effect of chronic K+ deficiency on papillary plasma flow (PPF) in the rat. PPF was measured by the radioactive albumin accumulation technique. Sprague-Dawley rats were fed identical quantities of water and either a normal or a K+-deficient diet for 21 days. Total GRR in the control rats, 1.7 +/- 0.17 (SE) ml/min, was similar to that in K+-deficient rats, 1.4 +/- 0.14 ml/min (P greater than 0.01). Total [3H]PAH clearance was also comparable in the two groups, i.e., 4.4 +/- 0.47 in control and 4.7 +/- 0.45 ml/min in K+-deficient rats (P greater than 0.06). PPF was significantly lower in K+-deficient rats, 19.7 +/- 1.1 ml-min-1-100 g-1, than in control rats, 59.8 +/- 1.6 ml-min-1-100 g-1 (P less than 0.001). The decrease in PPF in the K+-deficient rat may reflect a reduction in perfusion to the juxtamedullary nephrons, thereby resulting in a diminution in both solute delivery and blood flow to the papilla.