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Biomedical subjects

J Winaver

Publications and source records attributed to J Winaver.

At least 19 recordsLinked to original sources
PubMed1992

Effect of atrial natriuretic factor on renal cGMP production in rats with adriamycin-induced nephrotic syndrome.

Adriamycin-induced nephrotic syndrome in the rat is associated with a blunted natriuretic response to infusion of atrial natriuretic factor. To study the mechanism of renal hyporesponsiveness to the peptide in rats with experimental nephrosis, we evaluated the effects of the hormone on renal production of cGMP, the second messenger of the hormone. Baseline GFR and sodium excretion were lower in nephrotic as compared with normal controls. Infusion of synthetic rat atrial natriuretic factor (10 micrograms/kg/h) increased fractional sodium excretion by 7.3 +/- 2.4% in control rats but only by 1.4 +/- 0.5% in adriamycin-treated rats (P less than 0.05). However, the increments in urinary nucleotide excretion rate (UcGMP x V/GFR), in response to atrial natriuretic factor infusion, were comparable in control and nephrotic rats (control, 114.7 +/- 16.1 pmol/mL; adriamycin, 95.5 +/- 12.0 pmol/mL; P was not significant). The in vitro generation of cGMP in response to incremental doses of the hormone (10(-11) to 10(-6) M + 1 mM 3-isobutyl methyl xanthine) was of similar magnitude in isolated glomeruli derived from control (2.4 +/- 0.25 to 9.1 +/- 1.0 pmol/mg of protein) and nephrotic rats (2.9 +/- 0.2 to 10.3 +/- 1.0 pmol/mg of protein) and was not impaired in suspensions of medullary tissue derived from nephrotic rats (control, 8.4 +/- 0.6 to 14.2 +/- 1.2 pmol/mg of protein; adriamycin, 7.3 +/- 0.7 to 22.0 +/- 2.4 pmol/mg of protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Atrial natriuretic peptide and renal cGMP in rats with experimental heart failure.

Rats with chronic aortocaval (AV) fistula, an experimental model of congestive heart failure, display high plasma levels of atrial natriuretic factor (ANF) and a blunted natriuretic response to ANF infusion. We previously reported that rats with AV fistula either develop progressive sodium retention (urinary sodium excretion, UNaV less than 100 microeq/24 h) or compensate (UNaV greater than 1,200 microeq/24 h). To gain further insight into the mechanism of renal hyporesponsiveness to ANF, we evaluated the effect of ANF on renal guanosine 3',5'-cyclic monophosphate (cGMP) production in sham-operated control rats and in the two groups of rats with AV fistula. Infusion of synthetic ANF-(99-126) (at either 10 or 50 micrograms.kg-1.h-1) resulted in a reduced fractional sodium excretion (P less than 0.05) in both compensated rats (0.7 +/- 0.2 and 7.9 +/- 1.6%) and sodium-retaining rats (0.3 +/- 0.1 and 0.5 +/- 0.1%) compared with controls (8.5 +/- 1.2 and 13.7 +/- 2.3% for low and high doses, respectively). Similarly, urinary cGMP excretion corrected by glomerular filtration rate (UcGMPV/GFR) during low-dose ANF infusion was significantly reduced (P less than 0.05) in both groups with AV fistula (compensated: 39 +/- 10 pmol/ml; sodium-retaining: 55 +/- 13 pmol/ml) compared with controls (115 +/- 16 pmol/ml). During high-dose ANF infusion, compensated rats, but not sodium-retaining rats, displayed a significant increase in UcGMPV/GFR. The differences in UcGMPV/GFR are probably not due to variations in urine flow because furosemide infusion to a separate group of rats with AV fistula increased urine flow approximately eightfold but did not increase UcGMPV/GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

ANP inhibits Na(+)-H+ antiport in proximal tubular brush border membrane: role of dopamine.

Infusion of ANP to rats results in an inhibition of Na(+)-H+ antiport and Na(+)-Pi symport in brush border membrane vesicles (BBMV) prepared from kidneys of these animals (J Clin Invest 75:1983). iIn the present study we investigated the intrarenal mechanism by which infused ANP elicits these changes in proximal tubular transport systems. As in rats, infusion of ANP to rabbits resulted in a diuresis, natriuresis, and increase in GFR; however, unlike in rats, the fractional excretion of phosphate (Pi) was not changed. In BBMV prepared from cortices of ANP-infused rabbits, the rate of Na(+)-H+ antiport was decreased (delta -27%), but Na+ gradient-dependent uptakes of Pi and L-proline were not different from controls. Incubation of rabbit cortical tubule suspension in vitro with ANP 10(-7) M alone had no inhibitory effect on Na(+)-H+ antiport in BBMV prepared from these tubules, whereas incubation with other hormonal agents, 1 U/ml PTH (delta 61%) or with dopamine (DA) 10(-4) M (delta -34%), did inhibit the rate of Na(+)-H+ antiport in BBMV from the same pool of tubules. However, when tubules were incubated in the presence of (10(-5) M) DA, the addition of 10(-7) M ANP did cause a significant (delta -21%) decrease in Na(+)-H+ antiport activity in BBMV. In contrast, ANP did not show similar inhibitory effect in the presence of submaximal inhibitory doses of PTH. To explore whether ANP may act on proximal tubules in vivo indirectly, via mediation of DA, we evaluated the effect of ANP on some parameters of catecholamine system in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effect of converting-enzyme inhibition on renal response to ANF in rats with experimental heart failure.

Increased activity of the renin-angiotensin system is thought to play a major role in the pathogenesis of salt retention and edema formation in congestive heart failure. The present study evaluates the effects of chronic inhibition of angiotensin-converting enzyme on the response to infusion of exogenous atrial natriuretic factor (ANF) in salt-retaining rats with chronic arteriovenous (a-v) fistula, an experimental model of high-output congestive heart failure. Administration of ANF in incremental doses (5-50 micrograms.kg-1.h-1) to Inactin-anesthetized, sham-operated control rats resulted in dose-dependent increases in urine flow, sodium excretion, and glomerular filtration rate, and significant decreases in mean arterial blood pressure. These effects of atrial peptide were markedly attenuated in salt-retaining rats with a-v fistula. However, chronic oral treatment with the angiotensin-converting-enzyme inhibitor enalapril restored the natriuretic response of sodium-retaining rats with a-v fistula to high doses of ANF. At a dose of 50 micrograms.kg-1.h-1, fractional excretion of Na (FENa) in a-v fistula rats given enalapril was 4.0 +/- 0.5%, which was significantly greater than that in a-v fistula rats without enalapril (0.5 +/- 0.4%, P less than 0.05) and not different from the response in sham-control rats (4.9 +/- 0.7%). The improvement in the natriuretic response after enalapril was not associated with a significant increase in GFR and occurred despite a decrease in mean arterial pressure. Moreover, chronic enalapril treatment did not significantly alter the plasma levels of immunoreactive ANF in either the sham controls or in the rats with a-v fistula.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Cardiorenal actions of neutral endopeptidase inhibition in experimental congestive heart failure.

The present studies were designed to determine the action of neutral endopeptidase inhibition (NEP-I), an inhibitor of the degradation of atrial natriuretic factor (ANF), in congestive heart failure (CHF). Studies were conducted in two groups of anesthetized dogs with CHF induced by 8 days of rapid right ventricular pacing. Group 1 (n = 5) received a specific NEP-I (SQ 28,603) at two doses administered sequentially -30 mg/kg followed by a 60 mg/kg i.v. bolus. Group 2 (n = 5) received intravenous infusion of exogenous ANF (100 ng/kg/min) to achieve increases in plasma ANF concentration as observed in group 1. NEP-I resulted in a diuresis and natriuresis (p less than 0.05) with increases in the fractional excretion of sodium and fractional excretion of lithium, the latter a marker for proximal tubule sodium delivery. Such tubular actions occurred in the absence of increases in glomerular filtration rate or renal blood flow but were associated with significant increases in urinary ANF and urinary cyclic GMP. Plasma ANF increased after the 30 mg/kg NEP-I dose. In contrast, in group 2 with exogenous ANF and despite a marked increase in plasma ANF, no natriuresis was observed. Arterial pressure did not change in either group. These studies demonstrate for the first time in CHF that NEP-I may potentiate the natriuretic action of endogenous ANF by a mechanism that is independent of systemic or renal hemodynamics and does not parallel increases in plasma ANF. These studies support an important therapeutic role for NEP-I in CHF.

Animals↗
PubMed1990

Nonazotemic hyperkalemia with renal and extrarenal defects in potassium transport: association with high levels of digoxin-like immunoreactive factor.

We report a hypertensive patient with nonazotemic hyperkalemia caused by a combined disturbance in both the internal and external balance of potassium. During a follow-up of 30 months, exacerbations of hyperkalemia were observed, interposed with a return to the previous baseline. Two brief normokalemic periods were recorded. Blood pressure tended to be higher during hyperkalemic peaks. The following findings were detected: (1) hyperchloremic hyperkalemic acidosis with normal glomerular filtration rate, adequately elevated plasma aldosterone levels, and normovolemia; (2) a tubular defect in potassium excretion, refractory to intravenous sodium sulfate (nonreabsorbable anion) and mineralocorticoids; (3) impaired tissue uptake of potassium under insulin administration; (4) exaggerated hyperkalemia following beta-adrenergic blockade and blunted hypokalemic response to a beta-agonist; and (5) a defect in Na/K transport in erythrocytes detected in vitro, coexistent with an elevated level of free digoxin-like immunoreactive factor in serum. These results suggest that our patient had a generalized abnormality in potassium transport.

Acid-Base Equilibrium↗
PubMed1989

Brush-border membrane cation conducting channels from rat kidney proximal tubules.

This is a description and kinetic characterization of cation channels from rat kidney brush-border membrane vesicles and from apical membranes of proximal tubule cells in culture. Channel activity was demonstrated and characterized in both artificial phospholipid bilayers and in tissue culture. Intermediate conductance, approximately 50 pS, cation-selective channels were observed by both methods. Channels were characterized by a Na permeability (PNa)/K permeability (PK) of 1-5:1. Open-channel current-voltage curves were linear in symmetric 300 mM NaCl. In tissue culture the gating kinetics are described by two open-time constants and two closed-time constants. Channel activity was neither voltage nor Ca2+ dependent and the probability of being in the open state ranged from 0.6 to 0.95. In tissue culture experiments the channel demonstrated nonstationary gating activity. A second, 15-pS cation channel, seen in planar bilayers, demonstrated a higher selectivity for Na+ with a (PNa/PK ratio of greater than 10).

Animals↗
PubMed1989

Effects of systemic alkalosis on urinary magnesium excretion in the rat.

Metabolic alkalosis has previously been shown to have an antimagnesiuric influence. To further clarify this phenomenon, short-term clearance studies were performed on intact anesthetized rats subjected to 0.9% saline infusion, 0.15 M NaHCO3 infusion or acute respiratory alkalosis. The experimental protocols resulted in a similar degree of natriuresis in each of the three groups. The increase in plasma pH value was similar both in animals treated with NaHCO3 and animals with respiratory alkalosis. Filtered loads of Mg did not differ in the three experimental groups. However, only acute metabolic alkalosis was associated with a reduction in the absolute rate of Mg excretion (saline: 0.49 +/- 0.05 mu Eq/min; 0.15 M NaHCO3: 0.29 +/- 0.04 mu Eq/min; acute respiratory alkalosis: 0.48 +/- 0.03 mu Eq/min) and fractional Mg excretion (saline: 40.3 +/- 5.3%; 0.15 NaHCO3: 18.7 +/- 1.4%; acute respiratory alkalosis: 37.2 +/- 6.9%). A similar decrease in urinary Mg excretion in animals treated with bicarbonate infusion was observed following removal of the parathyroid gland. Moreover, for any given rate of urinary Na excretion, Mg excretion was lower in bicarbonate-treated animals than in rats infused with saline solution. Intact animals treated with increasing doses of NaHCO3 revealed a statistically significant inverse correlation between the Mg to Na clearance ratio and urinary and plasma bicarbonate concentration. In contrast, such a correlation was not observed during respiratory alkalosis. The findings suggest that bicarbonate ion directly stimulates tubular magnesium reabsorption independent of the presence or absence of parathyroid hormone.

Alkalosis↗
PubMed1988

Effects of atrial natriuretic factor in rats with experimental high-output heart failure.

The effects of atrial natriuretic factor (ANF) were evaluated in rats with chronic aorto-caval (A-V) fistula. In this experimental model of high-output heart failure, the animals display elevated atrial pressure and systemic vasodilation, but avidly retain sodium. Experiments were performed on Munich-Wistar rats, 8 to 14 days after placement of an infrarenal surgical anastomosis (side-to-side, 0.9 +/- 0.2 mm) and on sham operated controls. Infusion of synthetic ANF (3-28) intravenously (5 micrograms/kg prime; 0.17 microgram/kg.min) resulted in increases in urine flow (V) and fractional sodium excretion (FENa) and decreases in blood pressure (BP) that were significantly attenuated in rats with A-V fistula compared to controls. To control for the lower baseline BP that was present in rats with A-V fistula, a second series of studies was performed in which renal perfusion pressure was reduced in normal rats to 110 mm Hg with a servocontrolled pneumatic cuff. ANF infusion to this group led to significant increases in glomerular filtration rate (GFR), V and FENa that were greater than those seen in rats with A-V fistula (FENa = 2.7 +/- 0.3% vs. 0.48 +/- 0.12%, P less than 0.05). Thus, the moderately reduced BP in rats with A-V fistula did not account for the blunted response to ANF. To investigate whether the renal sensitivity to ANF is altered in this model, an additional series of experiments were performed in which ANF was infused over a range of doses (0.08 to 2.5 micrograms/kg.min) to both groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Hormonal determinants of sodium excretion in rats with experimental high-output heart failure.

The present study evaluates the inter-relationship between the alteration in atrial natriuretic factor (ANF) and the renal handling of Na in rats with chronic aortocaval (a-v) fistula, an experimental model of congestive heart failure. Balance studies in these animals showed two distinct patterns of Na excretion: some rats developed progressive Na retention [urinary sodium excretion (UNaV) less than 100 mueq/24 h], whereas others compensated and returned to normal Na balance (UNaV greater than 1,200 mueq/24 h). Base-line plasma ANF levels were equally elevated in Na-retaining and compensated rats with a-v fistula (588 +/- 70 vs. 621 +/- 114 pg/ml, P, NS). However, the response of the two groups to exogenous administration of synthetic rat ANF-(101-126) in incremental doses varied greatly. ANF infusion increased the fractional Na excretion (FENa) in compensated animals from 0.12 +/- 0.03 to 2.6 +/- 0.5%, whereas the rise in FENa in Na-retaining animals was markedly blunted (0.11 +/- 0.06 to 0.89 +/- 0.35%). A similar pattern of ANF action was observed on the glomerular filtration rate and urine flow. The blunted response to ANF in the Na-retaining animals was associated with a marked increase in plasma renin activity (PRA) (35.6 +/- 6.9 vs. 4.5 +/- 0.7 ng ANG I.ml-1.h-1 in sham control rats, P less than 0.05) and plasma aldosterone levels (729.3 +/- 28.2 vs. 42.6 +/- 18.4 ng/dl in sham control rats, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1986

Impaired renal acidification following acute renal ischemia in the dog.

Transient renal tubular acidosis may complicate acute renal failure (ARF). To clarify this phenomenon, the present study examined tubular H+ ion secretory capacity in an ischemic model of ARF. Clearance studies were performed in dogs subjected to 60 minutes, unilateral renal artery clamping. The contralateral kidney served as control. One hour after release of clamp, mean glomerular filtration rate (GFR) was reduced by 50 to 70 percent in the ischemic kidney. Bicarbonate reclamation (mEq/liter GFR) was comparable in both kidneys. However, ischemia resulted in impaired distal acidification as judged by three separate maneuvers: minimal urinary pH following sulphate infusion was higher in ischemic than in control kidney (6.61 +/- 0.39 vs. 5.39 +/- 0.26, P less than 0.01), mean urine to blood PCO2 difference (U-B PCO2) was significantly lower during phosphate infusion (ischemic: 13.8 +/- 4.1 mm Hg, control: 37.2 +/- 6.8 mm Hg, P less than 0.01) and was completely abolished during isotonic NaHCO3 infusion in the ischemic kidney (-1.9 +/- 3.4 mm Hg) compared to control (40.1 +/- 14.8 mm Hg, P less than 0.05). Urinary potassium excretion was intact following ischemia and was appropriately suppressed by amiloride. Administration of 0.7 M NaHCO3 solution at a rate sufficient to produce maximally alkaline urine resulted in a similar U-B PCO2/UHCO3 relationship in both kidneys in the face of impaired distal acidification in the ischemic kidney. This suggests either that the defect may be reversed by massive bicarbonate infusion or, alternatively, that U-B PCO2 difference may be related to other factors in addition to distal H+ secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis, Renal Tubular↗
PubMed1986

Effect of acute hypercapnia on renal and proximal tubular total carbon dioxide reabsorption in the acetazolamide-treated rat.

The present study evaluates the effect of acute hypercapnia on renal total CO2 (tCO2) reabsorption after inhibition of renal carbonic anhydrase. Simultaneous renal clearance studies and free-flow micropuncture studies of the superficial proximal tubule were performed on plasma-repleted Sprague-Dawley rats treated with acetazolamide, 50 mg/kg body weight. Acute hypercapnia (arterial PCO2, 120 mmHg; blood pH, 7.02) was induced by ventilation with a 10% CO2-90% O2 gas mixture. Control rats (PCO2, 49.5 mmHg, pH 7.34) were ventilated with room air. The renal fractional excretion of tCO2 was approximately 20% lower in the hypercapnic group compared with the rats given acetazolamide alone. Acute hypercapnia reduced the fractional delivery of tCO2 to the late proximal tubule by a comparable amount. The absolute proximal reabsorption of tCO2 was increased by hypercapnia to 410 +/- 47 vs. 170 +/- 74 pmol X min-1, P less than 0.05. The single nephron glomerular filtration rate was 32.6 +/- 0.7 nl X min-1 in the hypercapnic group and 43.8 +/- 1.7 nl X min-1 in the rats given acetazolamide only, P less than 0.01. Acute hypercapnia enhances renal sympathetic nerve activity. To eliminate this effect, additional experiments were performed in which the experimental kidney was denervated before study. Denervation prevented the change in the single nephron filtration rate during acute hypercapnia, but absolute and fractional proximal tCO2 reabsorption remained elevated in comparison to denervated controls. The concentration of H2CO3 in the late proximal tubule, calculated from the measured luminal pH and bicarbonate concentration and the estimated cortical PCO2, was higher in the hypercapnic group, which was a finding compatible with H2CO3 cycling from lumen into proximal tubular cell, which provided a source of hydrogen ions for secretion.

Absorption↗