Atrial Natriuretic Factor Infusion Research Articles

Mitofusin 2 Inhibits Angiotensin II-Induced Myocardial Hypertrophy

Myocardial hypertrophy is a common clinical finding leading to heart failure and sudden death. Mitofusin 2 (Mfn2), a hyperplasia suppressor protein, is downregulated in hypertrophic heart. This study examined the role of Mfn2 in myocardial hypertrophy and its potential signal pathway. In in vitro studies, neonatal cardiac myocytes were isolated and cultured. Incubation of cultured cardiomycytes with angiotensin II (Ang II) inhibited gene expression of Mfn2; induced cell hypertrophy and protein synthesis; and activated protein kinase Akt. Pretreatment of cells with AdMfn2-a replication-deficient adenoviral vector encoding rat Mfn2 gene-upregulated Mfn2 expression and subsequently attenuated Ang II-induced cell hypertrophy; protein synthesis; and Akt activation. In in vivo studies, direct gene delivery of AdMfn2 into myocardium decreased the infusion of Ang II-induced atrial natriuretic factor (ANF, a hypertrophic marker) expression and cardiomyocyte cross-sectional area. Consistently, upregulation of Mfn2 in myocardium decreased the thicknesses of anterior and posterior walls of left ventricle (LV) and the ratio of LV mass/body weight in Ang II-treated rats. Of note, AdGFP (control for AdMfn2) did not affect the effects of Ang II in vitro or in vivo. Upregulation of Mfn2 inhibits Ang II-induced myocardial hypertrophy. In this process, inhibition of Akt activation seems to play a significant role. These findings indicate Mfn2 is a critical protein in modulating myocyte hypertrophy.

Effects of ANF infusion on the renal responses to lower-body negative pressure in humans.

To investigate the role of atrial natriuretic factor (ANF) in renal responses to a decrease in central blood volume, we examined the effects of ANF infusion on renal function and hormones during prolonged lower-body negative pressure (LBNP). Ten healthy volunteers participated in two experimental sequences, each comprising a 120-min baseline period followed by the application of -20 mm Hg LBNP for 90 min. During one of the two sequences, ANF was infused throughout LBNP application at the constant rate of 2.5 ng/kg/min. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by using inulin and p-aminohippuric acid clearance techniques. LBNP induced a significant decrease in ERPF (534 +/- 28 to 457 +/- 26 ml/min; p < 0.05), GFR (120 +/- 2.5 to 112 +/- 2.5 ml/min; p < or = 0.01), in urine excretion (12 +/- 0.9 to 5.6 +/- 0.5 ml/min; p < 0.001), in sodium excretion (0.36 +/- 0.03 to 0.30 +/- 0.02 mmol/min; p < 0.05), and in plasma ANF (19 +/- 3 to 11 +/- 2 pg/ml; p = 0.001) concomitant with an increase in plasma renin activity (PRA; 0.48 +/- 0.09 to 0.87 +/- 0.16 ng/ml/h; p = 0.01) and of forearm vascular resistance (FVR; p < 0.05). The combination of ANF infusion with LBNP led to a slight increase in plasma ANF from baseline (from 20 +/- 2 to 28 +/- 3 pg/ml; p < 0.05). Compared with values obtained during LBNP with saline vehicle infusion, values obtained during LBNP with ANF infusion were similar for ERPF (463 +/- 23 vs. 457 +/- 26 ml/min), for GFR (111 +/- 2 vs. 112 +/- 2 ml/min), and for urine excretion (7 +/- 0.6 vs. 5.6 +/- 0.5 ml/min; p = 0.07), but greater for fractional excretion of sodium (2.38 +/- 0.25% vs. 1.91 +/- 0.11%; p < 0.05) and FVR (p < 0.05), and smaller for PRA (0.49 +/- 0.1 vs. 0.87 +/- 0.16 ng/ml/h; p < 0.01). These data show that ANF infusion attenuates the antinatriuretic effect of low-level LBNP and its PRA-increasing effects without altering renal hemodynamic responses to LBNP, although there is a decrease in the LBNP-induced forearm vasoconstriction. These results were obtained with plasma ANF levels slightly higher than those in baseline. They support the hypothesis that a decrease in ANF secretion might contribute to the antinatriuretic effect of LBNP.

Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation.

Recently, we developed a goat model of chronic atrial fibrillation (AF). Due to AF, the atrial effective refractory period (AERP) shortened and its physiological rate adaptation inversed, whereas the rate and stability of AF increased. The goal of the present study was to evaluate the role of (1) the autonomic nervous system, (2) ischemia, (3) stretch, (4) atrial natriuretic factor (ANF), and (5) rapid atrial pacing in this process of electrical remodeling. Twenty-five goats were chronically instrumented with multiple epicardial atrial electrodes. Infusion of atropine (1.0 mg/kg; n=6) or propranolol (0.6 mg/kg; n=6) did not abolish the AF-induced shortening of AERP or interval (AFI). Blockade of K+(ATP) channels by glibenclamide (10 micromol/kg; n=6) slightly increased the AFI from 95+/-4 to 101+/-5 ms, but AFI remained considerably shorter than during acute AF (145 ms). Glibenclamide had no significant effect on AERP after electrical cardioversion of AF (69+/-14 versus 75+/-15 ms). Volume loading by 0.5 to 1.0 L of Hemaccel (n=12) did not shorten AERP. The median plasma level of ANF increased from 42 to 99 pg/mL after 1 to 4 weeks of AF (n=6), but ANF infusion (0.1 to 3.1 microg/min, n=4) did not shorten AERP. Rapid atrial pacing (24 to 48 hours; n=10) progressively shortened AERP from 134+/-10 to 105+/-6 ms and inversed its physiological rate adaptation. Electrical remodeling by AF is not mediated by changes in autonomic tone, ischemia, stretch, or ANF. The high rate of electrical activation itself provides the stimulus for the AF-induced changes in AERP.

Indomethacin attenuates the renal actions of atrial natriuretic factor in dogs with chronic heart failure.

The interaction between renal prostaglandins and atrial natriuretic factor (ANF) for the regulation of renal hemodynamic and excretory function was examined in conscious dogs with arteriovenous fistula and chronic compensated high-output heart failure (n = 6). After two control clearance periods, 100 ng/kg/min ANF was administered for the duration of the study. After two clearance periods with ANF infusions, 10 mg/kg indomethacin intravenous bolus was given, and three additional clearance periods were obtained. Atrial natriuretic factor alone increased sodium excretion from a baseline of 25 +/- 7 microEq/min to 158 +/- 24 microEq/min (P < 0.05), whereas creatinine clearance was elevated by 9 mL/min (P < 0.05). Indomethacin reduced ANF-induced sodium excretion and creatinine clearance by 75% (P < 0.05) and 35% (P < 0.05), respectively. In a time control series in dogs with arteriovenous fistula (n = 4), indomethacin vehicle did not alter ANF-induced natriuresis or renal hemodynamic function. These results suggest a modulatory role of the prostaglandins on the renal response to ANF infusions in this canine model of compensated heart failure.

Indomethacin Attenuates the Renal Actions of Atrial Natriuretic Factor in Dogs With Chronic Heart Failure

AbstractThe interaction between renal prostaglandins and atrial natriuretic factor (ANF) for the regulation of renal hemodynamic and excretory function was examined in conscious dogs with arteriovenous fistula and chronic compensated high-output heart failure (n = 6). After two control clearance periods, 100 nglkglmin ANF was administered for the duration of the study. After two clearance periods with ANF infusions, 10 mglkg indomethacin intravenous bolus was given, and three additional clearance periods were obtained. Atrial natriuretic factor alone increased sodium excretion from a baseline of 25 ± 7 p,Eqlmin to 158 ± 24 p,Eq/min (P < 0.05), whereas creatinine clearance was elevated by 9 mUmin (P < 0.05). Indomethacin reduced ANF -induced sodium excretion and creatinine clearance by 75% (P < 0.05) and 35% (P < 0.05), respectively. In a time control series in dogs with arteriovenous fistula (n = 4), indomethacin vehicle did not alter ANF-induced natriuresis or renal hemodynamic function. These results suggest a modulatory role of the prostaglandins on the renal response to ANF infusions in this canine model of compensated heart failure.

Atrial natriuretic peptides increase calcitonin gene—related peptide within human circulation

Long-acting natriuretic peptide (LANP), vessel dilator, and atrial natriuretic factor (ANF) (each infused at 100 ng/kg body weight [BW] · min for 60 minutes) increased the circulating concentration of calcitonin gene—related peptide (CGRP) threefold to fourfold in 30 healthy humans. Within 30 minutes of stopping ANF infusion, the CGRP circulating concentration had returned to preinfusion levels, whereas its increase secondary to the other atrial peptides was still significant 2 to 3 hours after cessation of their infusions. There was a 50% decreased excretion ( P < .001) of CGRP into the urine secondary to LANP and vessel dilator, which correlated with the increase of CGRP in the circulation. The ANF-induced 50% decreased CGRP excretion occurred after the circulating concentration of CGRP had returned top preinfusion levels. Kaliuretic peptide did not affect CGRP breakdown of CGRP as part of their mechanism of increasing CGRP in plasma, whereas the ANF effect of increasing CGRP in plasma appears to be secondary to stimulating the release of CGRP.

Modulation by low sodium intake of glomerular response to cicletanine and atrial natriuretic factor.

1. The aim of the study was to investigate whether cicletanine (CIC), as a potential inhibitor of cyclic GMP phosphodiesterase, is able to restore glomerular response to atrial natriuretic factor (ANF) in rats under conditions of diet deprived of sodium. We examined the effects of CIC on glomerular filtration rate (GFR), natriuresis and nephrogenous cyclic GMP excretion in response to ANF and the effects of both agents on intracapillary volume and cyclic GMP accumulation in isolated glomeruli of rats on normal and low sodium diets. 2. CIC (0.25 mg min-1 kg-1 BW) of ANF (0.5 microgram min-1 BW) alone, given in pharmacological doses, increased Cin significantly in normal sodium rats, whereas the effect of each agent was blunted in low sodium diet rats. Pretreatment with CIC restored the increase in C(in) in response to ANF infusion in low sodium diet rats. In rats on either diet, there were no differences in the extent of diuresis and natriuresis induced by CIC or ANF alone. In contrast to FENa, combined effects of both agents on V and UNa V in rats on normal and low sodium diets were observed. 3. In normal sodium diet rats, CIC 10(-4) M or ANF 10(-6) M alone inhibited angiotensin II 10(-6) M (AII)-induced decrease in intracapillary volume reflected by the glomerular [3H]-inulin space (GIS). In contrast, CIC or ANF alone did not inhibit AII-induced decrease in GIS in low sodium diet rats. Both agents given together inhibited AII-induced decrease in GIS in low sodium diet rats. 4. CIC both alone and in combination with ANF increased nephrogenous cyclic GMP excretion and cyclic GMP accumulation in isolated glomeruli of rats on normal and low sodium diets. In rats on either diet, CIC abolished the difference in ANF-stimulated increase in nephrogenous cyclic GMP excretion and cyclic GMP accumulation in glomeruli. 5. These results suggest that CIC and ANF alone induce relaxation of glomeruli and a resultant increase in glomerular filtration rate in normal sodium diet rats; in contrast, these effects are blunted in the low sodium diet rats. CIC restores glomerular response to ANF in low sodium diet rats, apparently involving inhibition of the cyclic GMP phosphodiesterase.

Enhanced natriuretic response to intrarenal infusion of atrial natriuretic factor during ovine pregnancy.

Volume-loading and intravenous infusion studies have suggested that the natriuretic response of atrial natriuretic factor (ANF) is blunted or unaltered during pregnancy, but these findings may be influenced by changes in peripheral metabolism or clearance. To better define the direct renal actions of ANF, three doses (0.3, 1.5, and 3.0 pmol.kg-1.min-1) of ANF were infused directly into the renal artery of nonpregnant (n = 7) and 115- to 135-day pregnant (n = 6) unilaterally nephrectomized conscious sheep. Each dose was administered on a separate day according to a protocol that consisted of two 20-min control periods, two 20-min ANF infusions, and three 30-min recovery periods. The levels of basal mean arterial pressure averaged 86 +/- 25 mmHg and were similar and constant throughout all protocols in nonpregnant and pregnant ewes. Glomerular filtration rate (GFR) and renal blood flow (RBF) were increased during pregnancy, but GFR, RBF, and fractional proximal tubular reabsorption were not significantly altered by infusion of ANF. Nonpregnant sheep exhibited a selective renal response that was limited to an increase in urinary sodium excretion (UNaV). Pregnant sheep exhibited a selective renal response that included increases in UNaV and urine flow rate produced by suppression of distal sodium and, presumably, fluid reabsorption. The natriuretic and diuretic response of pregnant sheep was much greater than that of nonpregnant sheep despite a smaller proportional increment in intrarenal ANF concentration. These data suggest that the ovine renal response to ANF is limited to actions on the distal tubule that are enhanced during pregnancy.

Effect of atrial natriuretic factor on corticotrophin-releasing hormone-induced adrenocorticotrophin release in the mature ovine foetus.

1. Atrial natriuretic factor (ANF) and its analogues have been shown previously to inhibit corticotrophin-releasing hormone (CRH)-induced adrenocorticotrophin (ACTH) release, both in vivo and in vitro, and it has been suggested that ANF may be a, or the, physiological ACTH-inhibitory factor. To determine whether ANF is relevant in the regulation of ACTH secretion in the ovine foetus, the present study examines the effect of ANF on CRH-stimulated ACTH release in the mature ovine foetus. 2. Five chronically cannulated foetuses, studied between 129 and 140 days of gestation (term 145-150 days), received intraarterial infusions of ovine CRH (4 micrograms/h) 120 min after the start of a sustained infusion of human ANF5-28 (10 micrograms/h) or saline (1.2 mL/h). Appropriate control experiments were performed, with foetuses receiving ANF or saline infusion only. CRH, ACTH, ANF and cortisol levels were measured by sensitive and specific radioimmunoassays. Each animal received all four treatments, with the order being randomized and 2-3 days being allowed between experiments. 3. It was found that pretreatment (120 min) with ANF5-28 (at levels devoid of significant cardiovascular actions) had no effect on mean basal or peak ACTH and cortisol levels during CRH infusion. Given the current experimental parameters, these results suggest that ANF does not acutely modulate basal or CRH-stimulated ACTH and cortisol release in the mature ovine foetus.

Effect of Atrial Natriuretic Factor on Skin Microcirculation Versus Skeletal Muscle Blood Flow

The response of the skin microcirculation and of forearm skeletal muscle blood flow to infusion of alpha-human (99-126) atrial natriuretic factor (ANF) into the brachial artery was investigated in 15 young (18-25 years) healthy volunteers in a double-blind, randomized, placebo-controlled study. The forearm blood flow (FBF) was measured with venous occlusion plethysmography, and the skin flux was measured by using laser Doppler fluxmetry (LDF). Dose-response curves were made using increasing dosages of ANF: 1, 10, and 100 ng/min/dl forearm volume. The FBF showed a significant, dose-dependent increase during ANF infusion, averaging 107 + 22% during the highest ANF dosage, as compared with -5 +/- 9% during placebo (p < 0.001). For the LDF, these numbers were 34 +/- 21 and -6 +/- 10%, respectively (NS). In two subgroups of subjects, the effect of ANF on microvascular reactivity was assessed by registering the vasoconstrictor response to cold exposure (n = 7) and the vasodilator response to arterial occlusion (n = 7). ANF did not change the microvascular response to these stimuli. ANF induces a dose-dependent increase in skeletal muscle BF without a relevant response in the skin microcirculation. ANF does not play an important role in the regulation of skin perfusion.

Lack of inhibitory effect of atrial natriuretic factor on renin release induced by renal hypotension.

To examine the effect of atrial natriuretic factor (ANF) on renin release induced by renal hypotension, experiments were performed in seven barbiturateanaesthetized dogs with denervated kidneys. Renin release induced by renal arterial constriction to 55 mmHg was measured before and during intrarenal infusion of ANF (200 ng min-1 kg-1 body weight). Before ANF infusion, renal arterial constriction increased renin release from 0.2 +/- 0.1 to 21.8 +/- 3.3 micrograms angiotensin I min-1 (p < 0.05). During ANF infusion renal arterial constriction increased renin release as much as before from 0.8 +/- 0.6 to 23.7 +/- 4.6 micrograms angiotensin I min-1 (p < 0.05). Although ANF increased glomerular filtration rate from 33.9 +/- 4.2 to 43.4 +/- 5.6 ml min-1 (p < 0.05) and sodium excretion from 72 +/- 22 to 567 +/- 112 mumol min-1 (p < 0.05) at normal renal perfusion pressure, ANF was without effect on glomerular filtration rate and sodium excretion during renal arterial constriction. The present study shows that ANF is not an inhibitor of renin release induced by renal arterial constriction in anaesthetized dogs with denervated kidneys. Our findings indicate that ANF does not influence renin release induced by the haemodynamic mechanism.

Comparison of Candoxatril and Atrial Natriuretic Factor in Healthy Men

The purpose of these experiments was to compare the effects of endopeptidase inhibition with oral candoxatril on systemic and forearm hemodynamics and muscle sympathetic nerve activity with responses to a low-dose atrial natriuretic factor infusion. Eleven healthy men received at random on three separate days either intravenous saline, natriuretic factor (1.6 pmol/kg per minute) plus saline, or oral candoxatril (200 mg) plus saline. Measurements were made at baseline and 30, 60, and 90 minutes after interventions. Atrial natriuretic factor lowered diastolic pressure (P < .01), central venous pressure (P < .001), forearm blood flow (P < .05), and forearm vascular compliance (P < .05) but had no effect on systolic pressure, heart rate or its variability, stroke volume, sympathetic nerve activity, plasma norepinephrine, or endothelin-1. Plasma epinephrine increased (P < .01). Candoxatril lowered central venous pressure (P < .001) and increased systolic pressure (from 116 +/- 6 to 120 +/- 7 mm Hg; P < .05), endothelin (from 4.6 +/- 1.1 to 6.8 +/- 3.2 pmol/L; P < .02), and epinephrine (P < .05), without affecting any other variables. Candoxatril and atrial natriuretic factor lowered central venous pressure in healthy men without causing a reflex increase in sympathetic nerve activity or norepinephrine, yet epinephrine rose. This suggests that both interventions may specifically inhibit sympathetic nerve traffic to muscle at physiological plasma atrial natriuretic factor concentrations. However, whereas the peptide lowered blood pressure, candoxatril increased systolic pressure. These contrasting hemodynamic responses may be related to differences in plasma atrial natriuretic peptide concentration and to altered endothelin metabolism by candoxatril.

Noninvasive measurement of intrarenal blood flow distribution: kinetic model of renal 123I-hippuran handling.

A new technique for noninvasive measurement of intrarenal blood flow distribution over cortex and medulla is proposed. The technique involves analysis of 123I-labeled hippuran renography, according to a kinetic model that describes the flow of 123I-hippuran from the heart (input) through the renal cortex and medulla to the bladder (output). The method is validated and compared with the standard microsphere injection technique in anesthetized dogs. Changes in intrarenal blood flow distribution were induced by infusion of placebo (n = 6), angiotensin I (n = 5), or atrial natriuretic factor (n = 5). Baseline percentage medullary blood flow in the left kidney was 12 +/- 1% of total renal blood flow measured with microspheres and 15 +/- 1% with renography. During infusion of the placebo, medullary blood flow decreased slightly compared with baseline, as measured with both methods, by 2 +/- 6 (microspheres) and 1 +/- 8% (renography). Infusion of angiotensin I caused a marked fall in medullary blood flow by 42 +/- 11 (microspheres) and 57 +/- 8% (renography). In contrast, infusion of atrial natriuretic factor caused a small rise in medullary blood flow as measured with both methods (9 +/- 3 and 12 +/- 11%, respectively). The absolute and percent changes in medullary blood flow measured with renography correlated with those measured with microspheres (left kidney: r = 0.67, P = 0.005; r = 0.71, P = 0.003, respectively; right kidney: r = 0.62, P = 0.01; r = 0.68, P = 0.004, respectively). We conclude that the proposed kinetic model of renal 123I-hippuran handling can be used to measure changes in intrarenal blood flow distribution and, because of its noninvasive character, may be of use in clinical studies.

Kaliuretic peptide and long acting natriuretic peptide as well as atrial natriuretic factor inhibit aldosterone secretion

The present investigation was designed to determine whether atrial natriuretic peptides consisting of amino acids 1-30 (long acting natriuretic peptide), 31-67 (vessel dilator) and 79-98 (kaliuretic peptide) as well as 99-126 (atrial natriuretic factor (ANF)) of the 126 amino acid ANF prohormone inhibit aldosterone secretion. Thirty healthy human subjects were studied following infusion of 100 ng/kg body weight/min for 60 min of each of the respective peptides. Kaliuretic peptide decreased plasma aldosterone concentration by the greatest amount (6-fold) and plasma aldosterone was still significantly decreased (P < 0.001) three hours after stopping the infusion. In contrast, within 30 min of cessation of the ANF infusion, plasma aldosterone levels had returned to pre-infusion values. Long acting natriuretic peptide also significantly (P < 0.01) decreased plasma aldosterone levels which remained significantly (P < 0.001) decreased 3 h after cessation of infusion. Vessel dilator did not decrease plasma aldosterone levels. Kaliuretic peptide, ANF and long acting natriuretic peptide also decreased (P < 0.01) urinary aldosterone concentrations. None of these peptides changed the plasma potassium concentration. We conclude that two new peptide hormones (long acting natriuretic peptide and kaliuretic peptide) inhibit aldosterone secretion. The length of time that aldosterone secretion is inhibited following kaliuretic peptide and long acting natriuretic peptide infusion is significantly longer (P < 0.001) than following ANF infusion.

Influence of Atrial Natriuretic Factor on Spontaneous Baroreflex Sensitivity for Heart Rate in Humans

Our objective in these experiments was to evaluate the effects of atrial natriuretic factor on the gain of the spontaneous baroreceptor-heart rate reflex in humans. On two separate study days, we gave either atrial natriuretic factor during supine rest (16 nmol over 3 minutes, then 16 pmol/kg per minute) or saline (as vehicle) to nine healthy men (age, 23 +/- 1 years; mean +/- SEM) according to a random, double-blind design. Beat-by-beat RR interval and systolic pressure were recorded noninvasively. Sequences during which systolic pressure and the RR interval of the following beat changed in parallel (either increasing [Up] or decreasing [Down]) over at least three consecutive beats were identified and classified as baroreceptor-heart rate reflex sequences. Regression lines relating RR interval to the preceding systolic pressure were derived for each individual sequence. The mean value of the slopes of these regression lines was calculated to obtain the mean spontaneous baroreflex sensitivity for heart rate for each subject. Saline infusion did not change RR interval, systolic pressure, or number of baroreflex sequences nor the slope of the mean spontaneous baroreflex sensitivity for heart rate or slopes of Up or Down sequences. Atrial natriuretic factor, at a dose that lowers central venous pressure, did not affect systolic pressure, respiratory rate, or the number of baroreflex sequences but reduced RR interval from 952 +/- 35 to 930 +/- 40 ms (P < .04) and the mean slope of spontaneous baroreflex sensitivity for heart rate from 32.7 +/- 4.8 to 23.1 +/- 2.8 ms.mm Hg-1 (P < .04).(ABSTRACT TRUNCATED AT 250 WORDS)

Attenuation of renal effects of atrial natriuretic factor during rat pregnancy.

The influence of pregnancy on renal responses to atrial natriuretic factor (ANF) was determined in urethane-anesthetized Sprague-Dawley rats. Infusions of ANF caused a significantly greater increase in urinary excretion of fluid, sodium, and potassium in virgin than in pregnant (13-15 days and 21 days) rats. Guanosine 3',5'-cyclic monophosphate (cGMP) excretion, mean arterial pressure, plasma immunoreactive ANF, and glomerular filtration rate (GFR) following ANF infusions were not different in virgin and gravid rats, although increments in GFR over basal were greater in virgin than in gravid animals. Renal responses to ANF normalized during postpartum and were attenuated by progesterone treatment of virgin rats. Natriuretic effects of infusions of ANF plus ANF-(4-23) (a ligand for clearance receptors) or of ANF plus thiorphan (an endopeptidase inhibitor) in virgin and pregnant rats did not differ; ANF-(4--23) and thiorphan alone caused greater natriuresis in pregnant than in virgin rats. Effects of ANF on cGMP production by collecting duct cells isolated from virgin and pregnant rats did not differ. We concluded that the attenuation in the renal effects of ANF during pregnancy might be mediated by progesterone by an increase in the intrarenal metabolism of ANF and might reflect physiological adjustment to facilitate fluid/electrolyte expansion.

Inhibition of cGMP-phosphodiesterase restores the glomerular effects of atrial natriuretic factor in low sodium diet rats.

It was shown that atrial natriuretic factor (ANF)-induced increase in glomerular filtration rate (GFR) is blunted in low sodium diet. We investigated whether saralasin, as an angiotensin II receptor antagonist, or verapamil, as a calcium entry blocker, or theophylline and zaprinast, as inhibitors of cGMP-phosphodiesterase activity, could restore the effect of ANF on GFR increase in low sodium diet rats. ANF alone (5 micrograms/kg bolus then 0.5 micrograms/min/kg BW maintenance) increased diuresis and natriuresis to the same extend in low and normal sodium diet rats but had no GFR-increasing effect in low sodium diet rats. Infusion of ANF in the presence of verapamil, saralasin, theophylline or zaprinast induced a significant increase in GFR and filtration fraction (FF). Administration of verapamil or saralasin alone did not alter GFR and FF whereas theophylline or zaprinast alone resulted in moderate but significant increases in both parameters. The increase of nephrogenous cGMP excretion in response to ANF infusion in low sodium diet rats was markedly lower as compared to normal sodium diet rats (243.4 +/- 43.3 vs. 444.0 +/- 35.6 pmol/min, respectively, p < 0.01). Administration of a selective inhibitor of cGMP-phosphodiesterase activity (zaprinast) abolished the differences in ANF-stimulated nephrogenous cGMP excretion in low and normal sodium diet rats. Basal and peak ANF (0.5 microM)-stimulated cGMP formation by isolated glomeruli was significantly lower in low than normal sodium diet rats (1.4 +/- 0.1 vs. 2.9 +/- 0.2 and 7.1 +/- 0.5 vs. 12.5 +/- 1.1 pmol/mg protein, for basal and ANF-stimulated cGMP formation, respectively; both p < 0.05). Zaprinast both alone and in combination with ANF, potentiated cGMP formation by glomeruli isolated from both groups of rats. In the presence of zaprinast, there were no differences in both basal and peak ANF-stimulated cGMP formation by glomeruli isolated from low and normal sodium diet rats. cGMP-phosphodiesterase activity was the same in the medulla of both groups of rats but markedly higher in the renal cortex of low sodium diet rats as compared to normal sodium diet rats (82.6 +/- 6.0 vs. 59.8 +/- 4.3, respectively; p < 0.05). These data suggest that the lack of GFR-increasing response to ANF in low sodium diet rats is primarily due to the increase of cGMP hydrolysis in glomeruli.

Dietary Salt Extremes and Renal Function in Rats: Effect of Atrial Natriuretic Factor

1. Chronic reduction of salt intake can reduce the natriuretic effect of exogenously administered atrial natriuretic factor. The purpose of this study was to elucidate the intrarenal site(s) of such atrial natriuretic factor resistance. Renal clearance and collecting duct microcatheterization experiments were made before and during infusion of atrial natriuretic factor in three groups of rats: group 1 consisted of rats fed a high salt diet (8% NaCl) for 1 week before the experiment; group II were fed a low salt diet (< 0.008%); group III received the same low salt diet, but were acutely replenished with salt at the time of experiment. 2. Baseline sodium chloride excretion was 6480 +/- 810 nmol min-1 g-1 kidney weight in group 1 compared to 99 +/- 16 in group 1. Fractional reabsorptions in the medullary collecting duct were 37 +/- 6% and 95 +/- 2% of delivered load, respectively (P < 0.05). The fractions of filtered sodium remaining at the beginning of the medullary duct were 6.6 +/- 1.0% of filtered load in group 1 and 2.7 +/- 0.7% in group II (P < 0.05), indicating increased tubular reabsorption in group II, not only in the medullary duct, but also in upstream nephron segments.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular actions of atrial natriuretic factor in sheep with cardiac failure.

The present study examines in detail the short-term cardiovascular actions of atrial natriuretic factor (ANF) in sheep with experimental low-output cardiac failure. Five conscious sheep, surgically implanted with a ventricular pacing wire, were paced at 220 beats/min for 14 days. Most clinical symptoms of congestive heart failure (CHF) were apparent after the 14 days, characterized by low cardiac output, high venous pressure, increased total peripheral resistance, increased plasma levels of ANF, noradrenaline, arginine vasopressin and renin, and marked fluid retention. On day 14 of pacing, intravenous infusion of ANF at 100 micrograms/h for 60 min restored cardiac output to prepacing values and reduced both total peripheral resistance and right atrial pressure. These effects were sustained throughout the infusion period. No change was seen in blood pressure, plasma renin, or noradrenaline levels. These hemodynamic changes, produced by short-term infusion of ANF, contrasted with those seen in normal sheep, where there was a fall in cardiac output with increased total peripheral resistance. These changes reflect a return toward normal of the left ventricular function curve. This is the first study to report that ANF improves cardiac function in conscious sheep with CHF, primarily by a vasodilator action to reduce cardiac preload, and suggests that ANF may be useful in treating the hemodynamic effects associated with cardiac failure.

Cardiovascular Actions of Atrial Natriuretic Factor in Sheep With Cardiac Failure

The present study examines in detail the shortterm cardiovascular actions of atrial natriuretic factor (ANF) in sheep with experimental low-output cardiac failure. Five conscious sheep, surgically implanted with a ventricular pacing wire, were paced at 220 beats/min for 14 days. Most clinical symptoms of congestive heart failure (CHF) were apparent after the 14 days, characterized by low cardiac output, high venous pressure, increased total peripheral resistance, increased plasma levels of ANF, noradrenaline, arginine vasopressin and renin, and marked fluid retention. On day 14 of pacing, intravenous infusion of ANF at 100 μg/h for 60 min restored cardiac output to prepacing val ues and reduced both total peripheral resistance and right atrial pressure. These effects were sustained throughout the infusion period. No change was seen in blood pressure, plasma renin, or noradrenaline levels. These hemodynamic changes, produced by short-term infusion of ANF, contrasted with those seen in normal sheep, where there was a fall in cardiac output with increased total peripheral resistance. These changes reflect a return toward normal of the left ventricular function curve. This is the first study to report that ANF improves cardiac function in conscious sheep with CHF, primarily by a vasodilator action to reduce cardiac preload, and suggests that ANF may be useful in treating the hemodynamic effects associated with cardiac failure. Am J Hypertens 1994; 7:905–912