Central atrial natriuretic factor reduces vasopressin secretion in the rat

Atrial natriuretic factor (ANF, Arg 101-Tyr 126; 0.5 and 2.5 micrograms) administered into the lateral cerebral ventricle of conscious euhydrated and dehydrated rats resulted in a significant reduction in the plasma vasopressin concentration. The effect of ANF on vasopressin secretion was greater in the water-deprived animal. Central ANF was without effect on mean arterial blood pressure in both euhydrated and dehydrated rats. The data suggest that ANF occurring in the central nervous system may be important in the control of vasopressin secretion.     

Role of atrial natriuretic factor in renin release

Atrial natriuretic factor (ANF) was studied for its effect on renin release by rat renal cortical slices. ANF (rat) alone (10(-9)-10(-6) M) had no effect on basal renin release, but significantly (P less than 0.001) potentiated angiotensin II (AII) inhibition of renin secretion in doses as low as 10(-9) M. ANF also potentiated the inhibitory effect of AII on 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (which alters intracellular calcium) and calmidazolium (a calmodulin blocker) effects on renin release. ANF did not inhibit the action of isoproterenol, which probably acts through cAMP, at doses below micromolar concentrations. Large, probably pharmacological amounts (greater than 10(-6) M) produce some inhibition. Since AII action on renin is associated with increases in intracellular calcium, our studies suggest that ANF acts by altering the intracellular calcium-calmodulin-mediated steps of AII action on this tissue and not via cAMP.     

Modulation of renin secretion by atrial natriuretic factor prohormone fragment 31-67.

BACKGROUND: Earlier studies have indicated that the atrial natriuretic factor prohormone fragment 31-67 (Pro ANF31-67) has important effects for the promotion of sodium excretion and vasodilation in several animal species. However, the mechanisms for the natriuretic actions of Pro ANF31-67 are not completely defined. In the present study, the effects of synthetic Pro ANF31-67 on renin secretion were examined in sodium-depleted, anesthetized dogs with a single intact kidney (n = 5). METHODS: After 3 20-minute control renal clearance periods, synthetic dog Pro ANF31-67 was given intrarenally at a sustained dose of 0.03 microg/kg/min for 3 20-minute experimental intervals, and after discontinuation of the peptide infusion, 3 final 20-minute recovery periods were determined. RESULTS: Sustained intrarenal infusions of the Pro ANF31-67 produced striking decrements (p<0.05) in renin secretion, from a control value of 1418 +/- 243 to 401 +/- 223 ng of angiotensin I/min. This 66% fall in renin secretion was associated with significant (P < 0.05) increases in creatinine clearance (40%), renal blood flow (8%), urine flow (50%), and sodium excretion (17%). CONCLUSIONS: It is suggested that this inhibition of renin secretion was mediated, at least in part, in response to a ProANF31-67-induced increment in the sodium load delivered to the macula densa. An interaction of the peptide with the renal vascular receptor for suppression of renin release is also possible. ProANF31-67 may represent an important hormonal mechanism involved in the regulation of body-fluid balance.     

Central administration of atrial natriuretic factor inhibits saline preference in the rat

Atrial natriuretic factors (ANFs), produced in myocytes of mammalian atria, exert potent natriuretic and diuretic actions in the kidney as well as a variety of other actions coordinated to normalize extracellular fluid volume. Recently, ANF-like immunoreactivity has been detected in the hypothalamus of the rat, and central administration of ANF has been shown to block dehydration-induced water intake. We describe here the ability of 0.2 and 2.0 nmol atriopeptin III to inhibit saline intake when infused into the third ventricle of conscious, salt-depleted rats; an effect that was dose-related and long-lasting (24 h). These studies provide further evidence for a central nervous system action of ANF, which, together with its established renal and adrenal actions, might be an important feature of the coordinated physiological control of fluid volume.     

Effects of atrial natriuretic factor on hormone-induced renin release

The purpose of this study was to determine whether or not atrial natriuretic factor can act directly on the juxtaglomerular cell in vivo to inhibit hormone-induced renin release. To achieve this objective the interaction between synthetic atrial natriuretic factor and two different renin secretagogues was examined. To exclude any indirect effect of atrial natriuretic factor on renin release due to changes in sodium delivery to the macula densa, all studies were conducted in nonfiltering, canine kidneys. In one series of studies renin release was stimulated by intrarenal infusions of norepinephrine (3 micrograms/kg/min), and in a second series of studies renin release was induced by intrarenal infusions of prostacyclin (0.1 micrograms/kg/min). In both studies intrarenal infusions of atrial natriuretic factor (0.3 micrograms/kg/min), which provided supraphysiological levels of atrial natriuretic factor in the renal arterial plasma, failed to attenuate hormone-induced renin release. In contrast, adenosine, a well-known inhibitor of renin release, abolished the renin release response to both hormones. These data indicate that, at the dose used in this study, synthetic atrial natriuretic factor does not act directly on the juxtaglomerular cell to attenuate hormone-induced renin release. Further, these results imply that circulating endogenous atrial natriuretic factor cannot directly attenuate juxtaglomerular cell responsiveness.     

Atrial natriuretic factor inhibits isoproterenol- and furosemide-stimulated renin release in humans

The effects of atrial natriuretic factor (0.025 microgram/kg/min) on isoproterenol-(0.02 microgram/kg/min) and furosemide-(5 mg i.v. bolus) stimulated renin release were studied in seven salt-replete healthy volunteers. Isoproterenol or furosemide were given against a background infusion of 5% D-glucose (placebo day) or atrial natriuretic factor (experimental day). Atrial natriuretic factor abolished the rise in plasma renin activity caused by isoproterenol (p = 0.003) and significantly (p = 0.048) attenuated the rise in plasma renin activity after a bolus injection of furosemide. These results show that a pharmacological dose of atrial natriuretic factor inhibits stimulated renin release in humans. This attenuation is apparent with two heterogenous stimuli, which suggests a nonspecific effect.     

Alterations in the secretion of atrial natriuretic factor in atria from aged rats.

We measured plasma atrial natriuretic factor levels and atrial natriuretic factor secretion by isolated left atria from aging rats to determine the secretory response to stretch and adrenergic stimulation. Systolic arterial pressure and right atrial pressure were measured in vivo. Twenty-four hours later, atria were removed and studied in vitro in a perifusion system. After removal, stabilization at 0.7 g tension, and equilibration for 65 minutes, atria were stretched by increasing external tension for 20 minutes. After reequilibration atria were perifused with phenylephrine, 10(-5) M, for an additional 30 minutes. Right atrial pressure was not different between young (3 months) and aged (16-24 months) rats. Aged rats had higher plasma atrial natriuretic factor levels (52 +/- 8 versus 21 +/- 6 pmol/l; p less than 0.05) than young rats. Basal atrial natriuretic factor secretory rate in vitro was greater in atria from aged rats than young rats (875 +/- 35 versus 402 +/- 22 pg/min; p less than 0.05). Atria from aged rats had an increased response to phenylephrine compared with young rats (1,687 +/- 143 versus 788 +/- 113 pg/min; p less than 0.05) when means were adjusted for basal secretory rate. The secretory response to stretch was less than that of young rats (673 +/- 37 versus 773 +/- 27 pg/min), although this difference was not significant (p = 0.07). Atrial natriuretic factor secretion in response to adrenergic stimulation is increased with aging, and these secretory responses may contribute to increased plasma levels that occur during aging. In contrast to increased adrenergic responses, atrial natriuretic factor secretion after external stretch is not increased in aging rats.     

Synthetic atrial natriuretic factor does not dilate resistance-sized arteries

The effects of synthetic atrial natriuretic factor and atriopeptin III on induced tone in resistance-sized arteries from the rat were examined in vitro. Cylindrical segments of small mesenteric or cerebral arteries were mounted on a microcannula and pressurized to a transmural pressure of 75 mm Hg. After equilibration, the level of tone in cerebral arteries was on the order of - 35 change in diameter; addition of atrial natriuretic factor or atriopeptin III in cumulative doses from 10(-10) to 10(-7) M did not produce any transient or sustained changes in diameter. Similarly, atrial natriuretic factor or atriopeptin III did not alter the contractile responses of cerebral vessels to serotonin or prostaglandin F2 alpha. Mesenteric arteries, which do not possess an intrinsic myogenic tone, were precontracted with potassium (30 mM), norepinephrine (10(-6) M), or prostaglandin F2 alpha (1.1 X 10(-5) M) and exposed to the synthetic natriuretic peptides, also without effect. Transmural electrical stimulation (0.3-msec pulses; 180 mA; 4/second) relaxed cerebral and contracted mesenteric arteries; preincubation in 10(-7) M atrial natriuretic factor or atriopeptin III did not alter subsequent responses. These observations suggest that the hypotensive action of atrial natriuretic factor cannot be attributed to direct vasodilation of splanchnic or cerebral resistance-sized arteries.     

Hemodynamic and medicamentous modification of stimulated atrial natriuretic factor secretion

The secretion of atrial natriuretic factor (ANF) and its adaptation to pharmacologic and hemodynamic interventions were investigated in 36 patients with sinus rhythm. To provoke standardized secretion of ANF all patients underwent two periods of rapid right ventricular pacing for 4 min with a 15 min interval. Immediately after the first pacing eight patients received 5 mg verapamil, 10 patients 5 mg atenolol and 10 patients 4 mg molsidomine intravenously. Eight patients remained untreated and served as controls. The amounts of atrial pressure increments due to pacing were identical (70% over basal pressure) in all patients. After molsidomine, but not after the other drugs, basal right atrial pressure was lowered. In controls the secretion of ANF due to the second stimulation was significantly (2.5-fold) larger than the secretion induced by the first stimulation. In patients receiving verapamil the secretion response after the second pacing was blunted. Atenolol did not affect the release of ANF. After molsidomine the upward regulation of the ANF secretion rate - seen in controls - was abolished. Thus, the myoendocrine cells are capable for a fast upward regulation of their ANF secretion rate after repeated stimuli. Verapamil directly blocks stimulated ANF secretion, whereas beta-blockade shows no effect. Molsidomine seems to impair enhanced ANF release by lowering basal atrial pressure.     

Verapamil impairs secretion of stimulated atrial natriuretic factor in humans

The adaptation of the secretory rate of atrial natriuretic factor to repeated adequate stimuli and the influence of the calcium antagonist verapamil on the release of atrial natriuretic factor were investigated in 16 patients. In eight patients (Group 1) right atrial pressure was abruptly increased by rapid right ventricular pacing for 4 min (stimulation I). After a 15 min interval, the identical stimulation was repeated (stimulation II). Eight patients (Group 2) underwent the same protocol but received 5 mg of verapamil intravenously after stimulation I. Pacing increased right atrial pressure in both groups identically by 70%. In Group 1, release of atrial natriuretic factor caused by the second stimulation (median 290 pg/ml over basal) was significantly (2.5-fold) larger than atrial natriuretic factor release induced by the first stimulation (median 116 pg/ml over basal). In the verapamil-treated patients (Group 2), the effect of right atrial pressure increase on release of atrial natriuretic factor was abolished after stimulation II. In both groups, changes in plasma concentrations of cyclic guanosine monophosphate corresponded to changes in atrial natriuretic factor concentrations. Thus, the myoendocrine cells are apparently capable of a fast upward regulation of their response to repeated secretory stimuli. Verapamil appears to block the stimulatory effect of a sudden increase in right atrial pressure upon release of atrial natriuretic factor.     

Role of potassium channels in stretch-promoted atrial natriuretic factor secretion

The cardiac polypeptide hormone atrial natriuretic factor (ANF) plays important roles in the regulation of blood volume and pressure. Few specific details are known about basal or stretch-promoted ANF secretion. Here, we investigated the involvement of K⁺ channels in ANF secretion based on investigations of their nature as revealed by oligonucleotide microarray analysis and on protein-protein interactions evidenced by a yeast two-hybrid approach using a heterotrimeric Gαo-1 G protein subunit, which is particularly abundant in the atrium. Based on these data, we investigated the effect of drugs known to pharmacologically affect the function of specific K⁺ channels on ANF secretion from the isolated rat atrium. These included adenosine triphosphate-sensitive K⁺ channels, TWIK-related K⁺ channel 1 (TREK-1), and the Ca⁺²-activated intermediate conductance K⁺ channel (SK4). The sulfonylurea ligands tolbutamide and repaglinide, but not glibenclamide, increased stretch-promoted ANF secretion. The channel openers diazoxide, pinacidil, and cromakalim all decreased this type of stimulated ANF secretion. TRAM 34, a specific SK4 inhibitor, and oleylamine, a nonspecific TREK-1 inhibitor, significantly decreased or increased respectively, both basal and stretch-stimulated ANF secretion. Inhibition of Gi/o by pretreatment with Pertussis toxin often significantly affected the effect of these treatments. We concluded that the atria express K⁺ channels that are related to Gi/o protein signaling and that significantly affect the endocrine function of the heart. These findings are significant for the development of therapeutic drugs with properties related to the manipulation of ANF plasma levels.     

Atrial natriuretic factor inhibits the stimulation of aldosterone secretion by angiotensin II, ACTH and potassium in vitro and angiotensin II-induced steroidogenesis in vivo

Since atrial natriuretic factor (ANF) blocks the contractile effect of angiotensin II on vascular strips, we investigated the action of the synthetic 48-73 ANF (previously called 8-33 ANF) on another target tissue of angiotensin II, the adrenal glomerulosa. ANF did not affect basal aldosterone output by isolated rat adrenal glomerulosa cells. ANF inhibited aldosterone secretion stimulated by 10(-8)M angiotensin II with an IC50 of 1.3 X 10(-9)M. Aldosterone secretion stimulated by 2.9 X 10(-10)M ACTH and by 15 mM potassium was similarly inhibited by ANF. In vivo, ANF blocked the effect of angiotensin II infused iv on aldosterone secretion in conscious unrestrained rats. We conclude that ANF is a non-selective inhibitor of stimulated aldosterone output.     

Exaggerated natriuretic response to atrial natriuretic factor in rats developing spontaneous hypertension

The present study was designed to evaluate the renal response to atrial natriuretic factor (ANF) in young rats developing spontaneous hypertension (SHR) and compare this response to age-matched, normotensive controls (WKY) and adult animals. At 6 weeks of age, intravenous infusion of ANF (0.25 micrograms/kg min) in anesthetized, euvolemic rats produced a significantly larger natriuresis and diuresis in SHR compared with WKY rats; this strain difference was not observed in rats 11 weeks of age. SHR showed no age-related change in the natriuretic response to ANF, whereas adult WKY rats exhibited a greater response than young WKY rats. To determine the effect of renal perfusion pressure on the magnitude of the renal response to ANF, additional groups of 6- and 11-week-old SHR were studied while renal perfusion pressure was lowered acutely by aortic constriction (SHR-AC) to values similar to age-matched WKY rats. In young rats, the diuretic and natriuretic response to ANF was greatest in SHR, intermediate in SHR-AC, and lowest in WKY rats. In adult animals, the natriuretic and diuretic response was similar in SHR and WKY rats and tended to be less in SHR-AC. These results in both 6- and 11-week-old SHR are consistent with previous reports that the magnitude of the response to ANF is directly related to acute changes in renal perfusion pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Distinct plasma atrial natriuretic factor, renin and aldosterone responses to prolonged high-salt intake in hypertensive and normotensive rats.

Five weeks of high (8%) sodium intake, resulting in a decline of plasma atrial natriuretic factor (ANF) in normotensive Wistar-Kyoto (WKY) and Wistar rats, did not affect plasma ANF in spontaneously hypertensive rats (SHR) which became severely hypertensive. Regardless of salt consumption, SHR presented more pronounced glomerular particulate guanylate cyclase activation after large ANF doses in vitro than normotensive rats. In response to salt loading, plasma renin activity (PRA) and plasma aldosterone unexpectedly increased in SHR, in contrast to their decrease in the normotensive strains. Thus, SHR fail to react to prolonged high-salt intake as do normotensive rats, i.e. by a fall in plasma ANF, PRA and plasma aldosterone, and have higher stimulated glomerular particulate guanylate cyclase activity. Thus, ANF and its target response in SHR, as well as the PRA-plasma aldosterone reaction to prolonged salt loading, are distinct from those in normotensive strains. Since the relatively increased ANF and its target action in SHR appear to be a reactive antihypertensive defense rather than a primary event, systems other than ANF probably play an important role in the high salt-induced accelerated hypertension of SHR.     

In vivo heterologous regulation of rat glomerular and vascular atrial natriuretic factor receptors by angiotensin II

Since glomerular and vascular atrial natriuretic factor (ANF) receptor density may vary inversely with circulating ANF concentration, and the latter may respond to changes in blood pressure, we investigated whether ANF receptors are modified by a pressor agent, angiotensin II. Rats were infused intraperitoneally for 6 days with either a non-pressor (200 ng/kg per min) or pressor dose (800 ng/kg per min) of angiotensin II. Blood pressure was higher and plasma renin activity lower in the pressor than in the non-pressor or sham-infused groups. Plasma ANF was elevated only in animals infused with a pressor dose of angiotensin II. Glomerular ANF receptor density was higher in the non-pressor (Bmax = 1308 +/- 360 fmol/mg protein) and lower in the pressor (Bmax = 459 +/- 13 fmol/mg protein) than in the sham-infused group (Bmax = 755 +/- 303 fmol/mg protein). In vitro, angiotensin II-precontracted isolated glomeruli from animals infused with a pressor dose of angiotensin II were less sensitive to the relaxant effect of low ANF concentrations (10(-12) and 10(-11) mol/l) than those receiving a non-pressor dose of angiotensin II or sham-infused. Vascular ANF receptor density was similar in the control and non-pressor groups (Bmax = 64 +/- 12 and 62 +/- 20 fmol/mg protein, respectively) and decreased in the pressor group (Bmax = 30 +/- 4 fmol/mg protein). Norepinephrine-precontracted aorta strips from rats receiving a non-pressor dose of angiotensin II were more sensitive to the relaxant effect of ANF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular atrial natriuretic factor receptors in spontaneously hypertensive rats.

OBJECTIVE: The aim was to investigate vascular receptors for atrial natriuretic factor (ANF) in spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Wistar rats (WR) at different ages. METHODS: Relaxation and guanylate cyclase responses of blood vessels to atrial natriuretic factor were investigated, as was the binding of 125I-ANF to vascular membranes and ANF receptor subtypes, using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) in reducing conditions, after solubilisation and irreversible binding of 125I-ANF. RESULTS: Vascular relaxation responses of aorta showed an increased sensitivity to ANF in four week old SHR [pD2 = 8.9 (SEM 0.1) v 8.5(0.1) in WKY rats, p < 0.05] while sensitivity was similar for the three strains at older ages. Production of cyclic GMP in mesenteric arteries in response to 100 nmol.litre-1 ANF was greater (p < 0.05) in SHR than in WKY rats at four weeks of age, but was similar in older rats. The density of binding sites for ANF in mesenteric arteries, however, was lower in SHR at four weeks (p < 0.01), and increased in older rats, becoming similar to that of normotensive rats at 12 weeks of age. Affinity of ANF sites was similar in all strains. The proportion of high and low molecular weight ANF binding peptides in solubilised blood vessel membranes on SDS-PAGE was similar in all strains except in four week old SHR, in which binding to the high molecular weight band (presumably the guanylate cyclase containing receptor) was increased relative to the low molecular weight band (non-cyclase-coupled receptor) in comparison to other strains and ages. CONCLUSIONS: Activity of guanylate cyclase in response to occupancy of ANF receptors may be increased in young SHR. Normal relaxation of blood vessels in response to ANF in older SHR could result in failure to counteract the increased vasoconstrictor activity present in these rats, which could play a role in the increase in blood pressure.     

Antihypertensive effect of synthetic atrial natriuretic factor in vasopressin-infused rats

To assess the pathophysiological role of atrial natriuretic factors in the regulation of blood pressure, we studied the effect of chronic infusion of a synthetic atrial natriuretic factor of 25 amino-acid residues on blood pressure and sodium-water excretion. Experimental subjects were rats with hypertension made by chronic infusion of vasopressin on regular intakes of sodium or on sodium loading with 1% NaCl as drinking water. When a subdepressor dose (150 micrograms/kg/day) of synthetic atrial natriuretic factor was delivered via an osmotic minipump into the jugular vein simultaneously with 7.2 U/kg/day of vasopressin infused intraperitoneally by another osmotic minipump, the expected elevation of systolic blood pressure was completely inhibited. This was not accompanied by any changes in urine volume and urinary sodium excretion. The antihypertensive effect was sustained throughout the experimental period lasting 3 days in rats on regular sodium intake (p less than 0.01) or on sodium loading with 1% NaCl as drinking water (p less than 0.01). These results indicate that a subdepressor dose of synthetic atrial natriuretic factor can modulate the vasopressor effect of vasopressin. Therefore it is suggested that an atrial natriuretic factor may be involved in the regulation of blood pressure via its antagonizing effect to vasopressin.     

The influence of resting tension on immunoreactive atrial natriuretic peptide secretion by rat atria superfused in vitro

Atrial natriuretic peptide is a potent diuretic hormone secreted by the atria in response to volume expansion. We examined the effect of resting tension on atrial natriuretic peptide secretion by rat atria superfused in vitro. Left atria were hooked between an electrode and force transducer and superfused with medium 199. The atria were studied at a pacing frequency of 0 or 3 Hz. Atrial natriuretic peptide content of the superfusate was measured by radioimmunoassay. In nonpaced and paced atria, increasing resting tension three- to five-fold caused immunoreactive atrial natriuretic peptide secretion to increase by 35 +/- 5% (mean +/- SEM, n = 6, p less than 0.01) and 30 +/- 3% (n = 4, p less than 0.01), respectively. Lowering resting tension by 50% in nonpaced and paced atria lowered immunoreactive atrial natriuretic peptide secretion by 30 +/- 3% (n = 7, p less than 0.01) and 24 +/- 3% (n = 6, p less than 0.01), respectively. To exclude the possibility that release of norepinephrine or acetylcholine from endogenous nerve endings was mediating this effect, the atria were superfused with the combination of propranolol 0.1 microM, phentolamine 1.0 microM, and atropine 10 microM. These concentrations of the antagonists were 125-fold or higher than their Kd for binding to their respective receptors. The antagonists did not block the rise in immunoreactive atrial natriuretic peptide secretion; neither did they inhibit an established rise in immunoreactive atrial natriuretic peptide secretion induced by increasing the resting tension.(ABSTRACT TRUNCATED AT 250 WORDS)