Atrial Natriuretic Peptide Secretion In Response Research Articles

Modification of levosimendan-induced suppression of atrial natriuretic peptide secretion in hypertrophied rat atria

This study aimed to determine the effects of levosimendan, a calcium sensitizer, on atrial contractility and atrial natriuretic peptide (ANP) secretion and its modification in hypertrophied atria. Isolated perfused beating rat atria were used from control and isoproterenol-treated rats. Levosimendan and its metabolite OR-1896 caused a positive inotropic effect and suppressed ANP secretion in rat atria. Similar to levosimendan, the selective phosphodiesterase 3 (PDE3) or PDE4 inhibitor also suppressed ANP secretion. Suppression of ANP secretion by 1 µM levosimendan was abolished by PDE3 inhibitor, but reversed by PDE4 inhibitor. Levosimendan-induced suppression of ANP secretion was potentiated by KATP channel blocker, but blocked by KATP channel opener. Levosimendan alone did not significantly change cyclic adenosine monophosphate (cAMP) efflux in the perfusate; however, levosimendan combined with PDE4 inhibitor markedly increased this efflux. The stimulation of ANP secretion induced by levosimendan combined with PDE4 inhibitor was blocked by the protein kinase A (PKA) inhibitor. In isoproterenol-treated atria, levosimendan augmented the positive inotropic effect and ANP secretion in response to an increased extracellular calcium concentration ([Ca+]o). These results suggests that levosimendan suppresses ANP secretion by both inhibiting PDE3 and opening KATP channels and that levosimendan combined with PDE4 inhibitor stimulates ANP secretion by activating the cAMP–PKA pathway. Modification of the effects of levosimendan on [Ca+]o-induced positive inotropic effects and ANP secretion in isoproterenol-treated rat atria might be related to a disturbance in calcium metabolism.

Effects of endothelin family on ANP secretion

The endothelins (ET) peptide family consists of ET-1, ET-2, ET-3, and sarafotoxin (s6C, a snake venom) and their actions appears to be different among isoforms. The aim of this study was to compare the secretagogue effect of ET-1 on atrial natriuretic peptide (ANP) secretion with ET-3 and evaluate its physiological meaning. Isolated nonbeating atria from male Sprague-Dawley rats were used to evaluate stretch-activated ANP secretion in response to ET-1, ET-2, ET-3, and s6C. Changes in mean blood pressure (MAP) were measured during acute injection of ET-1 and ET-3 with and without natriuretic peptide receptor-A antagonist (A71915) in anesthetized rats. Changes in atrial volume induced by increased atrial pressure from o to 1, 2, 4, or 6cm H2O caused proportional increases in mechanically-stimulated extracellular fluid (ECF) translocation and stretch-activated ANP secretion. ET-1 (10nM) augmented basal and stretch-activated ANP secretion in terms of ECF translocation, which was blocked by the pretreatment with ETA receptor antagonist (BQ123, 1μM) but not by ETB receptor antagonist (BQ788, 1μM). ETA receptor antagonist itself suppressed stretch-activated ANP secretion. As compared to ET-1- induced ANP secretion (3.2-fold by 10nM), the secretagogue effects of ANP secretion by ET-2 was similar (2.8-fold by 10nM) and ET-3 and s6C were less potent (1.7-fold and 1.5-fold by 100nM, respectively). Acute injection of ET-1 or ET-3 increased mean blood pressure (MAP), which was augmented in the presence of natriuretic peptide receptor-A antagonist. Therefore, we suggest that the order of secretagogue effect of ET family on ANP secretion was ET-1≥ET-2>>ET-3>s6C and ET-1-induced ANP secretion negatively regulates the pressor effect of ET-1.

Regulation of ANP secretion by cardiac Na+/Ca2+ exchanger using a new controlled atrial model.

The myocardial interstitium is important in regulating cardiac function. Between the atrial lumen and the pericardial space are transmural pathways, and movement of interstitial fluid (ISF) through these pathways is one of the main driving forces regulating translocation of substances from the interstitium into the blood. To define how ISF translocation from the interstitial space into the luminal space is regulated by each component of atrial hemodynamics, we devised a new rabbit atrial model in which each physical parameter could be controlled independently. Using this system, we also defined the physiological role of the cardiac Na(+)/Ca(2+) exchanger on secretion of atrial natriuretic peptide (ANP) by depletion of extracellular Na(+) ([Na(+)](o)). Increases in stroke volume and atrial end-systolic volume increased ISF translocation and ANP secretion. However, an increase in atrial rate did not influence ISF translocation but, rather, increased ANP secretion. Gradual depletion of [Na(+)](o) caused gradual increases in ANP secretion and intracellular Ca(2+) ([Ca(2+)](i)), which were blocked in the presence of Ca(2+)-free buffer and Ni(2+), but not in the presence of KB-R7943, diltiazem, mibefradil, caffeine, or monensin. Amiloride and its analog blocked an increase in ANP secretion but not an increase in [Ca(2+)](i) by [Na(+)](o) depletion. Therefore, we suggest that ANP secretion and ISF translocation may be differently controlled by each physical factor. These results also suggest that the increase in ANP secretion in response to [Na(+)](o) depletion may involve inhibition of Na(+)/Ca(2+) and Na(+)/H(+) exchangers but not an increase in [Ca(2+)](i).

Inhibition of atrial wall stretch-induced cardiac hormone secretion by lavendustin A, a potent tyrosine kinase inhibitor.

The cellular processes linking mechanical wall stretch to atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) secretion from the heart are unclear. In the present study, a paced perfused rat heart preparation was used to study the signaling mechanisms of atrial wall stretch-induced secretion of ANP and BNP. Vehicle or drugs were infused into the perfusate for 40 min and right atrial wall stretch was superimposed for 10 min after 25-min drug infusions by elevating the level of the pulmonary artery cannula tip. Lavendustin A, a potent inhibitor of protein tyrosine kinases, at the concentrations of 0.5 and 1.3 microM decreased atrial wall stretch-induced ANP secretion (53% and 68%, respectively, P < 0.001) in the perfused rat heart preparation, whereas no difference in the hemodynamic variables (heart rate, contractile force and perfusion pressure) were noted between groups. Lavendustin A also completely abolished the wall stretch-induced secretion of BNP. Several other protein kinase inhibitors including staurosporine (protein kinase C inhibitor), ML-9 (myosin light chain kinase inhibitor), KN-62 (Ca2+/calmodulin-dependent protein kinase II inhibitor) and H-89 (protein kinase A inhibitor) had no significant effect on atrial wall stretch-stimulated ANP secretion. In a separate series of experiments, in which the right atria were stretched for 2 h, administration of lavendustin A (1 microM) but not staurosporine (30 nM) significantly decreased sustained wall stretch-induced ANP secretion. Okadaic acid, a potent protein phosphatase A2 (PPA2) and PP1 inhibitor, at the concentration of 100 nM had no effect on basal ANP secretion but significantly accelerated the ANP secretory response to atrial wall stretch (P < 0.05). In conclusion, the findings that inhibitors of protein tyrosine kinase and protein phosphatase selectively modulated atrial wall stretch-induced ANP secretion suggest a new mechanism involving endogenous protein tyrosine activity in the regulation of natriuretic peptide exocytosis from cardiac myocytes.

Mechanisms of mechanical load-induced atrial natriuretic peptide secretion: role of endothelin, nitric oxide, and angiotensin II.

There are three members in the natriuretic peptide hormone family, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, brain natriuretic peptide), and C-type natriuretic peptide (CNP), that are involved in the regulation of blood pressure and fluid homeostasis. CNP is found principally in the central nervous system and vascular endothelial cells while ANP and BNP are cardiac hormones. ANP is synthesized mainly in the atria of the normal adult heart, while BNP is produced by both the atria and ventricles. The mechanisms controlling ANP release have been the subject of intense research, and are now fairly well understood. The major determinant of ANP secretion is myocyte stretch. Although much less is known about the factors regulating BNP release from the heart, myocyte stretch has also been reported to stimulate BNP release from both atria and ventricles. However, whether wall stretch acts directly or via factors such as endothelin- , nitric oxide, or angiotensin II liberated in response to distension has not been established. Recent studies show that by stimulating endothelin type A receptors endothelin plays an important physiological role as a mediator of acute-volume load-induced ANP secretion from atrial myocytes in conscious animals. In fact, endogenous paracrine/autocrine factors liberated in response to atrial wall stretch rather than direct stretch appears to be responsible for activation of ANP secretion in response to volume load, as evidenced by almost complete blockade of ANP secretion during combined inhibition of endothelin type A/B and angiotensin II receptors. Furthermore, under certain experimental conditions angiotensin II and nitric oxide may also exert a significant modulatory effect on stretch-activated ANP secretion. The molecular mechanisms by which endothelin-1, angiotensin II, and nitric oxide synergistically regulate stretch-activated ANP release are yet unclear.

Alterations in atrial natriuretic peptide (ANP) secretion and renal effects in aging.

Aging is associated with hypertension and electrolyte disturbances. The purpose of this study was to determine the effect of aging upon secretion and renal actions of atrial natriuretic peptide (ANP). Rats were anesthetized and received tracheal, jugular vein, carotid artery, and bilateral uretheral catheterization. One set of young (2-3 mo) rats (Group 2, n = 9) and one set of old (18-21 mo) rats (Group 4, n = 7) received bilateral atrial appendectomies. Control young (Group 1, n = 8) and old (Group 3, n = 8) rats received a sham appendectomy. All rats were infused (iv) with 6% albumin in Krebs buffer, sufficient to increase blood volume by 15%. Finally, each rat was injected with ANP (1 microgram/kg). Sodium excretion rate (U(Na+)V) in response to volume expansion was significantly decreased in all groups compared to Group 1 (young control, p < .05). All groups demonstrated a striking increase in U(Na+)V with the ANP injection, but the response was greatest in young control rats when factored by body weight (p < .05). There were no significant differences in MAP between the groups, suggesting that the differences in U(Na+)V observed were not the result of hemodynamic factors. Isolated perfused atria from young (n = 9) and old (n = 8) rats were subjected to stretch and endothelin stimulation (50 nM). Atria from young rats showed a dramatic increase in ANP secretion in response to atrial stretch and a further marked increase in secretion in response to endothelin, whereas both of these responses were markedly attenuated in old rats (p < .05). These results suggested that the secretion and renal effects of ANP are impaired in aging. Changes in secretion and actions of ANP in aging could contribute to the development of hypertension or heart failure.

Regulation of ANP secretion by endothelin-1 in cultured atrial myocytes: desensitization and receptor subtype.

We examined endothelin-1 (ET-1) binding and ET-1-regulated atrial natriuretic peptide (ANP) secretion in primary cultures of adult rat atrial myocytes. ET-1 binding was analyzed as a reversible bimolecular reaction, with bimolecular association rate constant = 1.9 x 10(9) M-1.h-1, dissociation rate constant = 0.028 h-1, and a dissociation constant, calculated from these values = 0.015 nM. ET-1 increased ANP secretion with a one-half effective concentration (EC50) of 0.62 nM, which correlated with EC50 receptor occupancy under equivalent experimental conditions (0.75 nM). The secretory response rapidly desensitized (half-time = 10 min at 10 nM ET-1). The time courses for ET-1 binding, ET-1-stimulated secretion, and desensitization were all comparable. Recovery from desensitization was slow and paralleled the recovery of 125I-labeled ET-1 binding. The ETA receptor subtype-selective antagonist, BQ-123, inhibited 125I-ET-1 binding and ET-1-activated ANP secretion with high affinity, whereas the ETB-selective agonists, endothelin-3 and sarafotoxin S6c, inhibited binding with low affinity and did not effectively stimulate ANP secretion. We conclude that 1) ET-1 can stimulate ANP secretion by direct action on the atrial myocytes; 2) primary cultures of adult rat atrial myocytes express only the ETA receptor subtype; 3) the ANP secretory response to ET-1 desensitizes rapidly but recovers slowly; and 4) occupation of the ETA receptors by ET-1 initiates the unidirectional sequence of receptor activation, signal transduction, ANP secretion, and finally, desensitization.

Calcium dependency of frequency-stimulated atrial natriuretic peptide secretion.

In this study we examined the mechanism whereby atrial natriuretic peptide secretion is increased when the frequency of contraction is raised from 2 to 5 Hz. We tested the hypothesis that calcium plays a significant role in the frequency-stimulated response. Using superfused rat left atria, we found that lowering the superfusate calcium concentration from 1.8 to 0.2 mmol/L abolished the frequency-stimulated atrial natriuretic peptide secretory response. Superfusion with ryanodine (1 mumol/L), an inhibitor of sarcoplasmic reticulum calcium release, resulted in a minimal inhibitory effect. Superfusion with 50 mumol/L nitrendipine or 10 mumol/L diltiazem inhibited the frequency-stimulated response by 46% to 48%. The lack of total inhibition suggested that an additional mechanism of calcium influx was involved, namely, inward calcium movement carried by Na(+)-Ca2+ exchange. As intracellular sodium has been reported to rise with an increase in beat frequency, a fall in the sodium gradient would favor inward calcium movement by Na(+)-Ca2+ exchange. Because we could not directly assess the role of Na(+)-Ca2+ exchange in this experimental paradigm, we examined the effect of lowering the transmembrane sodium gradient on atrial natriuretic peptide secretion by superfusion with the sodium channel activator veratridine or the sodium ionophore monensin. Superfusion with 1 mumol/L veratridine increased atrial natriuretic peptide secretion by 2.3-fold, and 1, 5, and 10 mumol/L monensin increased secretion by 1.1-, 2.1-, and 15.7-fold, respectively. In addition, we examined the possibility that the reported rise in intracellular sodium associated with increased beat frequency was due to enhanced Na(+)-H+ antiporter activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of ryanodine on atrial natriuretic peptide secretion by contracting and quiescent rat atrium.

To elucidate the mechanism involved in the release of atrial natriuretic peptide (ANP), we studied the importance of ryanodine-sensitive Ca2+ release in stretch-secretion coupling. The experiments were made with a left atrial preparation, where the stretch of myocytes was induced by changing the intra-atrial pressure. When external pacing was not applied, the atrial preparation was not spontaneously contracting, and it was therefore possible to investigate the secretory mechanism in the quiescent atrium. The superfusate was collected in 2-min fractions and assayed for ANP immunoreactivity. Filtration analysis revealed that the major fraction in the superfusate in all experimental situations had a similar molecular weight as the ANP 1-28. Ryanodine (1.0 microM and 0.1 microM) inhibited stretch-stimulated ANP secretion dose dependently both in paced and non-paced atrium, but did not have any effect on basal secretion. The present results support the notion that intracellular Ca2+ transients from the intracellular stores are essential for stretch-stimulated ANP secretion, independently from excitation and contraction. Basal ANP secretion is not inhibited by blocking ryanodine-sensitive Ca2+ channels, either in contracting or in non-contracting atria. In addition our results confirm that the principal stimulus for ANP secretion in response to atrial distension is the stretch of myocytes. Length shortening of myocytes is not essential for ANP release.

Mechanisms of isoproterenol-induced atrial natriuretic peptide release from superfused rabbit atria.

The mechanisms for isoproterenol-induced atrial natriuretic peptide (ANP) release were studied in superfused rabbit sliced right atria. Addition of 1 microM norepinephrine to this preparation induced a significant monophasic twofold rise in ANP release. This effect was abolished by 1 microM propranolol and mimicked by 1 microM isoproterenol. Furthermore, addition of 200 microM 3-isobutyl-1-methylxanthine (IBMX) to the superfusing medium potentiated isoproterenol effect 31%. In addition, superfusion of slices with 0.5 mM N6,2-O-dibutyryladenosine 3',5'-cyclic monophosphate [(Bu)-2cAMP] enhanced ANP release in the same manner as the beta-agonist. After isoproterenol stimulation, adenosine 3',5'-cyclic monophosphate (cAMP) concentration in effluents increased significantly. ANP secretory response to isoproterenol was unaffected by extracellular calcium concentration or 1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). Finally, 10 microM indomethacin significantly reduced isoproterenol-stimulated ANP release. It is concluded that 1) norepinephrine-induced ANP release is mediated by its beta-agonist activity, 2) isoproterenol-stimulated release appears to be mediated by cAMP, 3) isoproterenol effect does not require extracellular calcium, and 4) prostaglandins may be involved in this beta-adrenergic effect.

Hypoxia-induced ANP secretion in subjects susceptible to high-altitude pulmonary edema

We investigated the effects of acute hypoxia (10% O 2) on plasma level of atrial natriuretic peptide (ANP) and pulmonary hemodynamics in five subjects with a history of high-altitude pulmonary edema (HAPE). Plasma renin activity and plasma levels of aldosterone, epinephrine and norepinephrine were also measured. The plasma ANP levels in HAPE-susceptible subjects rose significantly in response to 10% O 2 (from 34.8 ± 5.4 to 51.4 ± 7.3 pg·ml −1; P < 0.05), not associated with any increase in either atrial pressure. Compared with six control subjects, the rise of ANP level was greater in HAPE-susceptible subjects (16.6 ± 4.4 vs 3.9±1.2 pg·ml −1; P < 0.05). There was a significant positive correlation between the rise of ANP level and the increase of pulmonary arterial pressure. No significant difference was observed in any of other hormonal responses to acute hypoxia between the two groups. We interpret these results as indicating that the ANP secretory response to acute hypoxia in HAPE-susceptible subjects, which is not mediated by an increase in atrial pressure, may be greater than that in nonsusceptible subjects in association with a greater pressor response of pulmonary circulation.

Interaction between stretch and hormonally stimulated atrial natriuretic peptide secretion.

Atrial stretch and paracrine hormones stimulate atrial natriuretic peptide (ANP) secretion. The potential interplay between atrial stretch and paracrine hormones was examined. Isolated superfused rat left atria paced at 4 Hz were used for study. The effects of 0, 0.5, and 1.5 g settings of initial tension on the ANP secretory response to 1 microM norepinephrine and 10 nM endothelin were examined. The peak ANP secretory responses expressed as a percent of baseline for each of the tension settings were 109 +/- 8, 132 +/- 6, and 171 +/- 10% for norepinephrine and 285 +/- 15, 294 +/- 12, and 368 +/- 19 for endothelin, respectively. The effects of 0.5 microM norepinephrine, 1 nM endothelin, and 100 nM vasopressin on stretch-stimulated secretion were examined. Norepinephrine and endothelin increased ANP secretion 144 +/- 16 and 136 +/- 2% above baseline, respectively. Vasopressin did not increase ANP secretion. Norepinephrine and vasopressin did not significantly influence the ANP secretory response to stretch. In contrast, endothelin increased the response to stretch by 33% (P less than 0.035). We conclude 1) the greater the degree of atrial stretch, the greater is the response to norepinephrine and endothelin; 2) endothelin enhances the secretory response to stretch; and 3) norepinephrine and vasopressin do not affect stretch-stimulated release. These results predict a greater ANP secretory response to hormonal stimulation in vivo in volume-expanded states.

Parathyroid hormone modulates the release of atrial natriuretic peptide during acute volume expansion.

In this study we investigated the effect of volume expansion on plasma and atrial concentrations of atrial natriuretic peptide (ANP) in the presence and absence of the parathyroid gland and under normocalcemic and hypocalcemic conditions. After volume expansion ANP concentration in plasma was significantly (p < 0.001) higher in intact (702 +/- 86 pg/ml) than in hypocalcemic parathyroidectomized (PTX) (271 +/- 38 pg/ml) rats. Plasma ANP of PTX rats rendered normocalcemic with oral calcium supplementation increased to 402 +/- 85 pg/ml after volume expansion. Results from this study suggest that parathyroid hormone (PTH) is required for augmented ANP secretion in response to acute volume loading and alterations of extracellular calcium may modulate volume-induced ANP release in PTX rats. We would discuss that a parathyroid gland-cardiac atria interaction exists and that changes in serum level of PTH may play a role in the regulation of fluid homeostasis via ANP secretion.

Endothelin: A Potent Stimulus of Atrial Natriuretic Peptide Secretion by Superfused Rat Atria and Its Dependency on Calcium*

Endothelin, a hormone secreted by endothelial cells, has potent vasoconstrictive properties. Due to its potential paracrine nature, we examined the effect of endothelin-I on atrial natriuretic peptide (ANP) secretion in vitro. Isolated superfused rat left atria, paced at 2 Hz, were used for study. Endothelin (1-100 nM) increased ANP secretion in a dose-dependent manner from 1.6- to 6.7-fold above baseline. Spontaneously beating right atria increased ANP secretion by 2.3-fold in response to 10 nM endothelin without a change in beat frequency. However, the right atrial ANP secretory response was less than the 3.8-fold increase seen by left atria, and the time to peak response was slower. The calcium dependency of endothelin-stimulated ANP secretion was examined using paced left atria. The dependency of endothelin-stimulated secretion on calcium influx was examined by lowering the superfusate calcium from 1.8 to 0.2 mM. The ANP secretory response to 10 nM endothelin was reduced by 65% with 0.2 mM calcium. Influx of calcium through voltage-dependent calcium channels was examined by superfusion with 50 microM nitrendipine. Nitrendipine decreased endothelin-stimulated ANP secretion by 51% without affecting endothelin binding. The role of intracellular calcium release from the sarcoplasmic reticulum (SR) was examined by superfusion with 1 microM ryanodine, an inhibitor of SR calcium release. Ryanodine had no effect on endothelin-stimulated ANP secretion. We conclude: 1) Endothelin is a potent stimulus of ANP secretion in vitro. 2) The relative secretory response of right atria to endothelin expressed as a function of basal secretion is less and the time to peak secretion delayed relative to left atria. 3) Enhanced calcium influx, primarily through voltage-dependent calcium channels, plays a significant role in endothelin-stimulated secretion. 4) Release of intracellular calcium from the SR does not participate in the secretory response. 5) Part of the stimulatory signal appears to be independent of calcium influx or intracellular calcium release. Thus, endothelin may be an important secretagogue or modulator of ANP secretion in vivo; however, its physiological role in regulating ANP secretion in vivo remains to be determined.

Atrial Natriuretic Peptide in Plasma, Atria, Ventricles, and Hypothalamus of Long-Evans and Vasopressin- Deficient Brattleboro Rats*

To evaluate the role of vasopressin in the regulation of atrial natriuretic peptide (ANP) secretion, the plasma, atrial, ventricular, and hypothalamic levels of ANP were measured in Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. Total atrial immunoreactive ANP (IR-ANP) as well as right auricular IR-ANP concentration were higher in the DI than in the LE rats, whereas no significant difference was noted in left auricular IR-ANP concentration. In the left ventricle of DI rats, the IR-ANP concentration was 82% greater than that in the LE rats, while no substantial difference was found in the right ventricular IR-ANP concentration between the strains. Normal LE rats had low levels of left ventricular ANP mRNA and barely detectable ANP mRNA in the right ventricle, DI rats showed a 3-fold greater ANP mRNA concentration in the left ventricle than age-matched LE controls, and ANP mRNA levels were also increased in the left auricle of DI rats. The hypothalamic IR-ANP content, but not the concentration, was significantly increased in the DI compared to the LE rats. Despite increased cardiac IR-ANP and ANP mRNA levels, plasma IR-ANP concentrations were similar in the conscious DI rats (97 +/- 9 pg/ml; n = 13) and the LE rats (95 +/- 8 pg/ml; n = 15). Volume expansion (1.1 ml/100 g BW of 0.9% saline, iv) increased right atrial pressure and caused a significant rise in plasma IR-ANP in both strains (P less than 0.01). Elevations of plasma IR-ANP concentrations caused by volume loading were comparable in LE and DI rats in either the absence or presence of exogenous vasopressin (5 ng/kg.min, iv), which, when infused alone, did not significantly influence the plasma IR-ANP concentration. However, the relation between the change in IR-ANP concentration and the change in right atrial pressure shifted to the left, and thus, for a given increase in right atrial pressure, a greater amount of IR-ANP was released in the vasopressin-treated rats than in the control animals. These results demonstrate that although acute volume expansion does not necessarily require endogenous vasopressin for the ANP secretory response, vasopressin increased the ability of volume expansion to induce ANP release, thus modulating the direct mechanical stimulus-induced ANP secretion. The increased left ventricular levels of immunoreactive ANP and augmentation of ANP mRNA levels in Brattleboro rats despite normal left ventricular weight to body weight ratio show that increased ANP gene expression may occur in the ventricles independently of hypertrophy.

Effect of adrenergic and muscarinic cholinergic agonists on atrial natriuretic peptide secretion by isolated rat atria. Potential role of the autonomic nervous system in modulating atrial natriuretic peptide secretion.

Stretching of the atrial wall is a known stimulant for atrial natriuretic peptide (ANP) secretion. Little is known about other factors that may influence ANP secretion. We examined the effects of the neurotransmitters of the autonomic nervous system on ANP secretion from isolated rat left atria. Superfusion with 10 muM norepinephrine produced a biphasic rise in ANP secretion with a peak response 2.5-fold above baseline secretion. To determine whether the response to norepinephrine primarily reflected alpha- or beta-adrenergic receptor stimulation, atria were superfused with 0.1 muM isoproterenol or 10 muM phenylephrine and 1 muM propranolol. ANP secretion in response to isoproterenol was biphasic, similar to the response to norepinephrine. Phenylephrine evoked a monophasic ANP secretory response, which was delayed in onset relative to that of isoproterenol or norepinephrine. Superfusion with 10 muM methacholine alone had no effect on ANP secretion, but rapidly attenuated norepinephrine-stimulated secretion by 67%. From these observations we conclude: (a) Both alpha- and beta-adrenergic agonists directly and distinctively stimulate ANP secretion; (b) Norepinephrine stimulates ANP secretion by both alpha- and beta-adrenergic mechanisms, however the secretory response pattern of norepinephrine reflects a predominence of beta-adrenergic activity; (c) Under basal conditions, methacholine does not influence ANP secretion; and (d) Methacholine inhibits norepinephrine-stimulated ANP secretion. Thus, in vivo, activation of the sympathetic nervous system may enhance ANP secretion, whereas a rise in parasympathetic tone may lower ANP secretion.