Increased Plasma Atrial Natriuretic Peptide Research Articles

Effect of Cardiac Tamponade on Plasma Concentrations of Atrial Natriuretic Peptide (ANP) in Calves

To study the effect of cardiac tamponade on plasma concentrations of atrial natriuretic peptide (ANP) female calves received an infusion of 450 ml of 0.9% saline into the pericardial space. This was accompanied by a parallel rise in both, right atrial pressure (from 4.5 +/- 2.6 mm Hg to 14.1 +/- 3.8 mm Hg (p less than 0.01] and in intrapericardial pressure (from 0.4 +/- 2.0 mm Hg to 12.9 +/- 3.9 mm Hg (p less than 0.01] and a fall in cardiac output from 11.4 +/- 1.9 l/min to 8.5 +/- 2.4 l/min (p less than 0.01). Plasma concentrations of ANP remained unchanged in 7 of 9 experiments. During these seven experiments plasma concentrations of renin and aldosterone increased from 0.65 +/- 0.27 X 10 E-4 GU/ml to 1.04 +/- 0.43 X 10 E-4 GU/ml (p less than 0.01) and from 2.7 +/- 0.9 ng/dl to 11.4 +/- 6.1 ng/dl (p less than 0.01), respectively. On two occasions, which were characterized by an excessive fall in cardiac output (to less than 40% of initial values) cardiac tamponade was followed by an extensive rise in the plasma concentrations of ANP, renin and aldosterone. These results indicate that an increase in intra-atrial pressure per se is not the decisive factor in the control of ANP secretion. Since atrial transmural pressure does not change during cardiac tamponade ANP concentrations are, as a rule, unaltered by that condition. An increase in plasma ANP is seen only during preshock hemodynamic conditions possibly due to a reduced intra-atrial volume.

Atrial natriuretic peptide (ANP) in preeclampsia-like syndrome in a rat model.

The pathophysiology of preeclampsia has not been fully clarified. A variety of factors have been implicated with this disease including vasoactive peptides and hormones during the last 20 years. Inadequate generation of atrial natriuretic peptide (ANP) has been one of the mechanisms discussed as to possibly contribute to the development of hypertension. In human pregnancy multiple studies of ANP-plasma-concentration in normal or hypertensive pregnancies showed conflicting results. The complexity of the clinical findings of hypertension in pregnancy makes it very difficult to carry out comparative clinical and biochemical studies in humans. In an animal experience genetic as environmental influences could be excluded. Therefore, the present study shows an experimental preeclampsia-like syndrome in the rat by reduction of the utero-placental flow. We observed a significant increase of plasma ANP in pregnant rats with experimentally induced hypertension. Furthermore, our results suggest that the ventricles could be an important source of ANP gene expression.

Endogenous Cardiotonic Steroids and Differential Patterns of Sodium Pump Inhibition in NaCl-Loaded Salt-Sensitive and Normotensive Rats

Endogenous sodium pump inhibitors promote sodium excretion in normotensives and contribute to vasoconstriction in NaCl-sensitive hypertension. Marinobufagenin (MBG), an endogenous bufadienolide inhibitor of alpha-1 sodium pump, contributes to hypertension in Dahl salt-sensitive rats (DS). We hypothesized that in NaCl-loaded DS and normotensive Sprague-Dawley rats (S-D), MBG would elicit different patterns of sodium pump inhibition. We compared systolic blood pressure (SBP), renal sodium excretion, activity of the sodium pump in aorta and renal medulla, and levels of MBG, atrial natriuretic peptide (ANP), and cyclic guanosine monophosphate (cGMP) in salt-loaded DS and S-D (20% NaCl, 2.5 ml/kg, intraperitoneally). NaCl loading produced sustained elevations in renal MBG excretion in both DS (2.41 +/- 0.24 vs. 0.79 +/- 0.08 pmol/h/kg, P < 0.01) and S-D (1.97 +/- 0.37 vs. 0.60 +/- 0.07 pmol/h/kg, P < 0.01) vs. that at baseline (n = 10 for each group). In NaCl-loaded DS, SBP rose by 18 mm Hg (P < 0.01) and aortic sodium pump was inhibited by 22% (P < 0.05 vs. control), while in S-D, SBP and activity of aortic sodium pump did not change. NaCl-loaded S-D excreted twice as much sodium as DS; in S-D, renal sodium pump was inhibited by 24% vs. 14% inhibition in DS (P < 0.05). NaCl loading elicited increases in plasma ANP and in renal cGMP excretion in S-D but not in DS. Our present observations demonstrate that in NaCl-loaded S-D and DS, a comparable MBG response is associated with preferential inhibition of the sodium pump in the kidney and in vascular smooth muscle, respectively, resulting in an adaptive natriuresis in S-D but sodium retention and pressor response in DS.

Normotensive sodium loading in normal man: regulation of renin secretion during β-receptor blockade

Saline administration may change renin-angiotensin-aldosterone system (RAAS) activity and sodium excretion at constant mean arterial pressure (MAP). We hypothesized that such responses are elicited mainly by renal sympathetic nerve activity by beta1-receptors (beta1-RSNA), and tested the hypothesis by studying RAAS and renal excretion during slow saline loading at constant plasma sodium concentration (Na+ loading; 12 micromol Na+.kg(-1).min(-1) for 4 h). Normal subjects were studied on low-sodium intake with and without beta1-adrenergic blockade by metoprolol. Metoprolol per se reduced RAAS activity as expected. Na+ loading decreased plasma renin concentration (PRC) by one-third, plasma ANG II by one-half, and plasma aldosterone by two-thirds (all P < 0.05); surprisingly, these changes were found without, as well as during, acute metoprolol administration. Concomitantly, sodium excretion increased indistinguishably with and without metoprolol (16 +/- 2 to 71 +/- 14 micromol/min; 13 +/- 2 to 55 +/- 13 micromol/min, respectively). Na+ loading did not increase plasma atrial natriuretic peptide, glomerular filtration rate (GFR by 51Cr-EDTA), MAP, or cardiac output (CO by impedance cardiography), but increased central venous pressure (CVP) by approximately 2.0 mmHg (P < 0.05). During Na+ loading, sodium excretion increased with CVP at an average slope of 7 micromol.min(-1).mmHg(-1). Concomitantly, plasma vasopressin decreased by 30-40% (P < 0.05). In conclusion, beta1-adrenoceptor blockade affects neither the acute saline-mediated deactivation of RAAS nor the associated natriuretic response, and the RAAS response to modest saline loading seems independent of changes in MAP, CO, GFR, beta1-mediated effects of norepinephrine, and ANP. Unexpectedly, the results do not allow assessment of the relative importance of RAAS-dependent and -independent regulation of renal sodium excretion. The results are compatible with the notion that at constant arterial pressure, a volume receptor elicited reduction in RSNA via receptors other than beta1-adrenoceptors, decreases renal tubular sodium reabsorption proximal to the macula densa leading to increased NaCl concentration at the macula densa, and subsequent inhibition of renin secretion.

Normotensive sodium loading in conscious dogs: regulation of renin secretion during β-receptor blockade

Renin secretion is regulated in part by renal nerves operating through beta1-receptors of the renal juxtaglomerular cells. Slow sodium loading may decrease plasma renin concentration (PRC) and cause natriuresis at constant mean arterial blood pressure (MAP) and glomerular filtration rate (GFR). We hypothesized that in this setting, renin secretion and renin-dependent sodium excretion are controlled by via the renal nerves and therefore are eliminated or reduced by blocking the action of norepinephrine on the juxtaglomerular cells with the beta1-receptor antagonist metoprolol. This was tested in conscious dogs by infusion of NaCl (20 micromol.kg(-1).min(-1) for 180 min, NaLoad) during regular or low-sodium diet (0.03 mmol.kg(-1).day(-1), LowNa) with and without metoprolol (2 mg/kg plus 0.9 mg.kg(-1).h(-1)). Vasopressin V2 receptors were blocked by Otsuka compound OPC31260 to facilitate clearance measurements. Body fluid volume was maintained by servocontrolled fluid infusion. Metoprolol per se did not affect MAP, heart rate, or sodium excretion significantly, but reduced PRC and ANG II by 30-40%, increased plasma atrial natriuretic peptide (ANP), and tripled potassium excretion. LowNa per se increased PRC (+53%), ANG II (+93%), and aldosterone (+660%), and shifted the vasopressin function curve to the left. NaLoad elevated plasma [Na+] by 4.5% and vasopressin by threefold, but MAP and plasma ANP remained unchanged. NaLoad decreased PRC by approximately 30%, ANG II by approximately 40%, and aldosterone by approximately 60%, regardless of diet and metoprolol. The natriuretic response to NaLoad was augmented during metoprolol regardless of diet. In conclusion, PRC depended on dietary sodium and beta1-adrenergic control as expected; however, the acute sodium-driven decrease in PRC at constant MAP and GFR was unaffected by beta1-receptor blockade demonstrating that renin may be regulated without changes in MAP, GFR, or beta1-mediated effects of norepinephrine. Low-sodium diet augments vasopressin secretion, whereas ANP secretion is reduced.

Pharmacokinetic and pharmacodynamic effects of midodrine on blood pressure, the autonomic nervous system, and plasma natriuretic peptides: a prospective, randomized, single-blind, two-period, crossover, placebo-controlled study

Background: Midodrine is an α-agonist prodrug of desglymidodrine (DGM) that has been reported to be of clinical benefit in patients with neurocardiogenic syncope. Its effects may be mediated not only by its hypertensive properties but also by its neurohumoral influences independent of blood pressure (BP). Objective: The present study aimed to simultaneously characterize the effects of midodrine on BP, plasma catecholamines, plasma atrial natriuretic peptide (ANP), and power spectral analysis of heart rate (HR) in healthy volunteers. Methods: This was a prospective, randomized, single-blind, 2-period, crossover study in which a single, oral, 5-mg dose of midodrine was compared with placebo. The washout period between midodrine and placebo was 1 week. The study parameters included plasma DGM (as measured by high-performance liquid chromatography [HPLC]); systolic and diastolic BP (as measured with an oscillometric monitor); HR; plasma catecholamines (measured by HPLC); plasma ANP, also known as venous return (measured by a radio-immunoassay); and low- and high-frequency HR variation (calculated from computerized 5-minute electrocardiographic recordings). All study parameters were measured simultaneously 12 times just before and over a period of 8 hours after drug administration. Results: Fifteen healthy nonsmoking male subjects (14 white, 1 black; mean [SD] age, 28.6 [4.7] years; weight, 74.5 [16.4] kg; seated BP, 109.9 [9.0]/73.6 [9.5] mm Hg; seated HR, 63.8 [8.4] bpm) were randomized. No significant effects of midodrine on BP were observed. At C max, midodrine decreased norepinephrine from 188.4 (30.6) to 162.5 (29.8) pg/mL ( P = 0.011) and HR from 57.2 (7.3) to 54.9 (6.6) bpm ( P = 0.022). A significant correlation was found between DGM concentration and HR ( ϕ -0.61; P = 0.014). A DGM-related increase in plasma ANP (+29.6 [90.0] fmoL/mL) was observed. Conclusion: This study in healthy male volunteers found that midodrine has sympatholytic influences that are independent of BP but related to augmented venous return.

Glucocorticoid modulation of atrial natriuretic peptide, oxytocin, vasopressin and Fos expression in response to osmotic, angiotensinergic and cholinergic stimulation

The regulation of fluid and electrolyte homeostasis involves the participation of several neuropeptides and hormones that utilize hypothalamic cholinergic, alpha-adrenergic and angiotensinergic neurotransmitters and pathways. Additionally, it has been suggested that hypothalamus–pituitary–adrenal axis activity modulates hormonal responses to blood volume expansion. In the present study, we evaluated the effect of dexamethasone on atrial natriuretic peptide (ANP), oxytocin (OT) and vasopressin (AVP) responses to i.c.v. microinjections of 0.15 M and 0.30 M NaCl, angiotensin-II (ANG-II) and carbachol. We also evaluated the Fos protein immunoreactivity in the median preoptic (MnPO), paraventricular (PVN) and supraoptic (SON) nuclei. Male Wistar rats received an i.p. injection of dexamethasone (1 mg/kg) or vehicle (0.15 M NaCl) 2 h before the i.c.v. microinjections. Blood samples for plasma ANP, OT, AVP and corticosterone determinations were collected at 5 and 20 min after stimulus. Another set of rats was perfused 120 min after stimulation. A significant increase in plasma ANP, OT, AVP and corticosterone levels was observed at 5 and 20 min after each central stimulation compared with isotonic saline–injected group. Pre-treatment with dexamethasone decreased plasma corticosterone and OT levels, with no changes in the AVP secretion. On the other hand, dexamethasone induced a significant increase in plasma ANP levels. A significant increase in the number of Fos immunoreactive neurons was observed in the MnPO, PVN and SON after i.c.v. stimulations. Pre-treatment with dexamethasone induced a significant decrease in Fos immunoreactivity in these nuclei compared with the vehicle. These results indicate that central osmotic, cholinergic, and angiotensinergic stimuli activate MnPO, PVN and SON, with a subsequent OT, AVP, and ANP release. The present data also suggest that these responses are modulated by glucocorticoids.

Carvedilol Increases Atrial Natriuretic Peptide Plasma Levels in Hypertensive Patients

Twenty five patients with moderate essential hypertension were studied for 30 days in order to evaluate the medium term effects of carvedilol on atrial natriuretic peptide (ANP) levels. This drug blocks the β1 and β2 adrenenergic receptors as well as α1 adrenergic receptors. In addition, it has strong antioxidative and antiproliferative properties. The drug was given orally at a dose of 12.5 mg b.i.d. Quantitative determination of human ANP was made by radioimmunoassay procedure (RIA). At the end of this clinical trial, mean plasma levels of ANP had risen during treatment by 21.18% (from 37.60 pg/ml to 45.83 pg/ml) while both systolic (SBP) and diastolic (DBP) blood pressure as well as diameters of the left cardiac cavities had decreased in a statistically significant way. The ratio ANP/SBP was also increased by 46.6% in a statistically significant way. These findings support the suggestion that the increase in plasma ANP following the administration of β-adrenergic blockers to hypertensive patients is a primary effect of beta blockade and not a mechanical one secondary to a negative inotropic action on the left ventricle and obviously contributes to the anti-hypertensive action.

Overexpression of kidney neutral endopeptidase (EC 3.4.24.11) and renal function in experimental cirrhosis

Neutral endopeptidase degrades atrial natriuretic peptide (ANP) and bradykinin and may generate endothelin-1 from big-endothelin. In advanced cirrhosis, sodium retention is accompanied by elevated plasma ANP levels, and infusion of ANP causes hypotension, but in normal humans increasing the concentration of ANP through the inhibition of neutral endopeptidase, localized in renal proximal tubule cells, causes natriuresis without any arterial pressure drop. The purpose of this study was the assessment of kidney neutral endopeptidase expression and responses to candoxatrilat (a specific inhibitor of this enzyme) in rats with CCl4-induced cirrhosis. Two groups of control rats (n = 5) were injected with vehicle or 3 mg/kg candoxatrilat. Three groups of cirrhotic rats with ascites (n = 10) received vehicle alone or 3 or 10 mg/kg candoxatrilat. In cirrhotic rats, Western blot analysis revealed a 170% increase in renal neutral endopeptidase protein content (P < 0.03), mainly in the proximal nephron and macula densa, and both candoxatrilat dosages increased plasma ANP levels, urinary volume, and urinary excretion of sodium, ANP, and cGMP compared with vehicle alone (all P < 0.03). Candoxatrilat (10 mg/kg) also reduced tubular solute-free water reabsorption (P < 0.03) in cirrhotic rats, but renal blood flow, arterial pressure, and plasma renin activity were unaffected. Neutral endopeptidase inhibition has natriuretic and aquaretic actions in cirrhosis without any effect on blood pressure and kidney perfusion due to a significant overexpression of this enzyme in renal cortex.

Interactions between atrial natriuretic peptide and the renin–angiotensin system during salt-sensitivity exhibited by the proANP gene-disrupted mouse

To understand the involvement of the systemic and cardiac components of the renin-angiotensin system (RAS) in the development of cardiac hypertrophy induced by salt intake, the present study analyzed the effect of high dietary salt (8.0% NaCl) in mice possessing a full complement (+/+) or ablation (-/-) of atrial natriuretic peptide (ANP). A 3 week treatment of 8.0% NaCl was able to induce cardiac hypertrophy in both genotypes, though exaggerated hypertrophy was noted in the ANP -/- mouse. Although a marked decrease in angiotensin II (Ang II) plasma levels in both genotypes fed a high salt diet was observed, systemic RAS mRNA components were altered only in the ANP-/- animals and remained unchanged in ANP+/+ mice. Decreased Ang II plasma levels were better correlated with decreases in angiotensinogen protein expression observed in both genotypes. High salt had no effect on cardiac RAS mRNA components in the ANP-/- animals, but did cause a significant decrease in some cardiac RAS mRNA components in ANP+/+ mice. As expected, high salt was able to increase plasma ANP levels and ventricular mRNA expression of ANP (ANP+/+ mice only) and B-type NP in both genotypes. The latter peptides are key cardiac markers of hypertrophy whose increased expression correlate well with the physical salt-induced cardiac alterations observed in this study. These findings suggest that although the RAS does not play a key role in salt-induced cardiac hypertrophy, ANP is an important determinant of the degree of salt-sensitivity observed in the proANP gene-disrupted animal.

Urinary responses to acute moxonidine are inhibited by natriuretic peptide receptor antagonist

We have previously shown that acute intravenous injections of moxonidine and clonidine increase plasma atrial natriuretic peptide (ANP), a vasodilator, diuretic and natriuretic hormone. We hypothesized that moxonidine stimulates the release of ANP, which would act on its renal receptors to cause diuresis and natriuresis, and these effects may be altered in hypertension. Moxonidine (0, 10, 50, 100 or 150 microg in 300 microl saline) and clonidine (0, 1, 5 or 10 microg in 300 microl saline) injected intravenously in conscious normally hydrated normotensive Sprague-Dawley rats (SD, approximately 200 g) and 12-14-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) dose-dependently stimulated diuresis, natriuresis, kaliuresis and cGMP excretion, with these effects being more pronounced during the first hour post-injection. The actions of 5 microg clonidine and 50 microg moxonidine were inhibited by yohimbine, an alpha2-adrenoceptor antagonist, and efaroxan, an imidazoline I1-receptor antagonist. Moxonidine (100 microg) stimulated (P<0.01) diuresis in SHR (0.21+/-0.04 vs 1.16+/-0.06 ml h(-1) 100 g(-1)), SD (0.42+/-0.06 vs 1.56+/-0.19 ml h(-1) 100 g(-1)) and WKY (0.12+/-0.04 vs 1.44+/-0.21 ml h(-1) 100 g(-1)). Moxonidine-stimulated urine output was lower in SHR than in SD and WKY. Moxonidine-stimulated sodium and potassium excretions were lower in SHR than in SD, but not WKY, demonstrating an influence of strain but not of pressure. Pretreatment with the natriuretic peptide antagonist anantin (5 or 10 microg) resulted in dose-dependent inhibition of moxonidine-stimulated urinary actions. Anantin (10 microg) inhibited (P<0.01) urine output to 0.38+/-0.06, 0.12+/-0.01, and 0.16+/-0.04 ml h(-1) 100 g(-1) in SD, WKY, and SHR, respectively. Moxonidine increased (P<0.01) plasma ANP in SD (417+/-58 vs 1021+/-112 pg ml(-1)) and WKY (309+/-59 vs 1433+/-187 pg ml(-1)), and in SHR (853+/-96 vs 1879+/-229 pg ml(-1)). These results demonstrate that natriuretic peptides mediate the urinary actions of moxonidine through natriuretic peptide receptors.

Down-regulation of urinary AQP2 and unaffected response to hypertonic saline after 24 hours of fasting in humans

In rats, 24 hours of fasting impairs urinary concentrating ability by down-regulation of aquaporin-2 (AQP2). We tested the hypothesis that 24 hours of fasting in humans reduces the capability to form AQP2 and impairs the antidiuretic response to hypertonic saline infusion. In a crossover study of 14 healthy subjects, the effect of 24 hours of fasting was compared to a nonfasting control experiment on urinary excretion of AQP2 (u-AQP2), free water clearance (C(H(2)O)), plasma arginine vasopressin (AVP), urinary cyclic AMP (u-cAMP), and natriuretic peptides. The following response to 3% sodium infusion was measured using the same effect variables. U-AQP2, AVP, and u-cAMP were determined by radioimmunoassays. Fasting during 24 hours reduced u-AQP2 (14%), increased AVP (30%) despite a reduction in serum osmolality (P < 0.05), and depleted volume. C(H(2)O) and urine volume were not reduced, thus relatively increased after fasting. u-cAMP was not significantly different between the two procedures. Three percent saline resulted in the same relative increases in AVP, serum osmolality, u-AQP2, and u-cAMP and decreases in C(H(2)O) and urine volume independently of fasting. The reduced u-AQP2 and increased AVP after fasting were maintained during and after saline infusion. Twenty-four hours of fasting decreased u-AQP2 and reduced urine osmolality likely as a result of decreased sensitivity of collecting duct cells to AVP. Fasting-related insensitivity of collecting duct cells to AVP was restored by 3% saline infusion. Finally, after saline infusion, other factors such as the increased plasma atrial natriuretic peptide (p-ANP) levels could contribute to the u-AQP2 regulation.

CGS 35601 and its Orally Active Prodrug CGS 37808 as Triple Inhibitors of Endothelin-converting Enzyme-1, Neutral Endopeptidase 24.11, and Angiotensin-converting Enzyme

CGS 35601 is a potent triple inhibitor of endothelin-converting enzyme-1, neutral endopeptidase 24.11, and angiotensin-converting enzyme. It inhibited the activities of these three enzymes with IC50 values of 55, 2 and 22 nM, respectively. In conscious rats, CGS 35601 suppressed the big endothelin-1-induced pressor response by 82% and 72% at 30 and 120 minutes, respectively, following injection at a dose of 10 mg/kg, intravenously. At the same dose, CGS 35601 increased plasma atrial natriuretic peptide (ANP) immunoreactivity by 170% for up to 4 hours in conscious rats infused with ANP, and it inhibited the angiotensin I-induced pressor response by 74-94% within the first 2 hours after dosing. Similar in vivo activities were also observed with its orally active prodrug, CGS 37808. This compound blocked the big endothelin-1- induced pressor response by 71% and 67% at 30 and 120 minutes, respectively, after an oral dose of 10 mgEq/kg in conscious rats. It also increased plasma ANP immunoreactivity by 103% for up to 4 hours and inhibited the angiotensin I-induced pressor response by an average of 49% within the first 4 hours after the same dosing regimen. By suppressing the biosyntheses of endothelin-1 and angiotensin II, two potent vasoconstrictors, while simultaneously potentiating the circulating levels of ANP, a vasorelaxant and diuretic, CGS 35601 and CGS 37808 may represent novel agents for the treatment of cardiovascular and renal diseases.

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides.

Chronic stimulation of sympathetic nervous activity contributes to the development and maintenance of hypertension, leading to left ventricular hypertrophy (LVH), arrhythmias and cardiac death. Moxonidine, an imidazoline antihypertensive compound that preferentially activates imidazoline receptors in brainstem rostroventrolateral medulla, suppresses sympathetic activation and reverses LVH. We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I1-receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I1-receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I1-receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I1-receptors are involved in cardiovascular regulation. The presence of I1-receptors in the heart, the primary site of production of natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), cardiac hormones implicated in blood pressure control and cardioprotection, led us to propose that ANP may be involved in the actions of moxonidine. In fact, acute iv administration of moxonidine (50 to 150 microg/rat) dose-dependently decreased blood pressure, stimulated diuresis and natriuresis and increased plasma ANP and its second messenger, cGMP. Chronic SHR treatment with moxonidine (0, 60 and 120 microg kg(-1) h(-1), sc for 4 weeks) dose-dependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1beta concentration after 4 weeks of treatment. These effects were associated with a further increase in already elevated ANP and BNP synthesis and release (after 1 week), and normalization by 4 weeks. In conclusion, cardiac imidazoline receptors and natriuretic peptides may be involved in the acute and chronic effects of moxonidine.

Atrial natriuretic peptide contributes to the physiological control of lipid mobilization in humans

In humans, lipid mobilization is considered to depend mainly on sympathetic nervous system activation and catecholamine action. A contribution of ANP was hypothesized because we have previously shown that atrial natriuretic peptide (ANP) is a lipolytic agent on isolated human fat cells. Control of lipid-mobilizing mechanisms was investigated using in situ microdialysis in subcutaneous adipose tissue (SCAT) in healthy young men during two successive exercise bouts performed at 35% and 60% peak oxygen consumption (VO2max) after placebo or acute oral tertatolol (nonselective beta-antagonist) treatment. In placebo-treated subjects, infusion of propranolol in the probe (100 micromol/l) only partially reduced (40%) the increment in extracellular glycerol concentration (EGC) promoted by exercise. Moreover, oral beta-adrenergic receptor blockade did not prevent exercise-induced lipid mobilization in SCAT while exerting fat cell beta-adrenergic receptor blockade. Exercise-induced increase in plasma ANP was potently amplified by oral tertatolol. A positive correlation was found between EGC and plasma ANP levels but also between extracellular cGMP (i.e., index of ANP-mediated lipolysis) and EGC. Thus, we demonstrate that exercise-induced lipid mobilization resistant to local propranolol and lipid-mobilizing action observed under oral beta-blockade is related to the action of ANP. Oral beta-adrenergic receptor blockade, which potentiates exercise-induced ANP release by the heart, may contribute to lipid mobilization in SCAT. The potential relevance of an ANP-related lipid-mobilizing pathway is discussed.

Neurohumoral mechanism in the natriuretic action of intracerebroventricular administration of renin.

Intracerebroventricular (i.v.t.) administration of renin (R) decreases urinary volume and increases urinary sodium excretion. We investigated whether i.v.t.-R-induced natriuresis could be associated with the release of atrial natriuretic peptide (ANP), its interaction with renal ANP-A receptors (ANPR-A) and the subsequent increase of urinary cyclic 3-5 guanosine monophosphate (cGMP). In i.v.t. cannulated rats, the left carotid artery was catheterised with PE-50 tubing for blood collection, renin was injected i.v.t. and arterial blood samples were collected at 0, 2, 5, 10 and 15 minutes of injection, and urinary sodium and cGMP excretion at 1-, 3- and 6-hour periods of urine collection. Plasma ANP levels and urinary cGMP were determined by radioimmunoassay, and each urine sample was analysed for sodium concentration using a flame photometer. Our results demonstrate that i.v.t.-R administration increases plasma ANP levels after two minutes of injection and urinary cGMP concentration at 1-, 3- and 6 hour period of urine collection. The natriuretic action induced by i.v.t.-R was blunted by peripheral administration of anantin, an ANPR-A antagonist. We assessed the role of brain angiotensin II (Ang II) AT1-receptors on the i.v.t.-induced antidiuresis, natriuresis and cGMP urinary excretion, the last as an indirect index of ANP secretion. Blockade of brain Ang II AT1-receptors with losartan (LOS; 120 microg/3 microl, i.v.t.), inhibited the antidiuretic action and blocked the increased urinary sodium and cGMP excretion induced by i.v.t.-R (7.14 mGU/5 microl). The increase in urinary cGMP was independent of nitric oxide synthase stimulation, since L-NAME pre-treatment did not alter the renal actions induced by i.v.t.-R. Our results suggest that there is a link between the brain and the kidney. The activation of brain angiotensinergic neurons and stimulation of AT1- receptors may stimulate the release of ANP to the circulation. The released ANP circulates to the kidneys where it acts through renal ANPR-As and the consequent increase in cGMP to produce natriuresis.

Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition

Sodium/hydrogen exchange (NHE) inhibitors show promise as potential therapeutic agents for the treatment of heart failure, but it is not known whether they can reverse the maladaptive remodeling that results in heart failure. We sought to determine the effect of the NHE-1-specific inhibitor EMD-87580 (EMD) on heart failure produced by myocardial infarction in the rat and to assess whether up to 4 wk of treatment delay results in beneficial effects. Male Sprague-Dawley rats were subjected to coronary artery ligation (or a sham procedure) and followed for up to 3 mo, at which time hypertrophy and hemodynamics were determined. EMD was provided in the diet, and treatment commenced immediately or 2-4 wk after ligation. EMD significantly reduced hemodynamic abnormalities, including the elevation in left ventricular end-diastolic pressure, and diminished the loss of systolic function with all treatment protocols. Left ventricular dilatation and hypertrophy, as assessed by heart weight, cell size, and atrial natriuretic peptide (ANP) expression, were similarly reversed to sham or near-sham levels. In addition, the increased plasma ANP and pro-ANP values were reversed to levels not significantly different from sham. Surprisingly, virtually all beneficial effects were identical with all treatment protocols. These effects were observed in the absence of infarct size reduction or blood pressure-lowering effects. Our results suggest that NHE-1 inhibition attenuates and reverses postinfarction remodeling and heart failure with a treatment delay of up to 4 wk after infarction. The effect is independent of infarct size or afterload reduction, indicating a direct effect on the myocardium.

Atrial natriuretic peptide contributes to the antihypertensive action of many drugs.

Data derived from a 10 years research program of our team demonstrate that many categories of antihypertensive drugs like beta-adrenergic blockers, alpha1-adrenergic blockers, ACE inhibitors, AT1-receptor antagonists and calcium-entry blockers increase plasma atrial natriuretic peptide (ANP) levels after a medium-term treatment of patients suffering from moderate essential hypertension. ANP always increases despite the drop of the arterial pressure and the fact that the left atrial and ventricular diameters remain unchanged or slightly reduced. These findings indicate that the increase of ANP plasma levels is not the result of a mechanical overload in the left cardiac chambers but the result of a pharmacological action. In conclusion, ANP is a universal factor contributing to the antihypertensive action of many drugs.

Circulating bile is the main factor responsible for atrial natriuretic peptide release in experimental obstructive jaundice.

Biliary obstruction in the rabbit causes increased release of atrial natriuretic peptide (ANP). Circulating bile, raised biliary pressure or absence of bile in the duodenum may be implicated in this hepatocardiac syndrome. An experimental model was developed to elucidate the mechanism linking obstructive jaundice and increased plasma ANP. Hepatic and renal function, biliary tree pressure and ANP plasma concentrations were investigated in conscious rabbits 4 and 24 h after common bile duct ligation, biliovenous shunting or external drainage via a biliary fistula. Bilirubin concentration increased after bile duct ligation and creation of a biliovenous shunt. Plasma creatinine increased abruptly in rabbits with a biliovenous shunt. At 4 h, the ANP increase in animals with a biliovenous shunt was ninefold that observed after bile duct obstruction while no change was noted after external biliary diversion (mean 350 versus 45 versus 9 fmol/l; P < 0.01). Relief of biliary tree obstruction was associated with a return of ANP levels towards basal normal values. Raised plasma ANP in obstructive jaundice is not the result of an increased biliary pressure per se or absence of bile in the proximal duodenum but of the passage of bile components to the circulation.

Effectiveness of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker on atrial natriuretic peptide.

The aim of this study was to evaluate the effectiveness of an angiotensin-converting enzyne inhibitor (ACEI, quinapril) or angiotensin II receptor blocker (ARB, candesartan) on atrial natriuretic peptide (ANP) activity in rats with hypertension induced by nitric oxide (NO) inhibition. ACEI and ARB have a number of pharmacologic effects, including blood pressure reduction, myocardial preservation, and an unknown effect in the circulation. The changes in ANP in NO inhibitor-induced hypertensive rats were evaluated in order to elucidate the interaction between ANP and NO in the regulation of blood pressure. Thirty-six rats were divided into 4 groups and administered the experimental agents for 8 weeks: group CONTROL was given regular food (n=9), group N(G)-nitro-L-arginine (L-NNA) was administered L-NNA (25 mg. kg(-1). day(-1), n=9), group ACEI was administered L-NNA and quinapril (10 mg. kg(-1). day(-1), n=9), and group ARB was administered L-NNA and candesartan (10 mg. kg(-1). day(-1), n=9). Blood pressure, plasma ANP, atrial ANP, ANP mRNA, and ANP granules were measured. A significant elevation in blood pressure was observed in group L-NNA. However, there were no increases in plasma ANP (L-NNA: 138.8+/-64.4, CONTROL: 86.7+/-36.4), ANP mRNA (L-NNA: 2.2+/-1.0, CONTROL: 1.7+/-0.5) or ANP granules (L-NNA: 61.1+/-10.2, CONTROL: 64.5+/-8.5). No increase in blood pressure was seen in groups ACEI and ARB. However, plasma ANP (ACEI: 1,392.3+/-1,034.4, ARB: 1,142.8+/-667.3), ANP mRNA (ACEI: 52.8+/-29.1, ARB: 42.9+/-21.2), and ANP granules (ACEI: 122.5+/-23.4, ARB: 136.3+/-33.2) increased significantly. NO inhibitor-induced hypertension caused no changes in ANP concentrations. However, the ACEI and ARB had a direct effect on the induction of ANP secretion. The findings suggest that ANP secretion is directly effected by ACEI and ARB, which seems to play a key role in lowering blood pressure, relieving heart failure symptoms, and preserving the myocardium.