Synthetic Human Atrial Natriuretic Peptide Research Articles

Atrial natriuretic peptide induces peroxisome proliferator activated receptor γ during cardiac ischemia-reperfusion in swine heart.

Atrial natriuretic peptide is a cardiac atrium-derived hormone and its cardioprotective effects have recently been confirmed, but the actual mechanism underlying these effects has not been well elucidated. In this study, we proposed that atrial natriuretic peptide achieves its effects in part via peroxisome proliferator activated receptor γ, a nuclear receptor. Hemodynamic data in swine heart ischemia-reperfusion model were measured under the conditions of no medication for control (Group N, n=8) or that of carperitide (synthetic human atrial natriuretic peptide) systemic administration (Group A, n=8). After 30min of left anterior descending artery total occlusion and 4h of reperfusion, peroxisome proliferator activated receptor γ mRNA and protein expressions in cardiac muscle were examined. The mRNA expression of Liver X receptor α, the downstream agent of peroxisome proliferator activated receptor γ, was also evaluated. Creatine kinase-myocardial band and Troponin T elevations after reperfusion were evaluated as markers of cardiac damage. The dP/dT decrease during reperfusion was ameliorated in Group A. Peroxisome proliferator activated receptor γ mRNA expression in Group A was significantly higher in ischemic area than that in Group N, although the difference was not significant in the marginal and non-ischemic areas. The peroxisome proliferator activated receptor γ protein expression in ischemic area was also significantly dominant in Group A. Atrial natriuretic peptide may achieve its cardioprotective effects in part via the activation of the peroxisome proliferator activated receptor γ pathway, particularly in central areas of ischemic lesions.

The therapeutic potential of synthetic human atrial natriuretic peptide in nephrotic syndrome: a randomized controlled trial

BackgroundIn nephrotic syndrome, the combination of furosemide and albumin infusion is a standard regimen to treat systemic edema. The efficacy of synthetic human atrial natriuretic peptide (hANP) for nephrotic syndrome to ameliorate the systemic edema and retain renal functions has not been fully demonstrated.Trial designWe conducted a prospective, randomized, controlled, open-label clinical trial. Patients were randomly assigned by a stratified biased coin design.MethodsA total of 12 patients with nephrotic syndrome between the ages of 20 to 79 years were enrolled and randomly assigned to either the conventional (CON) group treated with furosemide and albumin, and hANP group, in which carperitide was administered in addition to the conventional therapies. The primary end points were: (1) the differences in serum creatinine levels, and (2) the reduction of total dosage of furosemide and albumin by the treatments of hANP. Secondary end points were body weight, systolic blood pressure, heart rate, serum protein, albumin, and urinary protein excretion.ResultsA total of 13 patients were enrolled, and one patient was excluded due to severe pneumonia. In both hANP (n = 7) and CON (n = 5) groups, body weight was reduced after 2-week treatments. Serum creatinine levels at follow-up significantly increased compared with baseline. The increase in serum creatinine levels (Δ serum creatinine) was smaller in the hANP group compared with the CON group (P = 0.31). The serum uric acid, serum urea nitrogen, and urinary protein excretion were reduced in the hANP group, and increased in the CON group, though these differences were not statistically significant. The usage of hANP significantly reduced the total dosage of furosemide (P < 0.05) during the treatment periods. No adverse effects were observed.ConclusionsThe concomitant use of synthetic hANP with conventional therapies is beneficial for reducing the dosage of loop diuretics, and the elevation of serum creatinine and uric acid may be avoided.

The Application of Synthetic hANP in Diabetic Nephropathy With Nephrotic Syndrome

Although the optimal time to initiate hemodialysis is not well defined, it is necessary to start extracorporeal ultrafiltration methods (ECUM) earlier in uremic diabetic patients to avoid life-threatening events, such as anasarca, heart failure, and lung congestion. These patients frequently manifest the poor response to the administration of high dosage of loop diuretics. To investigate the effectiveness of concomitant usage of synthetic human atrial natriuretic peptide (hANP) with loop diuretics, we administered carperitide (hANP) in a case with diabetic nephropathy and nephrotic syndrome. A 44-year-old woman with 10-year history of type 2 diabetes …

The Application of Synthetic hANP in Diabetic Nephropathy With Nephrotic Syndrome

Although the optimal time to initiate hemodialysis is not well defined, it is necessary to start extracorporeal ultrafiltration methods (ECUM) earlier in uremic diabetic patients to avoid life-threatening events, such as anasarca, heart failure, and lung congestion. These patients frequently manifest the poor response to the administration of high dosage of loop diuretics. To investigate the effectiveness of concomitant usage of synthetic human atrial natriuretic peptide (hANP) with loop diuretics, we administered carperitide (hANP) in a case with diabetic nephropathy and nephrotic syndrome. A 44-year-old woman with 10-year history of type 2 diabetes …

Prevention of Renal Impairment by Continuous Infusion of Human Atrial Natriuretic Peptide after Liver Transplantation

Acute renal failure occurring immediately after liver transplantation and requiring hemodialysis is a major problem resulting in a poor prognosis. We investigated the efficacy of human atrial natriuretic peptide, which has potent natriuretic effects and unique protective effects for glomeruli in preventing acute renal failure after liver transplantation. Thirty-seven patients who underwent live donor liver transplantation with model for end-stage liver disease scores greater than 15 were the subjects of the study. Subjects were prospectively randomized into two groups: patients that received synthetic human atrial natriuretic peptide infusion (Group H: n=19) and those that received conventional diuretics, furosemide and potassium canrenoate (Group C: n=18). The peri- and postoperative changes in hemodynamic status and renal function were compared between the two groups. There were no statistical differences in the changes in hemodynamic status between groups. Hemodialysis was required after liver transplantation in nine patients, two in Group H and seven in Group C (P=0.04). Postoperative creatinine clearance was higher in Group H (P=0.03). Aldosterone level was suppressed in group H (P=0.006). Continuous infusion of synthetic human atrial natriuretic peptide might be effective for preventing acute renal failure requiring hemodialysis after liver transplantation.

Impaired vasodilator responses to atrial natriuretic peptide in essential hypertension

Atrial natriuretic peptide (ANP) has vasodilating and diuretic/natriuretic properties, both of which contribute to lower blood pressure. These effects are mediated by binding of ANP to a cell-surface receptor [type A guanylyl cyclase (GC-A)]. It has been demonstrated by studies in monogenetic mouse models that the ANP/GC-A system participates in the maintenance of blood pressure homeostasis. In male patients with essential hypertension (EH; n = 36) as the only cardiovascular risk factor and normotensive controls (n = 12), blood flow was measured in the forearm circulation in response to i.a. infusion of synthetic human ANP, acetylcholine, orciprenaline, and sodium nitroprusside by strain-gauge venous plethysmography. In blood samples, cyclic guanosine'5-monophosphate (cGMP) and ANP concentrations were measured at resting conditions and during exogenous ANP infusion. In 200 patients with EH, genomic DNA was screened for an inhibitory deletion mutation of the GC-A gene, which has been recently linked to EH in a Japanese cohort. The vasodilatations in response to ANP and acetylcholine were impaired in the forearm circulation of patients with EH, whereas the responses to orciprenaline and nitroprusside were preserved. Plasma ANP and cGMP concentrations were increased in the patients with EH both at resting conditions and during ANP infusion; the resting plasma cGMP levels correlated significantly with the plasma ANP levels (r = 0.68). A specific deletion mutation of the GC-A gene did not account for the diminished relaxant effects of ANP in our study population. The vascular ANP/GC-A pathway is altered in patients with EH, in addition to the known defects on the nitric oxide/cGMP pathway. Attenuation of the vasodilative responses to ANP suggests impaired receptor or postreceptor responsiveness of GC-A. It is possible that this dysfunction participates in the pathomechanism of EH.

Postoperative synthetic human atrial natriuretic peptide infusion and oral spironolactone administration for a patient with giant atria and low plasma level of atrial natriuretic peptide

J Thorac Cardiovasc Surg 2002;124:206-9

Effects of human atrial natriuretic peptide in patients after coronary artery bypass surgery

Objectives: To determine the effects of synthetic human atrial natriuretic peptide (ANP) on renal function, hemodynamics, and levels of vasoactive peptides when infused in the immediate postoperative period after coronary bypass surgery in patients with normal kidney function. Design: A prospective, randomized, double-blind, placebo-controlled study. Setting: The Department of Cardiothoracic Anaesthetics and Intensive Care of a university hospital. Participants: Thirty patients with normal kidney function scheduled for elective coronary bypass surgery. Interventions: During the first 3 hours postoperatively, patients received an infusion of either ANP 7.5 pMol/kg/min (ANP) or vehicle alone (C). Measurements and Main Results: No differences were found between the two groups in respect to sex, degree of coronary disease, preoperative medical treatment, or duration of cardiopulmonary bypass and aortic occlusion. Plasma ANP levels increased nearly 10-fold from a mean of 7.0 ± 1.1 pMol/L in ANP and remained at baseline levels in C, ( p < 0.001). In ANP, there occurred significant increases in urine flow ( p < 0.001), inulin clearance ( p < 0.001), filtration fraction ( p = 0.007), and fractional clearance of sodium ( p < 0.001) and of osmoles ( p < 0.001) compared with C. During the study, no differences in mean arterial pressure, heart rate, and right atrial or pulmonary capillary wedge pressure were detected between the groups. Cardiac index decreased by 5% in ANP compared with a 9% increase in C ( p = 0.027). Vasopressin levels significantly increased in C but remained at baseline levels in ANP ( p = 0.031). There were no changes in levels of catecholamines or angiotensin II Conclusions: The results of this study show that ANP increases diuresis, natriuresis, and glomerular filtration in the immediate postoperative period after coronary bypass surgery.

Effect of atrial natriuretic peptide on renal and vascular permeability in diabetes mellitus.

Synthetic human atrial natriuretic peptide (ANP) (102-126) 0.01 microgram/kg per minute or vehicle was intravenously infused for 2 h in 10 patients with insulin-dependent diabetes mellitus and microalbuminuria (albumin excretion, 20 to 200 micrograms/min) and in 10 healthy subjects. In the diabetic group, the immunoglobulin G clearance was higher, but both size index and charge index as calculated from albumin and immunoglobulin clearances were equal compared with normal values. The fractional clearances of small dextrans (< 3.6 nm) were lower in diabetics, which was compatible with a depressed hydraulic permeability (Kf). During ANP infusion, the excretion of albumin and immunoglobulin G increased in the diabetic subjects (189 +/- 12 to 521 +/- 84 and 7.1 +/- 3.5 to 21 +/- 8.1 micrograms/min, respectively; both P < 0.05) only. In the diabetics, the clearance of dextrans > 54 A increased and our calculations indicated an increase in "shut-flow" (omega o). The transcapillary escape rate of albumin, which was elevated in the diabetics at baseline, increased in the diabetic group only. Thus, ANP uncovers altered size selectivity of the filtration barrier in a phase that is otherwise characterized by charge-selective changes only. Moreover, the increased susceptibility of the glomerular capillaries in diabetics to ANP seems to be part of a more generalized capillary abnormality, because ANP also increases the transcapillary escape of albumin.

Degradation and inactivation of human atrial natriuretic peptide by human pulmonary plasma membranes

Atrial natriuretic peptide (ANP) is extracted from plasma during its passage through the lungs. ANP is metabolized in rat lung membrane preparations by the enzyme neutral endopeptidase-24.11 (EC 3.4.24.11), but the hydrolysis of ANP in human lung has not been characterized. In the present study synthetic human atrial natriuretic peptide 1–28 (α-hANP) was separately incubated with human pulmonary plasma membranes from two non-smoking patients, and the major degradation products were separated from α-hANP by reverse-phase high pressure liquid chromatography. The degradation products were identified by sequence analysis and by mass-spectrometry, and biological activity was studied in vitro by exposing precontracted rabbit pulmonary arteries to α-hANP and the degradation products. The initial cleavage appeared, with membrane preparations from both patients, in the central ring structure between Arg 14 and Ile 15, followed by a cleavage of the bond Arg 3-Arg 4 at the N-terminal region of the peptide. The biological activity of this ring-opened product was about 1 500 of the activity of uncleaved α-hANP. Cleavage of the Arg 3-Arg 4 or Arg 14-Ile 15 bonds could not be inhibited by EDTA, iodoacetamide, benzamidine hydrochloride or pepstatin A. Neither did phosphoramidon (1 μM) or thiorphan (1 μM) inhibit the hydrolysis, indicating the presence in human lung of an ANP-degrading enzyme different from endopeptidase-24.11.

Effects of synthetic human atrial natriuretic peptide on the human coronary circulation in subjects with normal coronary arteries.

Atrial natriuretic peptide (ANP) is recognized as an "endogenous vasodilator". The purpose of this study was to determine the effects of a clinical therapeutic dose of synthetic alpha-human ANP on the coronary circulation in 15 subjects with normal coronary arteries and normal ventricular function. The epicardial coronary arterial diameter was measured by selective coronary arteriography. Coronary blood flow was estimated from the arterial cross-sectional area and the flow velocity determined using an subselective intracoronary Doppler catheter. ANP, 0.03 micrograms/min/kg given intravenously over 15 minutes, caused a dilation of the large epicardial coronary artery (n = 8): the diameter of the proximal left anterior descending artery dilated from 2.6 +/- 0.4 to 3.1 +/- 0.5 mm (p less than 0.01). Mean arterial pressure decreased from 89 +/- 5 to 83 +/- 5 mmHg (p less than 0.01); heart rate did not change during ANP infusion. Estimated coronary blood flow significantly increased (n = 6, p less than 0.01), and thus the coronary vascular resistance decreased after ANP infusion, suggesting an ANP-induced dilation of resistance vessels. The present study demonstrates that in human subjects a clinical dose of ANP by intravenous infusion dilates both the large epicardial and small resistance coronary vessels. These results suggest a potentially beneficial role for ANP in reducing the severity of myocardial ischemia in patients with ischemic heart disease.

Atrial natriuretic peptide in liver cirrhosis with mild ascites

To clarify the involvement of atrial natriuretic peptide (ANP) in the pathogenesis of liver cirrhosis, we measured plasma ANP in patients with various stages of cirrhosis and in age-matched normal subjects. Urinary cyclic guanosine monophosphate (cGMP) was also measured as a marker of active biological ANP. In addition, effects of exogenous synthetic human ANP (0.5 micrograms/kg) on renal functions were examined in normal subjects and in cirrhotics without ascites or with mild ascites. Plasma ANP levels were not significantly different among these 3 groups. Urinary cGMP concentrations were significantly higher in both cirrhotics without ascites and cirrhotics with mild ascites, (340 pmol/ml, P less than 0.05 and 496 pmol/ml, P less than 0.01 respectively) than normal subjects (95 pmol/ml). In normal subjects, marked increases in urinary volume (UV), sodium excretion (UNaV), fraction excretion of sodium (FENa) and free water clearance (CH2O) were induced after ANP infusion, and significant recoveries were subsequently observed in these parameters. However, in cirrhotics, the responses to ANP infusion of UV, FENa and CH2O were far less dramatic. The response of UV, UNaV and FENa in cirrhotics with mild ascites was delayed compared to cirrhotics without ascites. These results suggest that the blunted natriuretic responsiveness to ANP is contributory to the pathogenesis of initial sodium retention in cirrhotics.

The diuretic and natriuretic action of human atrial natriuretic peptide in humans: Lack of effect of exogenous insulin

The interaction of exogenous, synthetic human atrial natriuretic peptide [(hANP) (ANF 99–126)] and of exogenous insulin was investigated in six healthy men and in seven type I diabetic patients using the euglycemic clamp technique. A primed-continuous (1.0 mU/kg × min) infusion of biosynthetic human insulin was administered to acutely raise and maintain plasma insulin concentrations at approximately 75 to 100 μU/mL during four hours while plasma glucose concentrations were maintained constant at the fasting level by a variable infusion of glucose. In healthy men a decrease in natriuresis ( P < .01) was seen during a euglycemic clamp study without exogenous hANP. No changes in diuresis and natriuresis were seen during a control experiment without exogenous insulin and glucose. Both in healthy men and in the type I diabetics sequential IV bolus doses of hANP of 100, 200, and 400 μg induced an increase in urine flow ( P < .01) and in natriuresis ( P < .01). In healthy men these effects were comparable to those achieved by hANP in the absence of induced hyperinsulinemia. It is concluded that the antinatriuretic action of insulin is of no major relevance in counteracting the pharmacologic action of hANP in healthy men. The effects of pharmacologic doses of hANP on diuresis and natriuresis in patients with type I diabetes mellitus is comparable to that in healthy men.

Functional Atrial Natriuretic Peptide Receptor in Human Adrenal Tumor

The effects of synthetic human atrial natriuretic peptide (ANP) on the release of catecholamines, aldosterone, or cortisol were observed in human adrenal tumors obtained surgically from patients with pheochromocytoma, primary aldosteronism, or Cushing's syndrome, respectively. Each tumor tissue or adjacent normal cortical tissue was sectioned into slices, which were incubated in medium-199 in the presence or absence of adrenocorticotrophin (ACTH) and ANP. The amounts of epinephrine, norepinephrine, aldosterone, or cortisol released into the medium were measured. Existence of ANP receptors on the adrenal tissues was examined by binding assays, affinity labeling, and immunohistochemistry. Release of catecholamines from pheochromocytoma tissues was inhibited by ANP, and the presence of the ANP receptor on pheochromocytoma was further demonstrated by both binding assays and affinity labeling; Scatchard analysis revealed a single class of binding sites for ANP with a Kd of 1.0 nM and a Bmax of 0.4 pmol/mg of protein and the molecular size was estimated as 140 and a 70 kDa under nonreducing and reducing conditions, respectively. The presence of ANP receptors in pheochromocytoma was demonstrated by immunohistochemistry. ANP inhibited both basal and ACTH-stimulated aldosterone secretion in the slices of normal cortex, and localization of ANP receptors in zona glomerulosa cells was also demonstrated. However, ANP did not inhibit basal and ACTH-stimulated aldosterone and cortisol secretion in both tissue slices from aldosteronoma and Cushing's adenoma. Consistent with these observations, the absence of ANP receptors in adenoma tissues was determined by binding assays, affinity labeling, and immunohistochemistry.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of atrial natriuretic peptide on catecholamine release from human pheochromocytoma

The effect of synthetic alpha human atrial natriuretic peptide on catecholamine release from human pheochromocytomas was studied both in vivo and in vitro. Iv infusion of atrial natriuretic peptide at a rate of 0.1 microgram.kg-1.min-1 for 60 min into two normotensive patients with pheochromocytoma caused a small decrease in the mean blood pressure, increase in the heart rate, and marked increase in the plasma level of norepinephrine (2.08 to 6.83 nmol/l, and 1.15 to 2.83 nmol/l, respectively) compared with 0.60 +/- 0.10 to 1.19 +/- 0.20 nmol/l in normal subjects. Treatment with atrial natriuretic peptide also increased the plasma epinephrine level from 0.34 to 1.27 nmol/l, and from 0.67 to 0.79 nmol/l in the patients with pheochromocytoma, but not in the normal subjects (0.05 +/- 0.01 to 0.05 +/- 0.01 nmol/l). After removal of the tumour, the responses of the plasma norepinephrine and epinephrine to atrial natriuretic peptide infusion were normalized. There was no significant effect of 10(-8) to 10(-5) mol/l atrial natriuretic peptide on the basal release of catecholamines from isolated superfused pheochromocytoma tissue. Atrial natriuretic peptide (10(-7) mol/l) did not affect the increase in catecholamine release induced by glucagon (10(-5) mol/l). These results suggest that the exaggerated responses of plasma catecholamines to atrial natriuretic peptide in patients with pheochromocytoma may be due to a washout effect resulting from change in blood flow in the vessels feeding the tumour rather than increased sympathetic nerve activity induced by hypotension and hypovolemia. The results also suggest that atrial natriuretic peptide dose not have any direct action on pheochromocytoma tissue causing catecholamine release.

Direct vasodilatory action of atrial natriuretic factor on canine glomerular afferent arterioles.

Studies were performed to examine whether atrial natriuretic peptide (ANP) has a direct action on glomerular afferent arterioles, and if so, whether the action is mediated by guanosine 5'-cyclic monophosphate (cGMP). A single superficial afferent arteriole was dissected from the canine kidney and perfused with the single glomerular perfusion technique described by Osgood et al. [Am. J. Physiol. 244 (Renal Fluid Electrolyte Physiol. 13): F349-F354, 1983]. Norepinephrine (NE, 1 x 10(-6) M) significantly increased arteriolar resistance, calculated from the perfusion rate and arteriolar pressure. Synthetic human ANP (hANP) provoked afferent arteriolar dilation and attenuated the NE-induced increase in arteriolar resistance with 1 x 10(-10) to 1 x 10(-6) M concentrations. This vasodilatory effect was significantly potentiated by 2-o-propoxyphenyl-8-azapurin-6-one (M&B 22,948, 4 x 10(-12) M), a cGMP phosphodiesterase inhibitor, probably due to a sequential interaction of synergistic drugs. Also, the 1 x 10(-4) M concentration of 8-bromoguanosine 5'-cyclic monophosphate or dibutyryl guanosine, 5'-cyclic monophosphate (DBcGMP) lessened NE-induced arteriolar constriction, but DBcAMP did not. We conclude from these observations that ANP has a direct vasodilatory action on canine glomerular afferent arterioles, and that this ANP-induced vasodilation is mediated by enhanced cGMP synthesis.

Effect of human atrial natriuretic peptide on 1-deamino-D-Arg8-vasopressin-induced antidiuresis in man.

The interaction of exogenous synthetic human atrial natriuretic peptide (hANP), given in iv bolus doses of 100, 200, and 400 micrograms, and of various bolus-primed infusion of 1-deamino-D-Arg8-vasopressin (dDAVP), a nonpressor analog of antidiuretic hormone, were investigated in six normal men. A marked dose-dependent rise in plasma hANP concentrations occurred after the administration of hANP. The antidiuretic effect of dDAVP (P less than 0.01) was partially but not completely reversed by the concomitant administration of hANP (P less than 0.01). hANP-induced natriuresis was similar in the presence and absence of dDAVP-induced antidiuresis. While these results do not prove that hANP-dependent natriuresis and diuresis are independent phenomena, it is of clinical interest that natriuresis without diuresis can be induced by the simultaneous administration of hANP and dDAVP.

Mechanism of elevation of glomerular filtration rate induced by synthetic human atrial natriuretic peptide in isolated perfused rat kidney.

Mechanism of elevation of glomerular filtration rate induced by synthetic human atrial natriuretic peptide in isolated perfused rat kidney.

Participation of baroreceptor reflexes in blood pressure and sympathetic nerve responses to a synthetic human atrial natriuretic peptide in anesthetized dogs.

The effects of a synthetic alpha human atrial natriuretic polypeptide (hANP) on systemic blood pressure and renal nerve activity were studied before and after sinoaortic denervation with vagotomy in anesthetized dogs. Intravenous injection of hANP (1 microgram/kg) in animals with the neuraxis intact produced a mild decrease in systemic blood pressure and a significant increase in renal sympathetic nerve activity. However, in animals with sinoaortic denervation and vagotomy, a profound fall in blood pressure occurred after administration of hANP. Renal nerve activity in these animals was reduced significantly, in parallel with decreases in systemic blood pressure. These results indicate that activation of peripheral baroreceptors minimizes the hypotension induced by intravenous injection of hANP, and may mask at least centrally mediated cardiovascular effects of hANP.

Effects of synthetic human atrial natriuretic peptide (hANP) in conscious dogs.

The effects of synthetic human atrial natriuretic peptide (hANP) on arterial blood pressure, heart rate, and renal functions were evaluated in conscious trained dogs in moderate sustained water diuresis. Synthetic hANP was given i.v. over 3 min at doses of 0.27-2.16 micrograms kg-1 body wt. It did not cause significant changes in blood pressure or heart rate. The rate of sodium excretion increased 20-fold following 2.16 micrograms kg-1 and 2.5-fold after 0.54 micrograms kg-1. Natriuresis was immediate and vanished after 10 min, regardless of dose. The concomitant increase in diuresis was less than 50%, but significant for a longer period of time. Increases in potassium excretion were significant, but small, that is, by a factor of 1.5-2.8. All natriuretic doses of hANP increased PAH clearance (at constant blood pressure), but some did so without measurably affecting creatinine clearance.