atrial-natriuretic-factor and anaritide

Natriuretic peptides are a family of three structurally related hormone/ paracrine factors. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are secreted from the cardiac atria and ventricles, respectively. ANP signals in an endocrine and paracrine manner to decrease blood pressure and cardiac hypertrophy. BNP acts locally to reduce ventricular fibrosis. C-type natriuretic peptide (CNP) primarily stimulates long bone growth but likely serves unappreciated functions as well. ANP and BNP activate the transmembrane guanylyl cyclase, natriuretic peptide receptor-A (NPR-A). CNP activates a related cyclase, natriuretic peptide receptor-B (NPR-B). Both receptors catalyze the synthesis of cGMP, which mediates most known effects of natriuretic peptides. A third natriuretic peptide receptor, natriuretic peptide receptor-C (NPR-C), clears natriuretic peptides from the circulation through receptor-mediated internalization and degradation. However, a signaling function for the receptor has been suggested as well. Targeted disruptions of the genes encoding all natriuretic peptides and their receptors have been generated in mice, which display unique physiologies. A few mutations in these proteins have been reported in humans. Synthetic analogs of ANP (anaritide and carperitide) and BNP (nesiritide) have been investigated as potential therapies for the treatment of decompensated heart failure and other diseases. Anaritide and nesiritide are approved for use in acute decompensated heart failure, but recent studies have cast doubt on their safety and effectiveness. New clinical trials are examining the effect of nesiritide and novel peptides, like CD-NP, on these critical parameters. In this review, the history, structure, function, and clinical applications of natriuretic peptides and their receptors are discussed.

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; History, 20th Century; Humans; Natriuretic Agents; Natriuretic Peptide, Brain; Natriuretic Peptides; Peptide Fragments; Receptors, Atrial Natriuretic Factor

The fairly wide-ranging spectrum of tactics under investigation for ameliorating acute renal allograft dysfunction caused by harvest/preservation-related ischemia, acute CsA nephrotoxicity, and acute immunologic crises reflect the fact that no single approach has emerged as universally useful for mitigating the vasomotor nephropathy produced by the combined effects of each of these vectors of vasomotor renal allograft injury. Given the clinical heterogeneity of patients and allografts, it is the author's bias that, in addition to careful donor and recipient hemodynamic management, induction immunosuppressive regimens should be individualized on the basis of allograft function in the immediate postreperfusion period (judged by rate of diuresis, intraoperative parenchymal tone, renal scan profiles, and rate of decline of serum creatinine concentration) as well as patient-specific immunologic and general medical risk factors. Promising laboratory and clinical investigations of such agents as calcium channel blockers, substances promoting intrarenal vasodilator vs. vasoconstrictor prostaglandin formation, and atriopeptins have the potential to provide clinically helpful options with regard to adjunctive therapy for ameliorating acute renal allograft dysfunction associated with INF and ACR.

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Cyclosporine; Diuretics; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppression Therapy; Kidney Transplantation; Organ Preservation; Peptide Fragments; Reperfusion Injury

Atrial natriuretic peptide (ANP), an endogenous hormone synthesized by the cardiac atria, has been shown to improve renal function in multiple animal models of acute renal failure. In a recent multicenter clinical trial of 504 patients with acute tubular necrosis (oliguric and nonoliguric), ANP decreased the need for dialysis only in the oliguric patients. In the present study, 222 patients with oliguric acute renal failure were enrolled into a multicenter, randomized, double-blind, placebo-controlled trial designed to assess prospectively the safety and efficacy of ANP compared with placebo. Subjects were randomized to treatment with a 24-hour infusion of ANP (anaritide, 0.2 microgram/kg/min; synthetic form of human ANP) or placebo. Dialysis and mortality status were followed up for 60 days. The primary efficacy end point was dialysis-free survival through day 21. Dialysis-free survival rates were 21% in the ANP group and 15% in the placebo group (P = 0.22). By day 14 of the study, 64% and 77% of the ANP and placebo groups had undergone dialysis, respectively (P = 0.054), and 9 additional patients (7 patients, ANP group; 2 patients, placebo group) needed dialysis but did not receive it. Although a trend was present, there was no statistically significant beneficial effect of ANP in dialysis-free survival or reduction in dialysis in these subjects with oliguric acute renal failure. Mortality rates through day 60 were 60% versus 56% in the ANP and placebo groups, respectively (P = 0.541). One hundred two of 108 (95%) versus 63 of 114 (55%) patients in the ANP and placebo groups had systolic blood pressures less than 90 mm Hg during the study-drug infusion (P < 0.001). The maximal absolute decrease in systolic blood pressure was significantly greater in the anaritide group than placebo group (33.6 versus 23.9 mm Hg; P < 0.001). This well-characterized population with oliguric acute renal failure had an overall high morbidity and mortality.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Data Interpretation, Statistical; Diuretics; Double-Blind Method; Female; Heart Rate; Humans; Kidney Tubular Necrosis, Acute; Male; Middle Aged; Oliguria; Peptide Fragments; Placebos; Prospective Studies; Renal Dialysis; Risk Factors; Survival Rate; Treatment Outcome

We compared the clinical outcomes of patients with (n = 71) and without (n = 185) diabetes mellitus enrolled into the placebo arm of a large, multicenter clinical trial of patients with acute tubular necrosis (ATN). Compared with the nondiabetic patients, diabetic patients were older (65.5 +/- 12.9 versus 60.7 +/- 18.0 years, P < 0. 05), had higher usual serum creatinine concentration (1.7 +/- 0.6 versus 1.4 +/- 0.5 mg/dL, P < 0.001), and had a higher prevalence of underlying hypertension, coronary artery disease, and congestive heart failure (all P < 0.007). By day 21 after enrollment, neither mortality nor dialysis-free survival was different between the groups. Length of stay for surviving patients, in both the intensive care unit and the hospital, were significantly shorter for the diabetics. Among acute comorbidities predicting mortality or the need for dialysis, sepsis was more prevalent among the nondiabetic patients (18% versus 35%, diabetics versus nondiabetics, P < 0.05). In conclusion, clinical outcomes for diabetic patients with ATN were no worse than for nondiabetic patients, despite their older age and worse underlying renal function. Patients with diabetes mellitus had more chronic cardiovascular disease but were less acutely ill. We speculate that cardiovascular disease is a risk factor for ATN in patients with diabetes mellitus. These results fail to implicate the increasing prevalence of diabetes mellitus in the persistently poor prognosis of patients with ATN.

Topics: Aged; Atrial Natriuretic Factor; Diabetes Complications; Diabetes Mellitus; Diuretics; Humans; Kidney Tubular Necrosis, Acute; Middle Aged; Peptide Fragments; Prognosis; Renal Dialysis; Risk Factors; Survival Rate

Atrial natriuretic peptide, a hormone synthesized by the cardiac atria, increases the glomerular filtration rate by dilating afferent arterioles while constricting efferent arterioles. It has been shown to improve glomerular filtration, urinary output, and renal histopathology in laboratory animals with acute renal dysfunction. Anaritide is a 25-amino-acid synthetic form of atrial natriuretic peptide.. We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial of anaritide in 504 critically ill patients with acute tubular necrosis. The patients received a 24-hour intravenous infusion of either anaritide (0.2 microgram per kilogram of body weight per minute) or placebo. The primary end point was dialysis-free survival for 21 days after treatment. Other end points included the need for dialysis, changes in the serum creatinine concentration, and mortality.. The rate of dialysis-free survival was 47 percent in the placebo group and 43 percent in the anaritide group (P = 0.35). In the prospectively defined subgroup of 120 patients with oliguria (urinary output, < 400 ml per day), dialysis-free survival was 8 percent in the placebo group (5 of 60 patients) and 27 percent in the anaritide group (16 of 60 patients, P = 0.008). Anaritide-treated patients with oliguria who no longer had oliguria after treatment benefited the most. Conversely, among the 378 patients without oliguria, dialysis-free survival was 59 percent in the placebo group (116 of 195 patients) and 48 percent in the anaritide group (88 of 183 patients, P = 0.03).. The administration of anaritide did not improve the overall rate of dialysis-free survival in critically ill patients with acute tubular necrosis. However, anaritide may improve dialysis-free survival in patients with oliguria and may worsen it in patients without oliguria who have acute tubular necrosis.

Topics: Atrial Natriuretic Factor; Diuretics; Double-Blind Method; Female; Humans; Infusions, Intravenous; Kidney Tubular Necrosis, Acute; Male; Middle Aged; Oliguria; Peptide Fragments; Prospective Studies; Renal Dialysis; Survival Analysis; Treatment Outcome

Acute tubular necrosis (ATN) is the most common type of acute renal failure in hospitalized patients and is associated with a high morbidity and mortality. The cause of ATN can be divided into nephrotoxic, ischemic, or mixed.. To test the hypothesis that the cause of ATN affects its clinical outcome.. The study compares clinical outcomes of patients enrolled in the placebo arm of a multicenter, randomized, double-blinded, placebo-controlled trial of anaritide (Auriculin, synthetic atrial natriuretic peptide, Scios, Mountain View, Calif) in patients with well-defined ATN. Patients were divided prospectively into groups according to the cause of ATN: pure nephrotoxic, pure ischemic, or mixed nephrotoxic and ischemic. Outcomes of interest were dialysis-free survival and all-cause mortality on day 14 and day 21. The causal groups were compared with respect to the prevalence of several comorbidities suspected of affecting the clinical outcomes.. Mortality was 10% in the nephrotoxic group and 30% in the ischemic group on day 21. Dialysis-free survival was 66% in the nephrotoxic group and 41% in the ischemic group on day 21. Outcomes in the mixed and ischemic groups were similar. Compared with the nephrotoxic group, there was a significantly higher prevalence of cardiogenic shock, hypotension, sepsis, and respiratory failure and a tendency toward a higher prevalence of acute hepatic dysfunction in the ischemic group. Diabetes mellitus was more prevalent in the nephrotoxic group. Among patients with ischemic ATN, dialysis-free survival improved significantly and mortality tended to decline with advancing age.. Among patients with ATN, those in whom renal ischemia was causative had significantly higher mortality and lower dialysis-free survival than those whose ATN was purely nephrotoxic in origin. This difference in clinical outcomes was associated with a higher prevalence of serious commorbidities in the ischemic ATN group. Advancing age was associated with improved dialysis-free survival and a tendency toward reduced mortality in patients with ischemic ATN.

Topics: Adult; Aged; Atrial Natriuretic Factor; Diuretics; Double-Blind Method; Female; Humans; Ischemia; Kidney Tubular Necrosis, Acute; Male; Middle Aged; Natriuresis; Peptide Fragments; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Renal Dialysis; Risk Factors; Survival Analysis

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.

Topics: Adult; Albuminuria; Atrial Natriuretic Factor; Basement Membrane; Capillary Permeability; Dextrans; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Immunoglobulin G; Kidney Glomerulus; Male; Middle Aged; Models, Biological; Natriuresis; Peptide Fragments; Proteins; Proteinuria; Renal Circulation

The hemodynamic and renal effects of anaritide (human atrial natriuretic peptide 102-126), a synthetic analog of atrial natriuretic peptide, were evaluated in 35 patients with chronic New York Heart Association class II to IV heart failure. There were 32 men and 3 women, aged 33 to 75 (mean +/- standard error of the mean 56 +/- 2) years. In the first phase of the study, right-sided heart catheterization was performed, and anaritide was administered as 1-hour infusions. The rate of the infusion varied among patients from 0.03 to 0.3 micrograms/kg/min. In response to anaritide, there were decreases in mean systemic arterial (94 +/- 2 to 87 +/- 2 mm Hg), right atrial (10 +/- 1 to 8 +/- 1 mm Hg), mean pulmonary arterial (33 +/- 2 to 28 +/- 2 mm Hg) and pulmonary artery wedge (22 +/- 2 to 15 +/- 2 mm Hg) pressures (all p less than 0.05). Cardiac index increased (2.39 +/- 0.15 to 2.62 +/- 0.15 liters/min/m2, p less than 0.05) and heart rate was unchanged. Systemic vascular resistance decreased significantly, but pulmonary vascular resistance was unchanged. There were increases in urine volume (1.6 +/- 0.2 to 2.3 +/- 0.4 ml/min), sodium excretion (47 +/- 13 to 74 +/- 20 muEq/min) and fractional excretion of sodium (0.41 +/- 0.11 to 0.59 +/- 0.14%, all p less than 0.05), while potassium excretion and creatinine clearance did not change. In the second phase of the study, patients received 2-hour infusions of anaritide (0.03 to 0.6 micrograms/kg/min) and placebo with noninvasive monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Atrial Natriuretic Factor; Drug Administration Schedule; Female; Heart Failure; Hemodynamics; Humans; Kidney; Male; Middle Aged; Natriuresis; Peptide Fragments; Time Factors

The effects of anaritide, a 25-amino-acid synthetic analogue of ANP, were evaluated in 28 patients with cirrhosis complicated by ascites and/or edema. Each patient received two doses of the agent, as well as an infusion of placebo. Six different doses were tested ranging from 0.015-0.300 microgram/kg/min. The infusions lasted for 2 hours and were flanked by both baseline and recovery periods. There was a significant effect of placebo on urinary sodium and chloride excretion rates but no effect on urine flow rate. In response to anaritide, the urine flow rate increased at 0.03, 0.06, 0.075, and 0.100 microgram/kg/min. The sodium and chloride excretion rates increased at all doses except the highest dose. There was no definite effect of anaritide on urinary potassium, calcium, and phosphate excretion rates. There was also no significant effect on creatinine clearance. The mean arterial pressure decreased in response to the 0.060, 0.075, and 0.100 microgram/kg/min doses. In addition, five of the patients receiving the highest dose (0.300 microgram/kg/min) had decreases in their systolic pressures to 90 mm Hg or less. In conclusion, anaritide is natriuretic and diuretic in patients with cirrhosis complicated by ascites and/or edema. Its effect, however, on arterial pressure may limit its therapeutic potential in this patient population.

Topics: Atrial Natriuretic Factor; Blood Pressure; Calcium; Chlorides; Diuresis; Diuretics; Edema; Female; Hematocrit; Humans; Liver Cirrhosis; Magnesium; Male; Middle Aged; Natriuresis; Peptide Fragments; Phosphates; Potassium

We studied renal, hormonal and cardiovascular effects of ANF 102-126 (WY 47987) in seven patients with chronic renal failure (serum creatinine 25-68 mg/l) and in four normal volunteers. ANF or placebo bolus injections were given at 1, 2, and 3 micrograms/kg i.v. (each dose on separate days). As compared to placebo, ANF did not induce changes of renal excretory parameters, of plasma renin and aldosterone or of blood pressure and heart rate in patients. In healthy volunteers, however, the same dose of ANF increased urinary excretion of sodium, potassium, calcium, chloride and phosphorus as well as water, and creatinine clearances, and decreased plasma aldosterone. The data suggest blunted effectiveness of ANF bolus injections in patients with renal insufficiency.

Topics: Aldosterone; Atrial Natriuretic Factor; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Natriuresis; Peptide Fragments; Phosphorus; Potassium; Randomized Controlled Trials as Topic; Renin

Synthetic human ANP (102-126) or vehicle was intravenously administered to eight patients with non-edematous nephrotic syndrome to study its effect on protein and sodium excretion. ANP was given in ascending doses, each dose for one hour, two to three days apart. Four patients received 0.03, 0.10 and 0.45 microgram/kg/min of ANP, and four received 0.015, 0.06 and 0.20 microgram/kg/min. Natriuresis increased at all doses; by 179 +/- 13.6% (mean +/- SEM; P less than 0.05) at 0.015 microgram/kg/min and by 660 +/- 71.5% (P less than 0.01) at 0.20 microgram/kg/min. Urinary albumin excretion increased by 138 +/- 30.1% (P less than 0.05) at 0.015 microgram/kg/min of ANP and by 534 +/- 132% (P less than 0.01) at 0.20 microgram/kg/min. Immunoglobulin G excretion increased proportionally to albumin excretion. Hematocrit and serum albumin concentration increased after ANP. In each patient the percent reduction of plasma volume calculated from the effect on serum albumin was smaller than the hemoconcentration calculated from the effect on hematocrit, suggesting a loss of albumin from the intravascular compartment. This could not be accounted for by the increased glomerular filtration of albumin. Blood pressure and effective renal plasma flow decreased and filtration fraction increased after ANP. Plasma renin was suppressed at lower doses of ANP but was stimulated, together with plasma noradrenaline, at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Albuminuria; Atrial Natriuretic Factor; Diuretics; Hormones; Humans; Immunoglobulin G; Male; Natriuresis; Nephrotic Syndrome; Peptide Fragments

Synthetic atrial natriuretic factor (ANF) was administered in ascending doses (0.03, 0.20, 0.45 microgram/kg/min) to eight mildly essential hypertensive men on high (200 mEq/day) or low (10 mEq/day) sodium diets. Responses of blood pressure, heart rate, urinary volume and electrolyte excretion, renin, and aldosterone were measured. For the entire group, ANF lowered blood pressure and increased heart rate during the 0.20 and 0.45 microgram/kg/min infusions, and the antihypertensive effect of the peptide persisted for at least 2 hours after the infusions ended. Four patients (2 at 0.20 microgram/kg/min and 2 at 0.45 microgram/kg/min) experienced sudden bradycardia and hypotension at the end of or shortly after completion of ANF infusion. Renal excretion of water, sodium, chloride, calcium, and phosphorus increased in a dose-dependent fashion in response to infused ANF. Patients on the 200 mEq/day sodium diet had greater increases in urinary volume (11.1 +/- 2.8 vs 3.0 +/- 2.0 ml/min; p less than 0.05), sodium (870 +/- 134 vs 303 +/- 27 microEq/min; p less than 0.05), and chloride (801 +/- 135 vs 176 +/- 75 microEq/min; p less than 0.02) compared with patients on the low sodium diet. The apparent direct suppressive effect of a 0.03 microgram/kg/min infusion of ANF on renin and aldosterone levels was overcome at higher doses by counterregulation provoked by the depressor action. Renin was slightly (-12%) suppressed during the 0.03 microgram/kg/min infusion of ANF but increased at the 0.20 (+50%) and 0.45 microgram/kg/min (+90%; p less than 0.03) rates. Aldosterone declined significantly during the 0.03 microgram/kg/min infusion (-45%; p less than 0.01) of ANF but not during the two higher dose infusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Diuretics; Dose-Response Relationship, Drug; Heart Rate; Hormones; Humans; Hypertension; Hypotension; Male; Middle Aged; Peptide Fragments; Renin-Angiotensin System; Sodium Chloride; Water-Electrolyte Balance

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Humans; Natriuretic Peptides; Peptide Fragments; Treatment Outcome

Topics: Atrial Natriuretic Factor; Diuretics; Humans; Integrins; Kidney Tubular Necrosis, Acute; Peptide Fragments

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Biological Products; Clinical Trials as Topic; Diuretics; Humans; Insulin-Like Growth Factor I; Multicenter Studies as Topic; Peptide Fragments; Randomized Controlled Trials as Topic; Recombinant Proteins

The effects of three atrial natriuretic peptides (ANPs) have been tested for their ability to increase ion transport in muscle-stripped and intact preparations of rat colon. Anaritide (fragment 4-28 of human ANP), human ANP and rat atriopeptin III had no effect on short-circuit current in muscle-stripped preparations. Such insensitivity could not be explained by desensitisation, enzymic destruction or non-specific absorption. Short-circuit current was increased by 8-Br-cGMP and NaNP. The pharmacological activity of anaritide was demonstrated by abolition of phenylephrine-induced tone in rat aortic smooth muscle. In contrast to muscle-stripped colon, intact preparations responded with a tetrodotoxin-sensitive increase in short-circuit current to anaritide even though such preparations were less sensitive to acetylcholine and substance P. These results imply that selective neural damage or the lack of certain nerve pathways, caused by complete muscle stripping, will prevent the pro-secretory effects of anaritide in rat colon.

Topics: Animals; Atrial Natriuretic Factor; Biological Transport; Colon; Cyclic GMP; Electric Conductivity; Electric Stimulation; Ions; Male; Muscles; Nitroprusside; Peptide Fragments; Rats; Rats, Wistar

Contrasting data exist about a possible modulation of the autonomic function by atrial natriuretic factor (ANF) in human beings, particularly at low, biologically, significant concentrations. We have evaluated that possibility by increasing plasma ANF levels through the infusion of a synthetic analogue (WY-47,663, anaritide) in five male patients with mild to moderate uncomplicated hypertension. Nonhypotensive lower body negative pressure (-10 mm Hg x 5 min) was used to selectively deactivate cardiopulmonary receptors and to stimulate sympathetic efferent tone reflexogenically. ANF was given at either a low rate (0.005 micrograms/kg/min x 60 min, which was previously shown to increase plasma ANF in a range compatible with physiologic stimuli) or at a high rate (0.05 micrograms/kg/min x 60 min, each). Administration of ANF was preceded and followed by vehicle infusion (Haemacell x 30 min). Forearm blood flow (venous plethysmography), intraarterial blood pressure, and heart rate were monitored continuously, and venous immunoreactive ANF, plasma renin activity, aldosterone level, and venous hematocrit were measured at the end of both control and infusion periods. Arterial norepinephrine values, an indirect index of sympathetic discharge, were measured at rest and during lower body negative pressure conditions. Graded systemic ANF infusion increased immunoreactive ANF and venous hematocrit, decreased aldosterone level and plasma renin activity, whereas resting norepinephrine levels, blood pressure, and heart rate did not change. Lower body negative pressure decreased forearm blood flow during vehicle infusion, but it lost its vasoconstrictor effect during infusion of ANF. To identify the site of that inhibitory action, ANF was also infused into the brachial artery at rates that raised local but not systemic levels of immunoreactive ANF.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Diuretics; Forearm; Humans; Hypertension; Lower Body Negative Pressure; Male; Peptide Fragments; Pressoreceptors; Reflex; Sympathetic Nervous System; Vasoconstriction

The renal and hemodynamic responses to intravenous anaritide, a human atrial natriuretic factor [102-126] at 0.3 to 20 micrograms/kg in conscious rhesus monkeys with and without acute extracellular hypervolemia were analyzed and compared. Acute isotonic saline loading (intravenous bolus at 10 mL/kg plus continuous infusion at 0.25 mL/kg/min 30 min prior to and maintained throughout experiment) significantly augmented urine output (UV) and urinary Na+ excretion rate (UNaV) by 31% and 91%, respectively. Radial mean arterial pressure (MAP) and heart rate (HR) were not affected by volume expansion. Anaritide at doses higher than 0.3 micrograms/kg reduced MAP in a dose-dependent fashion in euvolemic monkeys. In contrast, reduction in MAP was observed only at the highest dose (20 micrograms/kg) of anaritide in hypervolemic monkeys. The hypotensive responses to anaritide at 20 micrograms/kg in euvolemic and hypervolemic animals were similar (-26 +/- 5 v -24 +/- 5 mm Hg, respective maximum changes in MAP). UV and UNaV were increased by anaritide at 3 to 20 micrograms/kg in both euvolemic and hypervolemic monkeys; however, the increases at each effective dose of anaritide were greater or tended to be greater in hypervolemic rhesus monkeys compared with euvolemic rhesus monkeys. Compared to vehicle responses, HR was not affected by anaritide in either group of animals. In conclusion, acute extracellular hypervolemia potentiates the renal but suppresses the hypotensive responses to anaritide in conscious rhesus monkeys.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Diuresis; Diuretics; Dose-Response Relationship, Drug; Heart Rate; Hemodynamics; Humans; Kidney; Macaca mulatta; Male; Natriuresis; Peptide Fragments; Plasma Volume

These studies examined the effects in dogs of dietary Na intake on plasma "ANF-like" immunoreactivity (PAI), and on the renal response to anaritide, a synthetic natriuretic peptide. There were no significant differences between high-Na (120 mEq/day) and low-Na (3 mEq/day) dogs in endogenous PAI, nor was PAI altered by oral or i.v. volume expansion with 0.9% saline. Renal arterial infusion of anaritide did not alter arterial pressure, renal blood flow or the frational excretion of lithium, but increased the fractional excretion of Na to similar degrees in both groups. The peptide increased GFR only in the low-Na group. Extremes of sodium balance do not seem to alter the renal response to anaritide, which apparently does not inhibit sodium reabsorption in the proximal tubule.

Topics: Animals; Atrial Natriuretic Factor; Dogs; Female; Glomerular Filtration Rate; Kidney; Kinetics; Lithium; Peptide Fragments; Renin; Sodium; Sodium, Dietary

With micropuncture techniques, the present study examined the delivery of chloride to the superficial late distal tubule and the base and tip of the papillary collecting duct in rats treated with either Wy 47663, a synthetic analogue of atrial natriuretic peptide (ANP), or vehicle alone. Whole kidney glomerular filtration rate (GFR) and single-nephron glomerular filtration rate were not significantly different between the two groups. Late distal tubule chloride delivery was also not different between ANP- (5.71 +/- 1.15%) and vehicle- (6.28 +/- 1.12%) treated animals. However, fractional delivery to the base of the papillary collecting duct was significantly greater in the ANP-treated rats (14.37 +/- 1.98%) compared with vehicle-treated rats (7.32 +/- 1.47%). Tip papillary collecting duct delivery was also significantly greater in the ANP-treated rats (1.97 +/- 1.96 vs. 3.09 +/- 0.60%). In addition, the percent of chloride delivered that was reabsorbed along the papillary collecting duct was significantly less in the ANP-treated rats. In conclusion, ANP inhibits reabsorption in some tubular segments between the superficial late distal tubule and papillary collecting duct base as well as in the accessible portion of the papillary collecting duct.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Chlorides; Glomerular Filtration Rate; Inulin; Kidney Tubules; Kidney Tubules, Distal; Male; Peptide Fragments; Rats; Rats, Inbred Strains; Reference Values; Renal Circulation

The hypotensive effects of anaritide (Wy-47,663), a 26 amino acid atrial natriuretic factor, were examined in conscious, monocrotaline-induced chronic pulmonary hypertensive rats. Anaritide (0.25-8 micrograms/kg per min i.v.) decreased systemic arterial pressure at 2-8 micrograms/kg per min by as much as -15.6 +/- 0.4 mm Hg. The pulmonary hypotensive response to anaritide was not different from vehicle treatment. We conclude that anaritide is more effective in decreasing systemic than pulmonary arterial pressures in monocrotaline-induced pulmonary hypertensive rats.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Hypertension, Pulmonary; Male; Monocrotaline; Peptide Fragments; Pulmonary Artery; Pyrrolizidine Alkaloids; Rats; Rats, Inbred Strains

The present study examined the bronchoprotective and bronchodilator efficacy of infused human atrial natriuretic factor [102-126] (Anaritide) in the guinea pig. Anesthetized and paralyzed male guinea pigs, ventilated via a tracheal cannula, were placed in a plethysmograph for measurement of agonist-induced changes in pulmonary mechanics. Reductions in dynamic compliance of the lung and airway conductance were produced either by 3 to 7 tidal volume breaths of leukotriene D4 (0.125 micrograms/ml) delivered through an ultrasonic nebulizer or by intravenous histamine (2.8 +/- 0.2 micrograms/kg). Infusion of Anaritide (1 microgram/kg/min), before evoking bronchoconstriction with either LTD4 or histamine, produced a significant protection against bronchoconstriction produced by aerosol LTD4, but not against histamine-induced bronchoconstriction of similar magnitude. In other experiments, Anaritide infusion (0.5-2 micrograms/kg/min) also rapidly reversed a stable LTD4-induced decrease in airway conductance, but did not produce a similar reversal of the decrease in dynamic compliance. The data provide evidence that intravenous Anaritide exerts both bronchoprotective and bronchodilator effects against LTD4-induced bronchospasm.

Topics: Animals; Atrial Natriuretic Factor; Bronchi; Bronchoconstriction; Bronchodilator Agents; Guinea Pigs; In Vitro Techniques; Male; Peptide Fragments; SRS-A

Alterations in the levels or activity of atrial peptides may be associated with cardiovascular pathologies such as hypertension and congestive heart failure that are more common in the elderly. In the present study, we examined the possibility that vascular relaxation to atrial peptides may be affected by animal age. In vitro evaluation of the relaxation produced by atrial peptide-25 (AP-25) in serotonin-contracted rat aorta, carotid artery and mesenteric artery indicated that relaxation was greatest in tissues from rats 1-2 months of age. Nevertheless, roughly 80% of the maximal possible relaxation to AP-25 occurred in arteries from older rats (up to 18-19 months of age). A similar profile of relaxant responsiveness occurred with AP-21 (atriopeptin I). Unlike the arterial preparations examined, portal veins from rats of all ages relaxed similarly to AP-25, consistent with the lack of age-related changes in relaxation to beta-agonists in the rat portal vein. In vivo, AP-25 given intravenously lowered blood pressure to a similar extent in rats of all ages. Thus, the greater in vitro sensitivity of arteries from rats 1-2 months of age did not result in a greater reduction in blood pressure in these young rats. This latter observation is consistent with the possibility that the effect of atrial peptides on blood pressure may not be associated with an arterial event, but rather with an alteration in venous return and/or cardiac output as previously proposed. Since arteries from older rats were able to respond to atrial peptides, our studies add further support to the impetus to develop clinical agents that might either enhance atrial peptide levels or mimic the action of atrial peptides since no major decline in receptor function of atrial peptides occurred with advanced age.

Topics: Aging; Animals; Arteries; Atrial Natriuretic Factor; Blood Pressure; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Peptide Fragments; Portal Vein; Rats; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Serotonin; Vasodilation

Two atrial natriuretic peptides, containing 25 amino acid residues, ANF IV, and 21 amino acid residues, ANF V, were synthesized by a solid phase method and oxidized with K3Fe(CN)6 to form a disulfide bridge. Synthetic ANF IV exhibited a natriuretic activity with an ED50 70 times higher than that of synthetic ANF V, whereas the longer peptide was only 2.5 times more potent in chick rectal smooth muscle relaxant activity. Both peptides inhibited norepinephrine-induced contraction of rabbit aorta. The shorter peptide, ANF V, was 300 times less efficient than the longer peptide, ANF IV. It is proposed that the carboxy-terminal of ANF IV seems to have a modulating effect on receptor affinity in kidney and vascular tissue.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Carbachol; Chickens; Chromatography, High Pressure Liquid; Furosemide; Indicators and Reagents; Muscle Proteins; Muscle Relaxation; Muscle, Smooth; Natriuresis; Norepinephrine; Peptide Fragments; Rats; Rectum