Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction.

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B-type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double-blinded placebo-controlled cross-over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (-4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (-4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01544998.

Detection of Neprilysin-Derived BNP Fragments in the Circulation: Possible Insights for Targeted Neprilysin Inhibition Therapy for Heart Failure.

BACKGROUND: Entresto™ is a new heart failure (HF) therapy that includes the neprilysin (NEP) inhibitor sacubitril. One of the NEP substrates is B-type natriuretic peptide (BNP); its augmentation by NEP inhibition is considered as a possible mechanism for the positive effects of Entresto. We hypothesized that the circulating products of BNP proteolysis by NEP might reflect NEP impact on the metabolism of active BNP. We suggest that NEP-based BNP cleavage at position 17-18 results in BNP ring opening and formation of a novel epitope with C-terminal Arg-17 (BNP-neo17 form). In this study, we use a specific immunoassay to explore BNP-neo17 in a rat model and HF patient plasma. METHODS: We injected BNP into rats, with or without NEP inhibition with sacubitril. BNP-neo17 in plasma samples at different time points was measured with a specific immunoassay with neglectable cross-reactivity to intact forms. BNP-neo17 and total BNP were measured in EDTA plasma samples of HF patients. RESULTS: BNP-neo17 generation in rat circulation was prevented by NEP inhibition. The maximum 13.2-fold difference in BNP-neo17 concentrations with and without sacubitril was observed at 2 min after injection. BNP-neo17 concentrations in 32 HF patient EDTA plasma samples ranged from 0 to 37 pg/mL (median, 5.4; interquartile range, 0-9.1). BNP-neo17/total BNP had no correlation with total BNP concentration (with r = -0.175, P = 0.680) and showed variability among individuals. CONCLUSIONS: BNP-neo17 formation is NEP dependent. Considering that BNP-neo17 is generated from the active form of BNP by NEP, we speculate that BNP-neo17 may reflect both the NEP activity and natriuretic potential and serve for HF therapy guidance.

Heads and Tails of Natriuretic Peptides: Neuroprotective Role of Brain Natriuretic Peptide.

BACKGROUND: Besides the relevant role of brain-type natriuretic peptide (BNP) as biomarker of cardioembolic strokes, new experimental evidences suggest that this peptide may mediate neuroprotective effects. In this study, we have evaluated for the first time the clinical association between BNP (by means of proBNP) and good outcome in ischemic stroke patients, and analyzed the effect of blood BNP increase in an ischemic animal model. METHODS AND RESULTS: A retrospective study with 2 different cohorts (262 patients in cohort I and 610 in cohort II) from the same prospective stroke registry was performed. proBNP concentration was analyzed within the first 12 hours from stroke onset. The primary predictor variable was functional outcome evaluated by modified Rankin Scale at 3 months. For the experimental study, BNP pretreatment was tested in an ischemic animal model subjected to a transient occlusion of the cerebral artery, and the infarct volume and sensorimotor deficit were evaluated for 14 days. Cardioembolic strokes presented a positive correlation between proBNP concentration and modified Rankin Scale at 3 months; however, noncardioembolic strokes presented a negative correlation. In the logistic regression analysis, noncardioembolic strokes with concentrations of proBNP ≥340 pg/mL were associated with a good outcome. In line with these clinical findings, the experimental study revealed that those BNP pretreated animals presented a reduction on infarct volumes at 24 hours and functional recovery at days 7 and 14 compared with the control groups. CONCLUSIONS: These clinical and experimental evidences support the potential role of BNP as a protective factor against cerebral ischemia.

Genetic and nongenetic factors influencing pharmacokinetics of B-type natriuretic peptide.

BACKGROUND: Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). However, there is wide individual variability in NP system activity, which could be partly genetic in origin. We explored genetic and nongenetic contributions to B-type natriuretic peptide (BNP) inactivation. METHODS: Chronic HF patients (n = 95) received recombinant human BNP (nesiritide) at standard doses, and BNP levels were measured at baseline, after 2 hours of infusion, and 30 minutes after discontinuation. Genomic DNA was genotyped for 91 single-nucleotide polymorphisms (SNP) in 2 candidate genes. We tested the association of patient characteristics and genotype with 5 pharmacokinetics (PK) parameters: elimination rate constant, ΔBNP, BNP clearance, adjusted BNP clearance, and half-life. Linear regression with pleiotropic analysis was used to test genotype associations with PK. RESULTS: Participants' mean age was 63 years, 44% were female, and 46% were African American. PK parameters varied widely, some >10-fold. HF type (preserved vs reduced) was associated with PK (P < .01), whereas renal function, demographics, and body mass index and were not. Two SNPs in MME (rs989692, rs6798179) and 2 in NPR3 (rs6880564, rs2062708) also had associations with PK (P < .05). CONCLUSIONS: The pharmacokinetics of BNP varies greatly in HF patients, differs by HF type, and possibly by MME or NPR3 genotype. Additional study is warranted.

Efficacy and safety of nesiritide in patients with acute decompensated heart failure.

Acute decompensated heart failure is a common clinical problem with associated poor outcomes. Over the last decade, attention to this area has greatly increased, with a focus on medical therapies that may safely offer improvement in acute symptoms and early outcomes. Previous therapies that focused on increased inotropy have generally failed to improve symptoms without adverse consequences. Thus, attention towards vasodilators and natriuretic peptides, such as nesiritide, has increased owing to nesiritide's symptomatic improvement and unique mechanism of improvement in hemodynamics. However, the pathophysiology of acute decompensated heart failure is complex and the impact of nesiritide on important clinical end points, beyond symptomatic and hemodynamic improvement, is unknown.

A sandwich ELISA for assessment of pharmacokinetics of HSA-(BNP)2 fusion protein in mouse plasma.

Brain natriuretic peptide (BNP) is a circulating hormone of cardiac origin that plays an important role in the regulation of intravascular blood volume and vascular tone. HSA-(BNP)(2), derived from the joining of human BNP to the C-terminus of human serum albumin (HSA), has been developed to prolong the BNP pharmacodynamic action. For the analysis of pharmacokinetics of the new drug, a novel sandwich enzyme-linked immunosorbent assay (ELISA) was established and validated to quantify HSA-(BNP)(2) fusion protein in mouse plasma. The ELISA method was calibrated with 1:10 and 1:100 dilutions of blank mouse plasma spiked with HSA-(BNP)(2) standard and validated with respect to parallelism, precision (intra- and inter-assay variation), accuracy (recovery), specificity and stability. The practical working range was estimated to be 31.2-2000ng/ml with the limit of detection was 7.8ng/ml. Recoveries ranged from 80.5 to 108.4%, while the intra- and inter-assay precisions were <2.73% and <4.32%, respectively. The terminal half-life of HSA-(BNP)(2) was 2.14h, which had extended more than 40 times compared to 3.1min half-life of BNP monomer in mouse.

Long-term effects of B-type natriuretic peptide infusion after acute myocardial infarction in a rat model.

INTRODUCTION: The effects of exogenous B-type natriuretic peptide (BNP) on postmyocardial infarction (MI) are not known. We tested the hypothesis that in vivo infusion of BNP would improve cardiac function and affect left ventricular (LV) remodeling in an experimental model of MI. METHODS: MI was induced by coronary ligation in rats and confirmed by echocardiography. 19 rats were randomized to 1 of 3 groups: sham (n = 7), MI + saline (n = 5), MI + BNP (400 ng.kg(-1).minute(-1)) (n = 7). Infusions were delivered for 7 days via venous catheters tunneled to an infusion pump. Rats were followed for 8 weeks. Echocardiography, hemodynamics, histology, and in vivo and ex vivo pressure-volume relationships were examined. RESULTS: LV systolic pressure, LV dP/dtmax, and infarct size improved with BNP treatment versus control MI group (132 +/- 4 vs.110 +/- 2 mm Hg, 8097 +/- 317 vs. 5816 +/- 378 mm Hg/s, 19.3% +/- 1.6% vs. 23.3% +/- 1.9%, respectively; all P < 0.05). Ex vivo end-diastolic pressure-volume relationship demonstrated reduced diastolic dysfunction after BNP therapy (P < 0.05 vs. control MI). Serum BNP levels confirmed delivery of BNP. CONCLUSIONS: We demonstrate beneficial effects on LV function and decreased LV remodeling with BNP infusion in an experimental model of acute MI.

Coupling of a vented column with splitless nanoRPLC-ESI-MS for the improved separation and detection of brain natriuretic peptide-32 and its proteolytic peptides.

The circulating concentration of a biomarker for congestive heart failure, Brain (B-type) Natriuretic Peptide (BNP-32), is measured using ELISA based assays in order to rapidly diagnose and monitor disease progression. The lack of molecular specificity afforded by these assays has recently come into question as emerging studies indicate there are potentially multiple heterogeneous forms of BNP in circulation with immunoreactive capabilities. In order to better understand the molecular biology of BNP-32 as it relates to congestive heart failure, it would thus be advantageous to use a detection platform such as Fourier transform ion cyclotron resonance mass spectrometry. This high resolving power mass spectrometer can provide unparalleled molecular specificity and can facilitate identification and characterization of the various molecular forms across all disease states. Unfortunately, BNP circulates at low concentrations (as low as 3fmol/mL). Thus, it will require a collaborative effort from a number of orthogonal front-end technologies to overcome the disconnect between the practical detection limits of this instrument platform and the physiological levels of BNP-32 and its alternative molecular forms. Herein, we begin optimization of these front-end techniques by first enhancing the conditions for online nanoLC-ESI-MS separations of BNP-32 and its proteolytic fragments. Through extensive analysis of various chromatographic parameters we determined that Michrom Magic C8 stationary phase used in conjunction with a continuous, vented column configuration provided advanced chromatographic performance for the nano-flow separations involving intact BNP-32 and its associated tryptic peptides. Furthermore, conditions for the tryptic digestion of BNP-32 were also studied. We demonstrate that the use of free cysteine as an alkylation quenching agent and a secondary digestion within the digestion scheme can provide targeted tryptic peptides with increased abundances. Combined, these data will serve to further augment the detection of BNP-32 by LC-MS.

Natriuretic peptides in cetaceans: identification, molecular characterization and changes in plasma concentration after landing.

Dolphins are aquatic animals free from gravity, and this may have imposed significant changes in their cardiovascular status and its hormonal regulation compared with terrestrial animals. This study molecularly characterized two major cardiovascular hormones, atrial and B-type natriuretic peptides (ANP and BNP) and measured their changes in dolphin plasma concentrations in relation to the cardiovascular status of the animal. We initially identified ANP and BNP in three species of dolphins (Lagenorhynchus obliquidens, Phocoenoides dalli and Tursiops truncatus). ANP precursors are highly conserved in most mammals, but dolphin BNP precursors were more variable. In molecular phylogenetic analyses, dolphin ANP and BNP precursors grouped with those of artiodactyls, particularly to the camel peptides. The chromatographic characterization of tissue and plasma molecular forms using specific radioimmunoassays showed that the predominant ANP and BNP in the atrium are prohormone and mature peptide, respectively, whereas mature ANP and BNP are circulating in the dolphin blood. A mass spectrometric analysis showed that atrial BNP consists of 26 amino acids, rather than the 32-amino-acid form detected in other mammals. Finally, changes in plasma ANP and BNP concentrations were examined in captive bottlenose dolphins (Tursiops truncatus) after their pool was drained. Plasma ANP and BNP concentrations did not change after landing, unlike terrestrial mammals. Plasma angiotensin II and cortisol concentrations did not change either, showing minor stress after landing. Since landed dolphins show a different cardiovascular status on land than terrestrial mammals, plasma ANP and BNP concentrations seem to reflect the cardiovascular status characteristic of dolphins.

ANP is cleared much faster than BNP in patients with congestive heart failure.

OBJECTIVE: To obtain a better understanding of the pharmacokinetics of atrial and brain natriuretic peptides (ANP and BNP, respectively), two peptide mediators used in the treatment of congestive heart failure (CHF). Although both peptides exert their effects by binding to a common receptor (natriuretic peptide receptor A) with about the same affinity, their respective loading and maintenance doses differ. METHODS: Sixteen CHF patients were randomized to be infused for 2 h with alpha-human ANP (0.05 microg/kg per minute) or BNP (0.01 microg/kg per minute). Plasma concentrations of both peptides were measured 0, 2, 5, 15, 30, 60 and 120 min post-infusion. The pharmacokinetic parameters were then calculated using a 1-compartment model. RESULTS: The plasma BNP concentrations in the ANP and BNP groups before infusion were 464.7 +/- 339.8 and 506.8 +/- 332.5 pg/ml, respectively. Following infusion, ANP disappeared from the circulation more rapidly than BNP: their plasma half-lives were 2.4 +/- 0.7 and 12.1 +/- 3.0 min, and their total body clearance volumes were 48.2 +/- 24.1 and 10.1 +/- 2.7 ml/min per kilogram, respectively. CONCLUSION: ANP has a shorter half-life in the plasma of CHF patients than BNP, which suggests that it controls hemodynamics more readily than BNP.

Introduction of metoprolol increases plasma B-type cardiac natriuretic peptides in mild, stable heart failure.

BACKGROUND: The effect of beta-blockade on the cardiac natriuretic peptides is poorly understood but could contribute to their beneficial treatment effect and may be relevant to clinical use of plasma brain natriuretic peptide (BNP)/N-terminal pro brain natriuretic peptide (NTproBNP) measurements in risk stratification and in titration of anti-heart failure therapy. METHODS AND RESULTS: Sixteen men with mild, stable heart failure (NYHA class II to III; left ventricular ejection fraction <40%) underwent serial blood sampling for plasma natriuretic peptide levels and received infusions of atrial natriuretic peptide (ANP) and BNP before and 6 weeks after the introduction and uptitration of metoprolol or 6 weeks unchanged therapy in a randomized, parallel-group design. Plasma natriuretic peptides (BNP, NTproBNP, ANP, and NTproANP) were increased by metoprolol (P<0.01 for all). The natriuretic responses to ANP and BNP infusions were sustained with the introduction of metoprolol despite reduced renal perfusion pressure. The levels of the noninfused natriuretic peptide were increased by both ANP and BNP infusions, and this effect was enhanced by metoprolol. The early plasma half-life (t(1/2)alpha) of BNP was prolonged by metoprolol (5.6+/-0.45 to 11+/-1.3 versus 5.7+/-0.8 to 6.6+/-1.3 minutes in control subjects; P=0.019). CONCLUSIONS: Plasma cardiac natriuretic peptide levels increase significantly with the introduction of metoprolol in heart failure as a result of effects on secretion and clearance. Natriuretic responses to NP infusions are sustained with beta-blockade despite reduced renal perfusion pressure. Clinicians should be aware that the introduction of metoprolol causes a rise in plasma BNP/NTproBNP that is unrelated to deterioration in clinical status and must be considered when measurements are undertaken for risk stratification or titration of treatment.

AlbuBNP, a recombinant B-type natriuretic peptide and human serum albumin fusion hormone, as a long-term therapy of congestive heart failure.

PURPOSE: B-type natriuretic peptide (BNP) has been in clinical use for the treatment of decompensated congestive heart failure. However, BNP has a very short half-life in circulation, which limits its application to acute CHF and requires continuous i.v. infusion. To provide superior pharmacological benefits of BNP to other stages of chronic congestive heart failure and to eliminate problems associated with drug delivery via continuous i.v. infusion, we have designed and evaluated AlbuBNP, a long-acting form of BNP by recombinant fusion to human serum albumin for use in chronic congestive heart failure, post-acute follow-up, and postmyocardial infarction. METHODS: Human BNP (1-32) was seamlessly fused to mature human serum albumin at N-terminus to create AlbuBNP. The bioactivities of AlbuBNP were evaluated by natriuretic peptide receptor-A mediated cGMP activation assay, hemodynamic responses, and plasma cGMP elevation. The pharmacokinetic properties were determined after single i.v. or s.c. bolus injection in C57/BL6 mice. RESULTS: AlbuBNP had approxiamtely the same maximal bioactivity as BNP to activate cGMP in the in vitro NPRA/cGMP assay. The EC50s were 28.4+/-1.2 and 0.46+/-1.1 nM for AlbuBNP and BNP, respectively. In spontaneously hypertensive rats, AlbuBNP lowered both systolic and diastolic blood pressure, having sustainable mean arterial pressure reduction for more than 2 days. Six nmol/kg AlbuBNP i.v. bolus in mice increased plasma cGMP level 5.6-fold over the baseline. The elimination half-life in mice was dramatically increased from 3 min for BNP to 12-19 h for AlbuBNP. CONCLUSIONS: AlbuBNP is bioactive and has desired pharmacokinetic properties for long-term use. It has the potential to be further developed as a new therapeutic option for chronic, acute, and post-acute CHF to alleviate symptoms, improve clinical status, and slow the disease progression by sustained drug exposure via infrequent simple subcutaneous injections.

Nesiritide for the treatment of decompensated heart failure.

Heart failure is the leading cause of hospitalizations in the USA, and is associated with significant morbidity, mortality and resource utilization. Established therapies for chronic heart failure have been shown to improve outcomes, but treatment for decompensated heart failure remains largely empiric. Nesiritide (Natrecor) is a synthetic analog of human B-type natriuretic peptide, a peptide released by the ventricular myocardium in response to increased wall tension. The physiologic effects of human B-type natriuretic peptide include natriuresis, vasodilation and neurohormonal modulation. In clinical trials, nesiritide has been shown to decrease cardiac filling pressures, increase cardiac index, and improve the clinical status of patients with acute decompensated heart failure. Compared with other available intravenous agents for heart failure, nesiritide is effective, generally well-tolerated with few adverse effects, and does not require invasive monitoring during administration. Nesiritide has proven to be an effective new treatment for patients with decompensated heart failure.

Nesiritide for the treatment of congestive heart failure.

Nesiritide (Natrecor) is a recombinant form of the human B-type natriuretic peptide (BNP) that has been shown, through several studies, to have beneficial natriuretic, diuretic and vasodilatory effects in the treatment of congestive heart failure (CHF). Nesiritide mimics the actions of endogenous BNP by binding to and stimulating receptors in the heart, kidney and vasculature. Nesiritide functions as both a potent venous and arterial vasodilator and has been shown to improve cardiac haemodynamics more rapidly and to a greater extent than intravenous nitroglycerin, as well as having fewer side effects. When compared in an open-label trial, nesiritide has also been shown to be less proarrhythmic than dobutamine. The major adverse effect of nesiritide, as with other vasodilators, is symptomatic hypotension, which occurred infrequently in clinical trials. Overall, nesiritide represents an effective and safe therapeutic option for the treatment of decompensated CHF.

Vascular effects of natriuretic peptides in healthy men.

BACKGROUND: Most effects of atrial (ANP) and B-type natriuretic peptide (BNP) result from stimulation of the guanylyl-cyclase type A receptor. Chronic elevation causes hyporesponsiveness to ANP, whereas BNP effects tend to be preserved, implying an additional pathway of action. We, therefore, investigated the hemodynamic effects of co-infusion of ANP, BNP, and, as a positive control acting on type B receptor, C-type natriuretic peptide (CNP). Furthermore, vascular responses to short and prolonged infusions were compared to investigate rapid hyporesponsiveness of guanylyl-cyclase type A receptor. METHODS: In 11 healthy volunteers, arterial response to continuous intra-arterial infusion of ANP (60 pmol/100 mL forearm tissue volume [FAV]/min) was assessed by venous occlusion plethysmography. Then, co-infusion of a similar dose of ANP, BNP, or CNP was administered in randomized order. Each infusion phase was followed by a washout period. Then, ANP was restarted, followed by co-infusion of one of the natriuretic peptides not yet infused. After a further washout period, ANP was restarted, followed by co-infusion of the natriuretic peptide not yet co-infused. In 6 subjects, infusion time was adjusted to plasma half-lives (5 times), and in the other 5 subjects, infusion time was 5 minutes. RESULTS: ANP alone caused the expected vasodilation from 2.7 +/- 0.3 mL/min/100 mL FAV to 6.0 +/- 0.9 mL/min/100 mL FAV (P < .004). This response remained unchanged in the group that received short-term infusions (6.2 +/- 0.8 mL/min/100 mL FAV to 6.6 +/- 1.1 mL/min/100mL FAV) but was reduced over time in the group receiving longer-term infusions (6.5 +/- 1.2 mL/min/100 mL FAV to 4.5 +/- 0.7 mL/min/100mL FAV, P < .05; difference between groups P < .05). Co-infusions of ANP, BNP, and CNP caused minor additional vasodilation (mean 0.8 +/- 0.2 mL/min/100ml FAV, P < .01), which did not differ between the different co-infused natriuretic peptides. CONCLUSION: Our data provide evidence for rapid desensitization of the guanylyl-cyclase type A receptor in humans, but do not support the presence of a BNP-specific receptor.

Nesiritide: a new therapy for the treatment of heart failure.

Human BNP serves to compensate for deteriorating cardiac function causing preload and afterload reductions, natriuresis, diuresis, suppression of the renin-angiotensin-aldosterone system (RAAS) and endothelin-1, and lowering of norepinephrine. Based on its unique pharmacologic profile, nesiritide results in clinically significant balanced vasodilation of arteries and veins, and may be well suited for patients presenting with various scenarios of decompensated CHF usually due to volume overload (NYHA classes II-IV). More than 1000 subjects have participated in clinical trials with nesiritide and more than 55,000 patients have been treated with nesiritide since it was approved for use in August 2001. Unlike nitroglycerin, tachyphylaxis did not appear to occur with Natrecor. The complete efficacy profile of nesiritide included preload reduction (PCWP and RAP), reductions in pulmonary artery pressures, afterload reduction (systemic vascular resistance), and increases in cardiac index and stroke volume index (which are dose-dependent and not the result of a direct inotropic effect), without increasing heart rate. Unlike inotropes, the beneficial hemodynamic effects produced by nesiritide do not cause an increase in myocardial oxygen consumption (MVO(2)), an important consideration for patients with acutely decompensated heart failure. Because Nesiritide is not an inotrope, it does not affect myocardial contractility, as does a beta-adrenergic receptor agonist, or a phosphodiesterase III inhibitor. As a result, nesiritide is not arrhythmogenic. Nesiritide should be considered for patients presenting with acutely typical or useful decompensated heart failure, especially those with dyspnea at rest or with minimal activity.

Brain natriuretic peptide (nesiritide) in the treatment of heart failure.

Over the last decade brain natriuretic peptide (BNP) emerged as a cardiac hormone of clinical interest in diagnosis, prognosis and treatment of patients with Heart Failure (HF). The diagnostic potential of BNP is now well established both in patients with suspected HF as well as in patients with asymptomatic left ventricular systolic dysfunction. The prognostic information obtained from BNP levels in HF and acute myocardial infarction patients seems even more promising. Nesiritide is a synthetic peptide, homologous to endogenous BNP. It is a balanced vasodilator with diuretic and natriuretic properties. It decreases the elevated levels of neurohormones resulting from activation of the sympathetic and renin-aldosterone systems in HF. The results of clinical trials involving more than 2000 patients with decompensated HF are now available. In these trials nesiritide was administered by single or repeated bolus injections, as well as by sustained infusions. Nesiritide has been shown to produce a potent, dose-related vasodilator effect that is rapid in onset and sustained during infusion. Balanced vasodilation is reflected by decreases in systemic vascular resistance, pulmonary artery wedge pressure and right atrial pressure. No tachyphylaxis has been observed in these trials. Efficacy of nesiritide in the treatment of decompensated HF has been demonstrated. Trials comparing nesiritide with conventional treatment of decompensated HF showed that nesiritide compares favorably to standard agents. The safety profile has been excellent with a dose-dependent hypotension as the major side effect. Ventricular arrhythmia was not more frequent in patients treated with nesiritide than with placebo. Thus, nesiritide appears to be useful as a first-line agent in the treatment of patients with decompensated HF.

Cardiac natriuretic peptides--hope or hype?

In recent years, biomedical science has witnessed the emergence of peptide biochemicals as significant topics of research. Some of these peptides are of little potential clinical use, while others, of which cardiac natriuretic peptides are an example, appear to be promising. This particular group of peptides (i.e. ANP, BNP and CNP) shows promising diagnostic as well as therapeutic potential for various pathological conditions. In the case of acute myocardial infarction, these peptides have significant diagnostic and predictive properties, more so than other biochemicals such as adrenaline, renin and aldosterone. In addition, ANP is found to have significant benefits over the classical anti-anginal drug glyceryl trinitrate. However, as is the case with other peptides, applying these benefits clinically may not be easy because of the structure of the compounds, but various strategies are now being applied to solve this problem. These include the use of non-peptide receptor ligands, inhibitors of ANP metabolism, gene therapy and so on. The development of drugs in clinical practice, which exploits the natriuretic peptides system therefore seems to be promising, and this article reviews advances in our understanding of these compounds.

Clearance of human brain natriuretic peptide in rabbits; effect of the kidney, the natriuretic peptide clearance receptor, and peptidase activity.

Although the synthetic version of the cardiac peptide human brain natriuretic peptide (hBNP) has demonstrated beneficial cardiovascular effects in clinical studies, little is known about mechanisms governing its elimination from the blood. This study measured the role of the kidney, the natriuretic peptide clearance (NP-C) receptor, and peptidase digestion on the elimination of synthetic hBNP from the plasma compartment of rabbits. The estimated plasma steady state resulting from a continuous i.v. infusion was achieved within 50 min and was related in a linear manner with the infusion rate of the drug. Complete restriction of kidney blood flow by bilateral suture-ligation of the renal arteries compared with sham-treated animals reduced the clearance of hBNP by approximately half (24 +/- 9 ml/min versus 47 +/- 14 ml/min, respectively, p <. 007). Pharmacological blockade of the NP-C receptor with a clearance receptor-specific analog of atrial natriuretic peptide increased in a statistically significant and dose-related manner the plasma steady-state level of hBNP during continuous i.v. infusion of hBNP (maximum effect of 1.9 +/- 0.3-fold, p <.01). The peptidase inhibitor phosphoramidon increased in a dose-related manner the plasma steady-state level of hBNP 1.7 +/- 0.4-fold during continuous i.v. infusion of hBNP in rabbits. These data suggest that the kidney, the NP-C receptor, and peptidases are all important in the elimination of hBNP from the plasma compartment.

Pharmacokinetics and biological actions of subcutaneously administered human brain natriuretic peptide.

Human brain natriuretic peptide (hBNP) has demonstrated favorable hemodynamic effects in patients with congestive heart failure; however, the peptidic nature of this compound has focused clinical testing on protocols involving intravenous delivery. We have studied subcutaneous delivery as an alternative method of administering hBNP. Administration of 30 microgram/kg hBNP by either subcutaneous or intravenous delivery protocols resulted in significant hBNP-immunoreactive material in the plasma with area under the plasma concentration-time curve values of 310 +/- 20 nmolxmins/liter and 187 +/- 47 nmolxmins/liter, respectively. Plasma cyclic GMP, a surrogate marker of activation of the biological receptor for hBNP, was elevated for a longer period of time following subcutaneous delivery compared with intravenous delivery. Subcutaneous delivery of 30 microg/kg hBNP resulted in natriuresis, diuresis and reduced systolic blood pressure in anesthetized normotensive rabbits, effects similar in magnitude yet prolonged in duration compared with those elicited by the same dose of hBNP delivered intravenously. Systolic blood pressure following hBNP treatment remained below base-line values for 50 and 150 min following intravenous and subcutaneous delivery protocols, respectively. These results suggests that subcutaneous delivery of hBNP may be a viable therapeutic alternative to intravenous modes of delivery.