Brain Natriuretic Peptide Infusion Research Articles

Clinical research of recombinant human brain natriuretic peptide combined with sodium nitroprusside in the treatment of acute decompensated heart failure

Objective To investigate the effects of recombinant human brain natriuretic peptide and sodium nitroprusside in the treatment of acute decompensated heart failure. Methods 82 patients with acute decompensated heart failure were randomly divided into observation group and control group, 41 cases in each group.The control group was given sodium nitroprusside intravenous infusion therapy on the basis of routine treatment.The observation group was given recombinant human brain natriuretic peptide infusion treatment on the basis of control group treatment.The clinical efficacy was compared between the two groups. Results The total effective rate of the observation group was 95.12%, which was significantly higher than 75.61% of the control group (χ2=5.33, P 0.05). Conclusion Recombinant human brain natriuretic peptide combined with sodium nitroprusside could significantly improve the clinical curative effect of acute decompensated heart failure, improve heart function of patients, and inhibit myocardial remodeling.It had good security. Key words: Recombinant human brain natriuretic peptide; Sodium nitroprusside; Acute decompensated heart failure

Defective Natriuretic Peptide Receptor Signaling in Skeletal Muscle Links Obesity to Type 2 Diabetes.

Circulating natriuretic peptide (NP) levels are reduced in obesity and predict the risk of type 2 diabetes (T2D). Since skeletal muscle was recently shown as a key target tissue of NP, we aimed to investigate muscle NP receptor (NPR) expression in the context of obesity and T2D. Muscle NPRA correlated positively with whole-body insulin sensitivity in humans and was strikingly downregulated in obese subjects and recovered in response to diet-induced weight loss. In addition, muscle NP clearance receptor (NPRC) increased in individuals with impaired glucose tolerance and T2D. Similar results were found in obese diabetic mice. Although no acute effect of brain NP (BNP) on insulin sensitivity was observed in lean mice, chronic BNP infusion improved blood glucose control and insulin sensitivity in skeletal muscle of obese and diabetic mice. This occurred in parallel with a reduced lipotoxic pressure in skeletal muscle due to an upregulation of lipid oxidative capacity. In addition, chronic NP treatment in human primary myotubes increased lipid oxidation in a PGC1α-dependent manner and reduced palmitate-induced lipotoxicity. Collectively, our data show that activation of NPRA signaling in skeletal muscle is important for the maintenance of long-term insulin sensitivity and has the potential to treat obesity-related metabolic disorders.

Abstract 325: Brain Natriuretic Peptide During Coronary Intervention Prevents Endothelial Dysfunction Post PCI via NP-cGMP Activation

Background: Contrast media (CM) administrated during percutaneous coronary intervention (PCI) is associated with endothelial dysfunction (ED) and systemic vascular injury. Brain natriuretic peptide (BNP) administration 24 hours post PCI decreases ED. Aims: To evaluate 1.The ability of human BNP (hBNP) infusion during PCI, to prevent ED in acute coronary syndrome's (ACS) patients post the PCI. 2. The effect of CM on human coronary microvascular endothelial cells (HCMEC).3. Explain ED by invitro study. Methods and results (in vivo): Non-ST elevation ACS patients who underwent PCI (111) were randomized into 2 groups: an hBNP group who received hBNP infusion during the procedure (n=44), and control group who received nitroglycerin (n=67). Flow mediated dilatation (FMD) (by ≥2.5%), BNP, corin, serum creatinine (sCr) and estimate Glomerular Filtration Rate (eGFR), before and 24 hr after operative were recorded, starting with the same baseline. The post PCI FMD and eGFR were significantly reduced in the control group (p=0.05, 0.002) but not in the hBNP group (p=0.16, 0.4). BNP, corin and sCr increased significantly in the control group (p=0.001, 0.003, 0.0002 respectively) but not in hBNP group (p=0.09, 0.07, 0.18). Methods and results (in vitro): HCMEC were treated with CM (10%) in the presence and absence of BNP. eNOS, corin and cGMP levels were measured by ELISA and the results were compared to untreated cells. In both treatments eNOS was significantly reduced (p=0.001) and corin was significantly increased (p=0.002). cGMP was not affected by CM treatment (p=0.278), but was increased significantly (p=0.001) by hBNP combination. cGMP immuno-flourescence staining of HCMEC showed distorted cellular cGMP appearance by CM treatment, that was corrected in the combination with hBNP with accentuated subsarcolemmal staining. Conclusions: CM reduces eNOS level in HCMEC. Therefore, reduced in NO-cGMP pathway's products, probably is the mechanism that induces ED in-vivo. BNP treatment reduces FMD diminution and kidney injury post PCI. A compensatory rise in corin that increases BNP as well as the hBNP administration, invivo and invitro, maintains cytosolic cGMP via NP-cGMP pathway, and compensates for NO-cGMP loss, (reduced sGC) and thus prevents ED.

Recent advances in natriuretic peptide family genes and cardiovas-cular diseases

Natriuretic peptide family consists of several hormones produced by cardiomyocyte, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). They possess similar gene structures and protective effects of cardiovascular physiology, such as anti-hypertrophy, anti-fibrosis, myocardial relaxation and blood pressure regulation. The corresponding natriuretic peptide receptor A, B and C mediate multiple effects of natriuretic peptides to maintain cardiovascular homeostasis. Specially, natriuretic peptide receptor-A preferentially binds ANP and BNP, while natriuretic peptide receptor-B is more selective for C-type natriuretic peptides. Natriuretic peptide receptor-C(NPR-C), binding all kinds of natriuretic peptides, clears natriuretic peptides from the circulation through receptor-mediated internalization and degradation. BNP levels were reported to be a good predictor of left ventricular dysfunction and decompensated heart failure from a clinical standpoint. BNP infusion is an effective treatment for acute heart failure. Investigations on natriuretic peptides' single nucleotide polymorphisms and biological function suggested that they could be associated with several cardiovascular diseases, such as atrial fibrillation, cardiomyopathy, heart failure and so on. Transgenic mice with natriuretic peptides and their receptors gene deletion display myocardial hypertrophy and fibrosis, which are associated with the development of hypertension, cardiomyopathy and heart failure. Certain stimuli triggering cardiac hypertrophy and ischemic injuries may be involved in regulating gene expression of natriuretic peptides and their receptors. Therefore, advances in understanding of natriuretic peptide family genes and their regulatory mechanisms will lead to greater insight into the pathogenesis of cardiovascular diseases and blaze a new trail in clinical treatment.

Therapeutic effects of continuous infusion of brain natriuretic peptides on postmyocardial infarction ventricular remodelling in rats

Previous studies have shown protective effects of brain natriuretic peptide (BNP) against the postmyocardial infarction (MI) remodelling process. The transcription factor NF-κB is known to play an important role after MI. To investigate if NF-κB is involved in the protective effects of BNP against adverse post-MI remodelling. Rats were randomly assigned to five groups: sham-operation; MI by coronary ligation; MI treated with chronic BNP infusion; MI treated with enalapril; MI treated with BNP+enalapril. Rats were closely monitored for survival rate analysis. Rats from each group were sacrificed on days 3, 7 and 28 postoperation. The results showed that chronic continuous BNP infusion achieved similar effects to enalapril therapy, as evidenced by improved survival rate within the 28-day observation period compared with MI group rats; this effect was closely associated with preserved cardiac geometry and performance. The treatment combination did not offer extra benefits in terms of survival rate. Both BNP and enalapril therapy produced higher heart tissue concentrations of cyclic guanosine monophosphate and lower expression levels of inflammatory cytokines, including tumour necrosis factor-α, interleukin-1 and interleukin-6. These benefits were associated with lower phosphorylation levels of NF-κB subunits IκBα, p50 and p65. While enalapril significantly inhibited extracellular matrix remodelling via regulation of the protein expression ratio of matrix metalloproteinase/tissue inhibitor of metalloproteinase and the activity of matrix metalloproteinase, these variables were not affected by BNP, indicating that the two therapies involve different mechanisms. Chronic BNP infusion can provide beneficial effects against adverse post-MI remodelling.

Slower onset of vasodilating action of brain natriuretic peptide (BNP) compared to atrial natriuretic peptide (ANP) in human forearm resistant vessels

To investigate possible differences in the time course of vasodilating effects of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in humans. We measured forearm blood flow (FBF) by strain gauge plethymography and cyclic GMP spillover during and after intra-arterial infusions of BNP and ANP at 16.2 pmol/min for 30 min in healthy subjects. The steady-state responses of FBF and cyclic GMP to the infusion were achieved approximately 20 min after commencement of the infusion of BNP, but within 5 min for ANP, with similar magnitudes of maximum responses. These parameters more slowly returned to the baseline value after withdrawal of the BNP infusion than after the ANP infusion. The onset and disappearance of the guanylate cyclase-stimulating and vasodilating effects of BNP were significantly slower than those of ANP. This differing mode of vasodilator action may be relevant to the therapeutic use of natriuretic peptides.

Acute combination therapy with Sildenafil and Brain Natriuretic Peptide attenuates monocrotaline (MCT)‐induced pulmonary hypertension (PH) in rats

Background: PH is a lethal disease characterized by changes in pulmonary vascular structure and function. We hypothesized that combination therapy using sildenafil (SILD) and brain natriuretic peptide (BNP) synergistically attenuates PH while minimizing systemic effects compared to monotherapies. Methods: Adult male SD rats were injected (SC) with MCT (n=36, 50mg/kg). After 5 weeks, under anesthesia, the rats were instrumented to measure mean arterial pressure (MAP) and right ventricular systolic pressure (RVSP) during infusions of vehicle, SILD (85 mcg/kg/min, IV), and BNP (50 and 100 ng/kg/min, IV) alone and in combination. Results: Vehicle infusions did not alter hemodynamic variables. SILD alone decreased RVSP (17±5.6%, P=0.01) and decreased MAP (4±4.7%, P=NS). BNP alone at 50 and 100 ng/kg/min decreased RVSP (28±5.3%; 27±2.9%, both P<0.001) and MAP (8.7±5.3%; 14±4.1%, P=NS, P=0.006). Combination therapy with SILD and BNP (100 ng/kg/min) lowered RVSP (27±3.2%, P<0.001) and increased systemic effect (−21±3.1%, P<0.001). Conclusions: Combination SILD and BNP attenuates MCT-induced PH compared with monotherapies while causing additive systemic side effects. At the tested doses, BNP and SILD monotherapies are preferred options. Further studies are needed to determine the efficacy of lower dose combination therapy before testing in humans. Research supported by Scios Corporation.

Introduction of Metoprolol Increases Plasma B-Type Cardiac Natriuretic Peptides in Mild, Stable Heart Failure

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. 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). 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.

Pulmonary Hemodynamic Responses to Brain Natriuretic Peptide and Sildenafil in Patients With Pulmonary Arterial Hypertension

Brain natriuretic peptide (BNP) blunts hypoxic pulmonary hypertension in animal models, but its acute hemodynamic effects in patients with pulmonary arterial hypertension (PAH) are not known. The aim of this study was to determine if human B-type natriuretic peptide is a safe and efficacious pulmonary vasodilator in patients with PAH and if the pulmonary hemodynamic effects are potentiated by phosphodiesterase inhibition. Open-label study. Medical ICUs of three tertiary care hospitals in New England. Thirteen consecutive adult patients undergoing right-heart catheterization and a pulmonary vasodilator trial for the initial evaluation of PAH. Patients were administered inhaled nitric oxide (iNO), i.v. epoprostenol, and a 3-h infusion of BNP alone and 1 h after an oral dose of the phosphodiesterase-5 inhibitor sildenafil. iNO and sildenafil alone decreased mean pulmonary artery pressure (mPAP) without a significant fall in pulmonary vascular resistance (PVR). Epoprostenol decreased both mPAP and PVR. BNP alone had no significant effect on pulmonary hemodynamics, but the combination of sildenafil plus BNP decreased mPAP and PVR for up to 6 h after stopping BNP. The decrease in mPAP with sildenafil plus BNP (+/- SE) was greater than after 1 h of sildenafil alone (44.6 +/- 3.8 to 40.6 +/- 3.9 mm Hg, p = 0.027). An acute vasodilator response, defined as a decrease in mPAP > 10 mm Hg and end mPAP < 40 mm Hg, was seen in 0 of 8 patients with iNO, 1 of 13 patients with epoprostenol, 0 of 13 patients with BNP, and 4 of 12 patients with sildenafil plus BNP. BNP decreased mean systemic arterial pressure (5.6 +/- 2.8 mm Hg) but had no effect on cardiac output or systemic vascular resistance. A 3-h BNP infusion does not significantly improve pulmonary hemodynamics in most patients with PAH but is well tolerated and augments the acute pulmonary vasodilator effect of sildenafil.

Acute Cardiopulmonary Hemodynamic Effects of Brain Natriuretic Peptide in Patients With Pulmonary Arterial Hypertension

Brain natriuretic peptide (BNP) has been shown to reverse hypoxic pulmonary vasoconstriction and to blunt the development of hypoxic pulmonary hypertension in animal models, but its acute cardiopulmonary effects on adult patients with established pulmonary arterial hypertension (PAH) has not been well-studied. We compared the acute pulmonary vasodilator effect of BNP to that of inhaled nitric oxide (iNO) [5, 10, 20 ppm] and/or IV epoprostenol (4 to 12 ng/kg/min) in 13 adult patients with PAH. Each patient received two BNP infusions (a 2 μg/kg bolus followed by a 3-h infusion at 0.01 μg/kg/min) separated by a washout period of at least 6 h.

Nitric oxide and potassium channels are involved in brain natriuretic peptide induced vasodilatation in man.

Brain natriuretic peptide (BNP) causes vasodilatation but the mechanisms by which this is accomplished are not fully known. The aim of the present study was to determine whether, besides K+Ca2+-channels, nitric oxide (NO) is involved in BNP-induced vasodilatation. We studied 10 healthy males twice, in random order, at an interval of 2 weeks. Experiments always started with infusion of BNP (8-16-32-64 pmol/dl per min) into the brachial artery. On the first day this infusion was followed by a second BNP infusion combined with the K+Ca2+-channel-blocker, tetraethylammonium (TEA, 0.1 mg/dl per min), and on the other day by BNP infusion combined with the NO-synthase inhibitor, l-NG-monomethyl arginine (l-NMMA, 0.8 mumol/dl per min). The latter was then followed by a combined infusion of BNP, l-NMMA and TEA. All infusions were separated by a 1 h washout period. Forearm blood flow (FBF) was determined by venous occlusion plethysmography. Mean arterial pressure and heart rate did not change during any of the experiments. BNP alone induced a dose-dependent dilatation, which was similar on both days. TEA, l-NMMA, and their combination all reduced the BNP-induced dilatation (P < 0.05). The combined infusion had a significantly greater effect than TEA alone (P = 0.005). BNP infusions were associated with a significant increase in plasma cyclic guanosine monophosphate (cGMP) and C-type natriuretic peptide (CNP) (P < 0.05). BNP induces arterial vasodilatation not only by opening K+Ca2+-channels, but also via stimulation of NO production. In addition, BNP stimulates net CNP increase.

Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs.

beta-Adrenergic hyporesponsiveness in congestive heart failure (CHF) is mediated, in part, by nitric oxide (NO). NO and brain natriuretic peptide (BNP) share cGMP as a second messenger. Left ventricular (LV) function and inotropic response to intravenous dobutamine (Dob) were assessed during sequential intracoronary infusion of saline, HS-142-1 (a BNP receptor antagonist), and HS-142-1 + N(G)-monomethyl-L-arginine (L-NMMA) in anesthetized dogs with CHF due to rapid pacing and in normal dogs during intracoronary infusion of saline, exogenous BNP, and sodium nitroprusside (SNP). In CHF dogs, intracoronary HS-142-1 did not alter the inotropic response to Dob [percent change in first derivative of LV pressure (% Delta dP/dt) 47 +/- 4% saline vs. 54 +/- 7% HS-142-1, P = not significant]. Addition of intracoronary L-NMMA to HS-142-1 enhanced the response to Dob (% Delta dP/dt 73 +/- 8% L-NMMA + HS-142-1, P < 0.05 vs. H142-1). In normal dogs, intracoronary SNP blunted the inotropic response to Dob (% Delta dP/dt 93 +/- 6% saline vs. 71 +/- 5% SNP, P < 0.05), whereas intracoronary BNP had no effect. In CHF dogs, the time constant of LV pressure decay during isovolumic relaxation increased with intracoronary HS-142-1 (48 +/- 4 ms saline vs. 58 +/- 5 ms HS-142-1, P < 0.05) and further increased with intracoronary L-NMMA (56 +/- 6 ms HS-142-1 vs. 66 +/- 7 ms L-NMMA + HS-142-1, P < 0.05). Endogenous BNP and NO preserve diastolic function in CHF, whereas NO but not BNP inhibits beta-adrenergic responsiveness.

Monoclonal antibody against brain natriuretic peptide and characterization of brain natriuretic peptide-transgenic mice.

Brain natriuretic peptide (BNP) is a ventricular hormone with natriuretic, diuretic and vasodilatory actions. Acute infusion of BNP reduces cardiac pre- and after-load in healthy and diseased subjects, but its long-term therapeutic usefulness remains unclear. We prepared a monoclonal antibody specific to mouse BNP, and characterized transgenic mice overexpressing BNP in the liver (BNP-Tg mice) as a model of its chronic overproduction. Radioimmunoassay and neutralization experiments using the monoclonal antibody, KY-mBNP-I, were performed in BNP-Tg mice in conjunction with examinations of blood pressure (BP) and other markers for body fluid homeostasis. We developed highly sensitive radioimmunoassay to mouse BNP. In BNP-Tg mice, the plasma BNP concentration increased more than 100-fold, while ventricular BNP concentration did not alter, suggesting that ventricular BNP production was not down-regulated in BNP-Tg mice. The BNP concentration in the kidneys was 10-fold higher than nontransgenic (nonTg) littermates, accompanied with marked reduction in the atrial natriuretic peptide (ANP) concentration, that may be due to binding of circulating BNP to the natriuretic peptide receptors. BNP-Tg mice showed significantly low arterial BP, and a bolus intraperitoneal administration of KYmBNP-I completely abolished enhanced cGMP excretion in the urine and significantly increased the systolic BP. These results suggested that biological actions of BNP last and reduce cardiac overload in its longterm overproduction in the transgenic mouse model.

Brain natriuretic peptide: Disease marker or more in cardiovascular medicine?

Brain natriuretic peptide (BNP) is predominantly a cardiac ventricular hormone that promotes natriuresis and diuresis, inhibits the renin-angiotensin-aldosterone axis, and is a vasodilator. Plasma BNP levels are raised in essential hypertension, and more so in left ventricular (LV) hypertrophy and heart failure. Plasma BNP levels are also elevated in ischemic heart disease. Attempts have been made to use plasma BNP levels as a marker of LV dysfunction, but these have shown that plasma BNP levels are probably not sensitive enough to replace echocardiography in the diagnosis of LV dysfunction. Pericardial BNP or N-BNP may be more suitable markers of LV dysfunction. Plasma BNP levels are also elevated in right ventricular dysfunction, pregnancy-induced hypertension, aortic stenosis, age, subarachnoid hemorrhage, cardiac allograft rejection and cavopulmonary connection, and BNP may have an important pathophysiological role in some or all of these conditions. Clinical trials have demonstrated the natriuretic, diuretic and vasodilator effects, as well as inhibitory effects on renin and aldosterone of infused synthetic human BNP (nesiritide) in healthy humans. BNP infusion improves LV function in patients with congestive heart failure via a vasodilating and a prominent natriuretic effect. BNP infusion is useful for the treatment of decompensated congestive heart failure requiring hospitalization. The clinical potential of BNP is limited as it is a peptide and requires infusion. Drugs that modify the effects of BNP are furthering our understanding of the pathophysiological role and clinical potential of BNP. Increasing the effects of BNP may be a useful therapeutic approach in heart failure involving LV dysfunction. The levels of plasma BNP are increased by beta-blockers, cardiac glycosides and vasopeptidase inhibitors, and this may contribute to the usefulness of these agents in heart failure. (c) 2001 Prous Science. All rights reserved.

Renal effects of brain natriuretic peptide in patients with congestive heart failure

The effect of a continuous infusion of human brain natriuretic peptide, 2 pmol.min-1.kg-1, during 60 min was studied in nine patients with congestive heart failure and in 10 healthy control subjects. Brain natriuretic peptide increased from 1.6 to 101 pmol/l in control subjects and from 25 to 173 pmol/l in congestive heart failure during infusion. Urinary sodium excretion increased significantly in both congestive heart failure (60%) and control subjects (71%), but the absolute increase was significantly lower in congestive heart failure (27 micromol/min) than in control subjects (190 micromol/min). Urinary flow rate did not change. The lithium clearance technique was used to evaluate the segmental tubular function; the distal fractional reabsorption of sodium decreased significantly less in congestive heart failure (DFRNa: -0.8%) than in control subjects (DFRNa: -3.7%). Baseline values for glomerular filtration rate and renal plasma flow were reduced in congestive heart failure, but brain natriuretic peptide induced no significant changes between congestive heart failure and control subjects. Brain natriuretic peptide induced the same absolute increase in secondary messenger cGMP in plasma and urine in both patients and healthy subjects. It is concluded that the natriuretic response to brain natriuretic peptide infusion was impaired in patients with congestive heart failure compared with healthy subjects, and it is likely that the impaired natriuretic response was caused by a reduced responsiveness in the distal part of the nephron.

Chronic infusions of brain natriuretic peptide in conscious sheep: bioactivity at low physiological levels.

1. The circulating cardiac hormones atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have similar bioactivity, as judged by comparative short-term studies. However, no study has reported the effects of longer-term administration of BNP. Accordingly, we have compared the haemodynamic, hormonal and renal actions of chronic (4-day) administration of BNP and ANP (0.5 pmol. min-1.kg-1) in a vehicle-controlled study in normal conscious sheep. 2.BNP infusions raised plasma BNP levels within the physiological range (4 pmol/l increment, P<0.001) and increased cyclic GMP levels (P=0.01). BNP infusions induced significant falls in right atrial pressure (P=0.048), stroke volume (P=0.014) and cardiac output (P=0. 003) associated with a rise in haematocrit (P=0.001). There were no significant renal effects or changes in renin-aldosterone. By comparison, equimolar infusion of ANP induced a smaller increment in plasma ANP levels (2 pmol/l, P=0.03) with qualitatively similar but statistically non-significant changes in plasma cyclic GMP and haemodynamic indices.3.In conclusion, chronic low-dose infusions of BNP elevate plasma cyclic GMP levels and induce significant haemodynamic actions. This study provides evidence that subtle variations in circulating BNP levels, well within the physiological range, may be important in long-term cardiovascular control.

Brain natriuretic peptide inhibits hypoxic pulmonary hypertension in rats.

Brain natriuretic peptide (BNP) is a pulmonary vasodilator that is elevated in the right heart and plasma of hypoxia-adapted rats. To test the hypothesis that BNP protects against hypoxic pulmonary hypertension, we measured right ventricular systolic pressure (RVSP), right ventricle (RV) weight-to-body weight (BW) ratio (RV/BW), and percent muscularization of peripheral pulmonary vessels (%MPPV) in rats given an intravenous infusion of BNP, atrial natriuretic peptide (ANP), or saline alone after 2 wk of normoxia or hypobaric hypoxia (0.5 atm). Hypoxia-adapted rats had higher hematocrits, RVSP, RV/BW, and %MPPV than did normoxic controls. Under normoxic conditions, BNP infusion (0.2 and 1.4 micro g/h) increased plasma BNP but had no effect on RVSP, RV/BW, or %MPPV. Under hypoxic conditions, low-rate BNP infusion (0.2 micro g/h) had no effect on plasma BNP or on severity of pulmonary hypertension. However, high-rate BNP infusion (1.4 micro g/h) increased plasma BNP (69 +/- 8 vs. 35 +/- 4 pg/ml, P < 0.05), lowered RV/BW (0.87 +/- 0.05 vs. 1.02 +/- 0.04, P < 0.05), and decreased %MPPV (60 vs. 74%, P < 0.05). There was also a trend toward lower RVSP (55 +/- 3 vs. 64 +/- 2, P = not significant). Infusion of ANP at 1.4 micro g/h increased plasma ANP in hypoxic rats (759 +/- 153 vs. 393 +/- 54 pg/ml, P < 0.05) but had no effect on RVSP, RV/BW, or %MPPV. We conclude that BNP may regulate pulmonary vascular responses to hypoxia and, at the doses used in this study, is more effective than ANP at blunting pulmonary hypertension during the first 2 wk of hypoxia.

Effect of BNP on renal hemodynamics, tubular function and vasoactive hormones in humans

The effect of a continuous infusion of human brain natriuretic peptide (BNP) was studied in 48 healthy men. The study was randomized, placebo controlled, and single blind. BNP was given in doses of 1, 2, or 4 pmol.kg-1.min-1 for 60 min, and peak values of BNP in plasma were 38, 85, and 199 pmol/l, giving increments in plasma as seen in heart or renal failure. BNP infusion increased the urinary flow rate and the excretion of sodium in a dose-dependent way. The maximal effects were +65 and +156%, respectively. GFR increased and RPF decreased, the latter in a dose-dependent manner. Blood pressure, heart rate, angiotensin II, and aldosterone were all unaffected by infusion of BNP, whereas a direct inhibition of renin secretion was seen. With the use of the lithium clearance technique, we concluded that the tubular site of action is in both the proximal and distal segments, and the major effect on sodium handling is in the distal parts of the nephron.

Effects of Brain Natriuretic Peptide on Exercise Hemodynamics and Neurohormones in Isolated Diastolic Heart Failure

Experimental models suggest that brain natriuretic peptide (BNP) can modify left ventricular diastolic performance. The aim of this study was to evaluate the effects of BNP on resting and exercise hemodynamics and neurohormones in patients with isolated diastolic heart failure. Six patients with isolated diastolic heart failure were studied. After baseline hemodynamic measurements were obtained with use of thermistor-tipped pulmonary artery catheters, patients were randomized to receive infusion of BNP or placebo in a single-blind, crossover study. Hemodynamic and neurohormonal parameters were measured at rest after 30 minutes of infusion and during incremental supine bicycle exercise. BNP did not significantly affect resting hemodynamics but attenuated the rise in both pulmonary capillary wedge pressure (placebo, 23 +/- 2 mm Hg; BNP, 16 +/- 2 mm Hg; P < .01) and mean pulmonary artery pressure (placebo, 34 +/- 3 mm Hg; BNP, 29 +/- 3 mm Hg; P < .05) during exercise without affecting changes in heart rate, systemic blood pressure, or stroke volume. In response to BNP, there was significant suppression of plasma aldosterone concentration (placebo, 551 +/- 107 pmol/L; BNP, 381 +/- 56 pmol/L; P < .05). BNP infusion causes beneficial hemodynamic and neurohormonal effects during exercise in patients with isolated diastolic heart failure.

Acute effects of ANP and BNP on hypoxic pulmonary vasoconstriction in humans.

1. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have pulmonary vasorelaxant activity with plasma concentrations being elevated in patients with hypoxaemic pulmonary hypertension. However, their effects on acute hypoxic pulmonary vasoconstriction (HPV), the initiating stimulus for pulmonary hypertension have not to date been investigated. We have therefore studied the effects of ANP and BNP on acute HPV in humans. 2. Eight healthy volunteers were studied on three separate occasions. After reaching a resting haemodynamic state (t0), an infusion of either ANP (10 pmol kg-1 min-1), BNP (10 pmol kg-1 min-1) or placebo (5% dextrose) was commenced. This was given alone for 30 min (t30) before subjects were rendered hypoxaemic (SaO2 75-80%) for a further 30 min (t60), with the initial infusion continuing to t60. Pulsed-wave Doppler analysis of pulmonary artery flow was used to measure mean pulmonary arterial pressure (MPAP) and hence total pulmonary vascular resistance (PVR) was calculated. 3. MPAP and PVR both tended to decrease in response to ANP and BNP infusion, although compared with placebo, the difference at t30 was only statistically significant for PVR. Hypoxaemia increased MPAP and PVR, although values at t60 were significantly lower following both ANP and BNP compared with placebo. 4. In terms of the actual change in PVR (delta PVR) induced by hypoxaemia (from t30 to t60), BNP (146(16) dyn s cm-5), but not ANP (183(21) dyn s cm-5) significantly attenuated delta PVR compared with placebo (194(26) dyns s cm-5): mean difference BNP versus placebo 48 dyn s cm-5, 95% Cl 3-93. An identical pattern was observed for delta MPAP where BNP (15.9(1.1) mmHg), but not ANP (18.0(1.2) mmHg) significantly attenuated delta MPAP compared with placebo (19.0(1.7) mmHg): mean difference BNP versus placebo 3.1 mmHg, 95% Cl 0.7-5.5. 5. Thus, although both ANP and BNP exhibit pulmonary vasorelaxant activity, only BNP significantly attenuated the MPAP and PVR responses to acute hypoxaemia. This suggests that the natriuretic peptides may have a role in attenuating pulmonary hypertension secondary to hypoxaemia.