Action Of B-type Natriuretic Peptide Research Articles

Inhibitory action of B-type natriuretic peptide on adrenocorticotropic hormone in patients with acute coronary syndrome.

In addition to the classical actions of hemodynamic regulation, natriuretic peptides (NPs) interact with various neurohumoral factors that are deeply involved in the pathophysiology of cardiovascular diseases. However, their effects on the hypothalamic-pituitary-adrenal (HPA) axis, which is activated under acute high-stress conditions in acute coronary syndrome (ACS), remain largely unknown. We investigated the impact of plasma B-type NP (BNP) on plasma adrenocorticotropic hormone (ACTH)-cortisol levels during the acute phase of ACS ischemic attacks. The study population included 436 consecutive patients with ACS for whom data were collected during emergency cardiac catheterization. Among them, biochemical data after acute-phase treatment were available in 320 cases, defined as the ACS-remission phase (ACS-rem). Multiple regression analyses revealed that plasma BNP levels were significantly negatively associated with plasma ACTH levels only during ACS attacks (P < 0.001), but not in ACS-rem, whereas plasma BNP levels were not significantly associated with plasma cortisol levels at any point. Accordingly, covariance structure analyses were performed to clarify the direct contribution of BNP to ACTH by excluding other confounding factors, confirming that BNP level was negatively correlated with ACTH level only during ACS attacks (β = -0.152, P = 0.002), whereas BNP did not significantly affect ACTH in ACS-rem. In conclusion, despite the lack of a significant direct association with cortisol levels, BNP negatively regulated ACTH levels during the acute phase of an ACS attack in which the HPA axis ought to be activated. NP may alleviate the acute stress response induced by severe ischemic attacks in patients with ACS.NEW & NOTEWORTHY BNP negatively regulates ACTH during a severe ischemic attack of ACS in which hypothalamic-pituitary-adrenal axis ought to be activated, indicating an important role of natriuretic peptides as a mechanism of adaptation to acute critical stress conditions in humans.

The therapeutic effect of B-type natriuretic peptides in acute decompensated heart failure.

B-type natriuretic peptide (BNP) exhibits roles in natriuresis and diuresis, making it an ideal drug that may aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these have demonstrated beneficial outcomes. The current challenge for BNP research in acute HF lies in addressing a failure of concept and a reluctance to abandon an ineffective research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP, as well as better integration of basic and clinical science.

P883Thermogenic action of B-type natriuretic peptide in patients with cardiovascular diseases according to covariance structure analysis

P883Thermogenic action of B-type natriuretic peptide in patients with cardiovascular diseases according to covariance structure analysis

B-type natriuretic peptide and heart failure: what can we learn from clinical trials?

The B-type natriuretic peptide (BNP) may favour natriuresis and diuresis, making it an ideal drug to aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these has resulted in a better outcome. The current challenge for BNP research in acute HF lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP as well as a better integration of basic and clinical science.

Efficacy of B-Type Natriuretic Peptide Is Coupled to Phosphodiesterase 2A in Cardiac Sympathetic Neurons

Elevated B-type natriuretic peptide (BNP) regulates cGMP-phosphodiesterase activity. Its elevation is regarded as an early compensatory response to cardiac failure where it can facilitate sympathovagal balance and cardiorenal homeostasis. However, recent reports suggest a paradoxical proadrenergic action of BNP. Because phosphodiesterase activity is altered in cardiovascular disease, we tested the hypothesis that BNP might lose its efficacy by minimizing the action of cGMP on downstream pathways coupled to neurotransmission. BNP decreased norepinephrine release from atrial preparations in response to field stimulation and also significantly reduced the heart rate responses to sympathetic nerve stimulation in vitro. Using electrophysiological recording and fluorescence imaging, BNP also reduced the depolarization evoked calcium current and intracellular calcium transient in isolated cardiac sympathetic neurons. Pharmacological manipulations suggested that the reduction in the calcium transient was regulated by a cGMP/protein kinase G pathway. Fluorescence resonance energy transfer measurements for cAMP, and an immunoassay for cGMP, showed that BNP increased cGMP, but not cAMP. In addition, overexpression of phosphodiesterase 2A after adenoviral gene transfer markedly decreased BNP stimulation of cGMP and abrogated the BNP responses to the calcium current, intracellular calcium transient, and neurotransmitter release. These effects were reversed on inhibition of phosphodiesterase 2A. Moreover, phosphodiesterase 2A activity was significantly elevated in stellate neurons from the prohypertensive rat compared with the normotensive control. Our data suggest that abnormally high levels of phosphodiesterase 2A may provide a brake against the inhibitory action of BNP on sympathetic transmission.

Differential Cardiac versus Renal Response to Acute Volume Overload in Human Preclinical Systolic Dysfunction and Renal Dysfunction with the Combination of PDEV Inhibition and BNP Administration

Preclinical systolic dysfunction (PSD) is defined by LVEF < 45% without symptoms of heart failure (HF) (Stage B HF). We have previously demonstrated that an impaired cardiorenal response to acute volume loading (AVL) exists in PSD. Type V phosphodiesterase (PDEV) metabolizes cGMP, second messenger of the B-type natriuretic peptide (BNP). Preclinical studies have demonstrated that PDEV inhibition (PVEVI) enhances the cardiorenal actions of BNP. The objective of the current study is to determine if the combination of PDEVI and BNP will result in a greater enhancement of the cardiorenal response to AVL as compared to PDEVI alone in PSD.

β-Adrenergic blockade combined with subcutaneous B-type natriuretic peptide: a promising approach to reduce ventricular arrhythmia in heart failure?

AimsClinical studies failed to prove convincingly efficiency of intravenous infusion of neseritide during heart failure and evidence suggested a pro-adrenergic action of B-type natriuretic peptide (BNP). However, subcutaneous BNP therapy...

B-type natriuretic peptide protect cardiomyocytes at reperfusion via mitochondrial calcium uniporter

B-type natriuretic peptide (BNP) is a regulatory autacoid in the mammalian myocardium, whose functions play significant roles in health and disease. Previous work has identified that BNP protect myocardium through mitochondrial pathway-dependent mechanism against ischemia-reperfusion (I/R) injury. Mitochondria are both essential effectors of cardioprotection and primary targets of cardioprotective signaling. In particular, mitochondrial channel are activated to act as the major determinants of cell life and death. Since the discovery of mitochondrial calcium uniporter (MCU), MCU has been its contribution to cardiomyocytes under specific physiological or pathological conditions. The role of mitochondria and MCU, in mediating reperfusion-induced heart injury is a novel investigative area. In addition, the relationship of BNP with MCU in cardiomyocytes undergoing reperfuison is unclear. In this study, we used cultured neonatal rat cardiomyocytes to investigate the effect of BNP on MCU during reperfusion, the well-characterized pathological process of heart diseases. Our results demonstrated that treatment with BNP protected cardiomyocytes from apoptosis against I/R injury. Further investigation of underlying mechanisms revealed that BNP could partly prevent opening of mitochondrial calcium uniporter during I/R. And these mechanisms were associated with BNP-attenuated dissipation of mitochondrial membrane potential (Δ ψ m), generation of reactive oxygen species (ROS). BNP also increased the level of anti-apoptotic Bcl-2 protein, decreased the expressions of pro-apoptotic Bax and Smac/DIABLO. In summary, we demonstrated that BNP exerts protective functions within reperfusion by blocking mitochondrial calcium uniporter. Our findings also suggested that phosphatidylinositol 3-kinase (PI3K) dependent pathway may be involved in the actions of BNP.

The Tumultuous Journey of Nesiritide

Almost 3 decades ago, we witnessed the discovery of the natriuretic peptides and the role of the heart as an endocrine organ in which peptides of cardiovascular origin emerged as a humoral link between the heart and the kidney in cardiorenal homeostasis. In the United States, one such natriuretic peptide, B-type natriuretic peptide (BNP), was approved by the US Food and Drug Administration in 2001 as a drug (nesiritide) for the treatment of acute decompensated heart failure (ADHF). The rationale for the use of BNP as a cardiovascular therapy was in response to laboratory-based research and a series of clinical trials. What emerged was a theme that BNP was an endogenous ligand for the natriuretic peptide-A receptor that is linked to particulate guanylyl cyclase and the second messenger 3′,5′-cyclic guanosine monophosphate (cGMP).1 After receptor activation, the biological actions of BNP include vasodilatation, diuresis and natriuresis, positive lusitropism, inhibition of the renin-angiotensin-aldosterone system, suppression of the myocardial hypertrophy response to pressure overload, and attenuation of myocardial fibrosis. Article p 9 Although a hallmark of acute and chronic congestive heart failure (CHF) is an increased plasma level of BNP, there are functional derangements in the BNP/cGMP signaling pathway that provide additional rationale for the exogenous administration of BNP or nesiritide to treat CHF. The 2 most compelling abnormalities include increased production of less biologically active BNP forms and increased renal resistance to BNP in severe experimental CHF.2–5 Since the initial report in 1991 by Yoshimura et al6 and after several clinical trials over the past decade,7–10 the consensus has been that human recombinant BNP (nesiritide) in patients with ADHF improved cardiovascular hemodynamics and/or renal function in association with improved symptoms of HF. Moreover, some investigators reported that nesiritide therapy was safer than the use of positive inotropic drugs …

Abstract 2494: Beneficial Actions of Co-Targeting Particulate and Soluble Guanylate Cyclase Dependent cGMP Pools in Experimental Heart Failure

Background: B-type natriuretic peptide (BNP) signals via particulate guanylyl cyclase (pGC) and cyclic guanosine monophosphate (cGMP). In heart failure (HF), BNP reduces cardiac filling pressures and in selected patients augments sodium excretion and glomerular filtration rate (GFR). Studies have established that pGC and soluble guanylyl cyclase (sGC), the main target of nitric oxide (NO), can be compartmentalized with both enzymes affecting distinct intracellular cGMP pools, resulting in different biological actions. Importantly, sGC may be oxidized in disease states like HF making it unresponsive to NO and nitrovasodilators. BAY 58 –2667 (BAY) is a novel NO and heme independent sGC activator that preferentially stimulates oxidized sGC. We hypothesized that adding direct sGC stimulation with BAY to pGC activation with BNP in HF would enhance vasodilation and cardiac unloading without attenuating the distinct renal actions of BNP. Methods: Severe HF was induced by tachypacing in 13 dogs. On day 11, cardiorenal function was assessed in an acute study under anesthesia at baseline and with intravenous BNP (50 ng/kg/min) alone or in combination with BAY (0.3 ug/kg/min). Results: BNP significantly increased urine flow (UV), urinary sodium excretion (UNaV), GFR, renal blood flow (RBF) and systemic vascular resistance (SVR) and decreased cardiac output (CO), mean arterial pressure (MAP), right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP). Despite a greater decrease in MAP compared to BNP, BAY+BNP resulted in similar increases in UNaV, UV and GFR. Dual pGC and sGC stimulation resulted in greater decreases in SVR, RAP and PCWP together with an augmentation of CO compared to BNP alone. Conclusion: Particulate GC activation with BNP in experimental HF enhances renal function and leads to renal but not systemic vasodilation. Addition of the sGC stimulator BAY provides systemic vasodilation, greater cardiac unloading, and augmented CO. Despite a larger decrease in MAP, additional sGC stimulation does not impair the renal actions observed with pGC stimulation alone. These findings support coactivation of sGC with BAY and pGC with BNP as a novel and beneficial therapeutic strategy in HF to optimize activation of distinct GC enzymes and cGMP.

The role of iNOS-derived NO in the antihypertrophic actions of B-type natriuretic peptide in neonatal rat cardiomyocytes

In the infarcted rat heart, the increase of NO occurs in the hypertrophied myocardium of non-infarcted areas and its antihypertrophic efficacy has been well established. As another endogenous regulator and the reliable index of heart pathology, B-type natriuretic peptide also exhibits the antihypertrophic properties in many tissues by elevating intracellular cGMP. Several studies indicate that natriuretic peptides family may exert some actions in part via a nitric oxide pathway following receptor-mediated stimulation of iNOS. Therefore, it raises our great interest to ask what role NO plays in the antihypertrophic actions of B-type natriuretic peptide in cardiomyocytes. Incubation of cardiomyocytes under mild hypoxia for 12 h caused a significant increase in cellular protein content, protein synthesis and cell surface sizes. This growth stimulation was suppressed by exogenous B-type natriuretic peptide in a concentration dependent manner. Furthermore, the generation of intracellular cGMP, the upregulation of iNOS mRNA expression, the increase of iNOS activity and subsequent nitrite generation in hypertrophic cardiomyocytes was also increased by B-type natriuretic peptide. AG, a selective iNOS inhibitor, inhibited the upregulation of iNOS expression and the increase of iNOS activity by the combination of B-type natriuretic peptide/mild hypoxia or by the combination of 8-bromo-cGMP/mild hypoxia. Rp-8-br-cGMP, cGMP dependent protein kinase inhibitor, attenuated the actions of B-type natriuretic peptide and 8-bromo-cGMP which increases intracellular cGMP independent of B-type natriuretic peptide. In conclusion, our present data suggest that B-type natriuretic peptide exerted the antihypertrophic effects in cardiomyocytes, which was partially attributed to induction of iNOS-derived NO by cGMP pathway.

B-Type Natriuretic Peptide Enhances Mild Hypoxia-Induced Apoptotic Cell Death in Cardiomyocytes

In the case of left ventricle remodeling after myocardial infarction, cardiomyocyte apoptosis is attributed to increased cardiac workload by the stimulus such as chronic hypoxia. B-Type natriuretic peptide, being known as a reliable prognostic of cardiovascular pathology, plays an important role in the myocardial infarction. However, the action of B-type natriuretic peptide on cardiomyocytes undergoing apoptosis is unclear. In the present study, B-type natriuretic peptide have exhibited the enhancive effects on the mild hypoxia-induced cardiomyocyte apoptosis with the manifestation of facilitating phosphatidylserine evagination and increasing typical fragmented nuclei. In addition, B-type natriuretic peptide aggravated the dissipation of delta psi(m), the depletion of intracellular ATP and the increase of caspase-3 activity. 8-Bromo-cGMP, which increased cGMP independent of B-type natriuretic peptide, could mimic B-type natriuretic peptide's effects; whereas cGMP-dependent protein kinase inhibitor, Rp-8-br-cGMP inhibited that. Further study revealed the enhancive effect of BNP on down-regulation of Bcl-2 mRNA expression in the presence of mild hypoxia. In conclusion, the present study demonstrated that B-type natriuretic peptide aggravated the cardiomyocyte apoptosis by influencing hypoxia-induced mitochondrial death pathway, which is true at least in this oxygen deprivation model; and this effect was partially realized through intracellular cGMP.

Potent cardiorenal actions in experimental heart failure with dual activation of soluble and particulate guanylate cyclases by bay 58-2667 and B-type natriuretic peptide: a novel therapeutic strategy

Background: Soluble guanylate cyclase (sGC) is an important enzyme, which via cyclic guanosine monophosphate (cGMP) production mediates potent vasodilating actions in multiple vascular beds. Particulate guanylate cyclase (pGC) via cGMP results in potent renal natriuretic and diuretic actions with vasodilating properties. Importantly, sGC and pGC may in part be differentially localized which may limit maximal cGMP activating pathways with sole activation of either pGC or sGC. BAY 58-2667 belongs to the new pharmacological class of direct sGC activators that, unlike conventional nitrates, activate sGC without the development of tolerance and without cGMP-independent actions. B-type natriuretic peptide (BNP), which is a pGC activator, is natriuretic and vasodilating, but in experimental congestive heart failure (CHF) does not increase cardiac output or reduce systemic vascular resistance. We hypothesized that co-administration of BAY 58-2667 and BNP in experimental CHF would complement the beneficial cardiac unloading actions of BAY 58-2667 with the beneficial renal actions of BNP. Methods: CHF was induced in two groups of male dogs (both N=7) by tachypacing. After 10 days, cardiorenal parameters were measured in clearances at baseline and with two intravenous doses of BAY 58-2667 (0.1 and 0.3 μg/kg/min, respectively) alone or in combination with BNP (10 and 50 ng/kg/min, respectively). Clearances were compared within groups by repeated measures ANOVA, while groups were compared qualitatively. Results: BAY 58-2667 alone potently (p<0.05) decreased mean arterial pressure, cardiac filling pressures, and systemic and renal vascular resistance, while cardiac output and renal blood flood increased. These actions occurred to a similar degree when BNP was added to BAY 58-2667. However, in addition there were significant (p<0.05) increases in urinary flow, urinary sodium excretion, glomerular filtration rate, and filtration fraction. Both regimens did not further activate the renin-angiotensin-aldosterone system. Conclusion: Direct sGC activation by BAY 58-2667 has potent beneficial cardiac unloading actions in experimental CHF. While additional pGC activation with BNP does not augment hemodynamic actions with BAY 58-2667, it enhances renal function. These findings suggest that coactivation of sGC and pGC may be a beneficial and a novel strategy in the treatment of CHF.

Haemodynamic action of B‐type natriuretic peptide substantially outlasts its plasma half‐life in conscious dogs

1. The objective of the present study was to determine the plasma half-life of B-type natriuretic peptide (BNP) in conscious dogs after intravenous administration and to compare this with its haemodynamic effects. In six chronically instrumented dogs, plasma BNP concentrations were measured under basal conditions, during a constant infusion of canine BNP-32 (10 pmol/kg per min; 25 min) to steady state and at nominated time points up to 75 min after stopping the infusion. Concomitant, continuous measurements of mean arterial blood pressure (MAP), heart rate (HR), central venous pressure (CVP) and mesenteric blood flow (MBF) were obtained. 2. Baseline plasma BNP levels were 15.0 +/- 2.3 fmol/mL and rose approximately 10-fold to 159 +/- 23 fmol/mL after 20-25 min BNP infusion. When the infusion was turned off, plasma BNP levels declined in a biphasic manner, with an initial half-life of 1.57 +/- 0.14 min and a terminal half-life of 301 +/- 85 min. The metabolic clearance rate of BNP was 2.29 +/- 0.34 L/min. 3. The infusion of BNP reduced MAP (approximately 10%), CVP (approximately 65%) and MBF (approximately 25%), whereas haematocrit (approximately 4%) and mesenteric vascular resistance (MVR) increased (approximately 40%; all P < 0.05). Plasma BNP levels returned to baseline by 20 min after BNP infusion had been stopped, whereas none of the haemodynamic variables returned to normal by this time. Mean arterial pressure returned to resting levels within 10-15 min after plasma BNP returned to normal. However, CVP, haematocrit and MBF remained substantially below baseline values for more than 20 min after circulating BNP levels had returned to pre-infusion levels. Of these, only mesenteric vascular changes were returned to baseline within 60 min of plasma BNP levels normalizing. 4. These results demonstrate that the removal of BNP from the canine circulation is rapid, similar to observations made regarding the metabolism of circulating atrial natriuretic peptide in dogs. The half-life of BNP in dogs was shorter than that in rats, sheep or humans. However, the haemodynamic actions of BNP substantially outlasted its plasma half-life. Whether this disparity in plasma level and haemodynamic activity of BNP reflects long-lasting activation of second messenger systems or slow recovery from the hydraulic changes at the capillary level, reflected in the haematocrit and CVP, remains to be answered.

The Endocrine Heart: B-type Natriuretic Peptide as a Diagnostic and Therapeutic Agent in Cardiovascular Disease

Since their discovery 20 years ago, natriuretic peptides have rapidly moved to the forefront in cardiovascular medicine, and have contributed to an appreciation that the heart is an important endocrine organ. Of the natriuretic peptides, brain (B-type) natriuretic peptide (BNP) has proven to be the most clinically useful. Physicians now measure circulating levels of BNP and the Nterminal fragment of its prohormone (N-proBNP) for diagnostic and prognostic assessment in patients with suspected congestive heart failure (CHF), and administer recombinant human BNP as a therapeutic agent for patients with decompensated CHF. This review will highlight the mechanisms of natriuretic peptide regulation, the physiologic actions of BNP, and its utilization in patients with cardiovascular diseases.

Glomerulonephritis in Pregnancy

B-type natriuretic peptide (BNP) is a hormone expressed exclusively in the heart. BNP is found in tetrapods and teleosts, whereas the ANP gene is lost in avian, reptilian, and some teleost species. Thus, BNP is thought to be a principal cardiac natriuretic peptide in vertebrates. As BNP shares a biological receptor (NPR-A) with ANP, the actions of BNP are similar to those of ANP: natriuretic and diuretic effects that result in a reduction of blood volume and a vasodepressor effect. Contrary to similar biological actions, the transcriptional regulation, secretory pathway, half-life in plasma, and susceptibility to receptors of these peptides are different. BNP is of great importance in clinical usage. Plasma BNP concentration is elevated dramatically in patients with congestive heart failure. BNP is used as an ideal diagnostic and prognostic marker for cardiovascular diseases.