Natriuretic Peptide Activity Research Articles

Neurohumoral Activation in Heart Failure.

In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance. Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms. There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might benefit from specific therapies, irrespective of the degree of left ventricular dysfunction. These therapies are directed against these neurohumoral systems (neurohumoral antagonists) and classically comprise beta blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and vaptans. Recently, the RAAS blockade has been refined by the introduction of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, which combines the RAAS inhibition and neprilysin blocking, enhancing the actions of natriuretic peptides. All these issues relating to the neurohumoral activation in HF are herein reviewed, and the underlying mechanisms are pictorially illustrated.

Abstract P366: Natriuretic Peptides Potentiate Cardiac Hypertrophic Response To Norepinephrine In Rats

Background: The natriuretic peptide (NP) family consisting of ANP, BNP, and CNP is assumed to exert protective actions for the heart, alleviating hypertrophy and/or fibrosis of the myocardium. Excessive activation of the sympathetic nervous system is involved in cardiovascular damage including cardiac hypertrophy. In contrast to the previous notion, we show in the present study that both atrial and C-type natriuretic peptides (ANP and CNP) potentiate cardiac hypertrophic response to norepinephrine (NE) in rats. Methods and Materials: Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 μg/h NE without or with persistent intravenous administration of either 1.0 μg/h ANP or CNP for 14 days. The NE plus ANP groups were treated orally without or with either 5 mg/day prazosin or 50 mg/day atenolol during this study period. Sample sizes are follows: control, NE, NE plus ANP, n=8 to 9; CNP, NE plus CNP, prazosin, atenolol, n=6 to 7. Blood pressure (BP) was recorded via a catheter placed in the abdominal aorta under an unrestrained condition by a radiotelemetry system. Cardiac hypertrophic response to NE was evaluated by heart weight to body weight (HW/BW) ratio. Left ventricular (LV) tissues were also examined microscopically to measure individual myocyte size and collagen deposition. Results: Mean BP levels at the light and dark cycles rose by 20 and 17 mmHg, respectively, following NE infusion for 14 days, with slight increases in HW/BW ratio (+7.6%) and ventricular myocyte size (+20%), compared to control (P>0.05). Infusions of ANP and CNP had no significant effects on mean BP in NE-infused rats, while two natriuretic peptides potentiated cardiac hypertrophic response to NE at day 14 (HW/BW and myocyte size: NE plus ANP, +37% and +64%; NE plus CNP, +47% and +56%, respectively; P<0.01 for all). No differences were noted in collagen volume fraction of LV among all study groups. Cardiac hypertrophy induced by co-administration of NE and ANP was attenuated by treatment with prazosin or atenolol. Conclusion: Both ANP and CNP potentiated α1- and β1-adrenergic receptor-mediated cardiac hypertrophic response to continuously infused NE in rats, suggesting a possible pro-hypertrophic action of NPs on the heart.

Natriuretic peptides potentiate cardiac hypertrophic response to noradrenaline in rats

Excessive activation of the sympathetic nervous system is involved in cardiovascular damage including cardiac hypertrophy. Natriuretic peptides are assumed to exert protective actions for the heart, alleviating hypertrophy and/or fibrosis of the myocardium. In contrast to this assumption, we show in the present study that both atrial and C-type natriuretic peptides (ANP and CNP) potentiate cardiac hypertrophic response to noradrenaline (NA) in rats. Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 micro-g/h NA without or with persistent intravenous administration of either 1.0 micro-g/h ANP or CNP for 14 days. Blood pressure (BP) was recorded under an unrestrained condition by a radiotelemetry system. Cardiac hypertrophic response to NA was evaluated by heart weight/body weight (HW/BW) ratio and microscopic measurement of myocyte size of the left ventricle. Mean BP levels at the light and dark cycles rose by about 20 mmHg following NA infusion for 14 days, with slight increases in HW/BW ratio and ventricular myocyte size. Infusions of ANP and CNP had no significant effects on mean BP in NA-infused rats, while two natriuretic peptides potentiated cardiac hypertrophic response to NA. Cardiac hypertrophy induced by co-administration of NA and ANP was attenuated by treatment with prazosin or atenolol. In summary, both ANP and CNP potentiated cardiac hypertrophic effect of continuously infused NA in rats, suggesting a possible pro-hypertrophic action of natriuretic peptides on the heart.

Guanylyl cyclase/natriuretic peptide receptor-A: Identification, molecular characterization, and physiological genomics.

The natriuretic peptides (NPs) hormone family, which consists mainly of atrial, brain, and C-type NPs (ANP, BNP, and CNP), play diverse roles in mammalian species, ranging from renal, cardiac, endocrine, neural, and vascular hemodynamics to metabolic regulations, immune responsiveness, and energy distributions. Over the last four decades, new data has transpired regarding the biochemical and molecular compositions, signaling mechanisms, and physiological and pathophysiological functions of NPs and their receptors. NPs are incremented mainly in eliciting natriuretic, diuretic, endocrine, vasodilatory, and neurological activities, along with antiproliferative, antimitogenic, antiinflammatory, and antifibrotic responses. The main locus responsible in the biological and physiological regulatory actions of NPs (ANP and BNP) is the plasma membrane guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), a member of the growing multi-limbed GC family of receptors. Advances in this field have provided tremendous insights into the critical role of Npr1 (encoding GC-A/NPRA) in the reduction of fluid volume and blood pressure homeostasis, protection against renal and cardiac remodeling, and moderation and mediation of neurological disorders. The generation and use of genetically engineered animals, including gene-targeted (gene-knockout and gene-duplication) and transgenic mutant mouse models has revealed and clarified the varied roles and pleiotropic functions of GC-A/NPRA in vivo in intact animals. This review provides a chronological development of the biochemical, molecular, physiological, and pathophysiological functions of GC-A/NPRA, including signaling pathways, genomics, and gene regulation in both normal and disease states.

Pharmacologic blockade of the natriuretic peptide clearance receptor promotes weight loss and enhances insulin sensitivity in type 2 diabetes

While natriuretic peptides (NPs) are primarily known for their renal and cardiovascular actions, NPs stimulate lipolysis in adipocytes and induce a thermogenic program in white adipose tissue (WAT) that resembles brown fat. The biologic effects of NPs are negatively regulated by the NP clearance receptor (NPRC), which binds and degrades NPs. Knockout (KO) of NPRC protects against diet induced obesity and improves insulin sensitivity in obese mice. To determine if pharmacologic blockade of NPRC enhanced the beneficial metabolic actions of NPs in type 2 diabetes, we blocked NP clearance in a mouse model of type 2 diabetes using the specific NPRC ligand ANP(4-23). We found that treatment with ANP(4-23) caused a significant decrease in body weight by increasing energy expenditure and reducing fat mass without a change in lean body mass. The decrease in fat mass was associated with a significant improvement in insulin sensitivity and reduced serum insulin levels. These beneficial effects were accompanied by a decrease in infiltrating macrophages in adipose tissue, and reduced expression of inflammatory markers in both serum and WAT. These data suggest that inhibiting NP clearance may be an effective pharmacologic approach to promote weight loss and enhance insulin sensitivity in type 2 diabetes. Optimizing the therapeutic approach may lead to useful therapies for obesity and type 2 diabetes.

CLINICAL SIGNIFICANCE OF NATRIURETIC PEPTIDES (review)

Natriuretic peptides are widely known for their protective effects against the development of metabolic syndrome and cardiovascular disease. The important role of determining the levels of natriuretic peptides in the diagnosis, assessment of severity, prognosis and effectiveness of treatment of heart failure has been proven in many studies and noted in clinical guidelines worldwide. Visceral obesity reduces the production and action of natriuretic peptides, increasing the risk of heart failure and diabetes mellitus 2 type. Metabolic syndrome is present in 60% of patients with chronic heart failure, most of its components contribute to the development and progression of chronic heart failure and include obesity, hypertension, dyslipidemia, insulin resistance, impaired glucose tolerance. The prevalence of metabolic syndrome in the general population is 34% and is constantly increasing due to unhealthy diet, sedentary lifestyle and chronic stress. The prevalence of chronic heart failure is increasing rapidly in all industrialized countries, affecting 2% of adults and 10% of the elderly. Therefore, the problem of early diagnosis and treatment of metabolic syndrome and chronic heart failure is very relevant nowadays. The review focuses on the pathophysiological relationships between natriuretic peptides, heart failure and metabolic syndrome, and the approaches to the correction of natriuretic peptides’ metabolism.

Distribution of Cardiac and Renal Corin and Proprotein Convertase Subtilisin/Kexin-6 in the Experimental Model of Cardio-Renal Syndrome of Various Severities.

Congestive heart failure (CHF) often leads to progressive cardiac hypertrophy and salt/water retention. However, its pathogenesis remains largely unclarified. Corin, a cardiac serine protease, is responsible for converting proANP and proBNP to biologically active peptides. Although the involvement of corin in cardiac hypertrophy and heart failure was extensively studied, the alterations in corin and proprotein convertase subtilisin/kexin-6 (PCSK6), a key enzyme in the conversion of procorin to corin, has not been studied simultaneously in the cardiac and renal tissues in cardiorenal syndrome. Thus, this study aims to examine the status of PCSK6/corin in the cardiac and renal tissues of rats with CHF induced by the creation of aorto-caval fistula (ACF). We divided rats with ACF into two subgroups based on the pattern of their urinary sodium excretion, namely, compensated and decompensated. Placement of ACF led to cardiac hypertrophy, pulmonary congestion, and renal dysfunction, which were more profound in the decompensated subgroup. Corin immunoreactive peptides were detected in all heart chambers at the myocyte membranal and cytosolic localization and in the renal tissue, especially in the apical membrane of the proximal tubule, mTAL, and the collecting duct. Interestingly, the expression and abundance of corin in both the cardiac ventricles and renal tissues were significantly increased in compensated animals as compared with the decompensated state. Noteworthy, the abundance of PCSK6 in these tissues followed a similar pattern as corin. In contrast, furin expression was upregulated in the cardiac and renal tissues in correlation with CHF severity. We hypothesize that the obtained upregulation of cardiac and renal PCSK6/corin in rats with compensated CHF may represent a compensatory response aiming at maintaining normal Na+ balance, whereas the decline in these two enzymes may contribute to the pathogenesis of avid sodium retention, cardiac hypertrophy, and blunted atrial natriuretic peptide/brain natriuretic peptide actions in decompensated CHF.

Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension treatment.

Angiotensin receptor-neprilysin inhibitors (ARNIs) are a new class of cardiovascular agents characterized by their dual action on the major regulators of the cardiovascular system, including the renin-angiotensin system (RAS) and the natriuretic peptide (NP) system. The apparent clinical benefit of one ARNI, sacubitril/valsartan, as shown in clinical trials, has positioned the drug class as a first-line therapy in patients with heart failure, particularly with reduced ejection fraction. Accumulating evidence also suggests that sacubitril/valsartan is superior to conventional RAS blockers in lowering blood pressure in patients with hypertension. To decide whether to apply an ARNI to treat hypertension clinically, it is important to understand the potential properties of the drug in modulating multiple factors inside and outside the cardiovascular system beyond its effect on reducing peripheral blood pressure. In this context, ARNIs are distinct from preexisting antihypertensive medications in terms of the multiple actions of NPs in various organs and the pharmacological potential of neprilysin inhibitors to modulate multiple cardiac and noncardiac peptides. In particular, analysis of the clinical trials of sacubitril/valsartan implies that ARNIs can provide additional clinical benefits independent of their original purpose, including alleviation of glycemic control and renal impairment in patients with heart failure. Understanding the potential mechanisms of action of ARNIs will help interpret the relevance of their additional benefits beyond lowering blood pressure in hypertension. This review summarizes the comprehensive clinical evidence and relevance of ARNIs by specifically focusing on the potential properties of this new drug class in treating patients with hypertension.

Possible Association Between Body Temperature and B-Type Natriuretic Peptide in Patients With Cardiovascular Diseases

BackgroundIn addition to various biological effects of natriuretic peptides (NP) on cardiovascular systems, we recently reported that NP raises intracellular temperature in cultured adipocytes. We herein examined the possible thermogenic action of NP in consideration of hemodynamic parameters and inflammatory reaction by proposing structural equation models. Methods and ResultsThe study population consisted of 1985 consecutive patients who underwent cardiac catheterization. Covariance structure analyses were performed to clarify the direct contribution of plasma B-type NP (BNP) to body temperature (BT) by excluding other confounding factors. A hierarchical path model showed increase in BNP, increase in C-reactive protein and decrease in left ventricular ejection fraction were mutually associated. As expected, C-reactive protein was positively correlated with BT. Importantly, despite a negative correlation between BNP and left ventricular ejection fraction, a decrease in the left ventricular ejection fraction was associated with BT decrease, whereas elevation in BNP level was associated with BT increase independently of C-reactive protein level (P = .007). ConclusionsPatients with LV dysfunction tend to manifest a decrease in BT, whereas BNP elevation is associated with an increase in BT independently of inflammatory response. These findings suggest the adaptive heat-retaining property of NP (and/or NP-associated factors) when BT falls owing to unfavorable hemodynamic conditions in a state of impaired cardiac function.

Collaborative Activities of Noradrenaline and Natriuretic Peptide for Glucose Utilization in Patients with Acute Coronary Syndrome

Glucose is an important preferential substrate for energy metabolism during acute coronary syndrome (ACS) attack, although insulin resistance (IR) increases during ACS. Increasing evidence indicates that natriuretic peptides (NP) regulate glucose homeostasis. We investigated possible compensatory actions of NP in collaboration with other neurohumoral factors that facilitate glucose utilization during ACS. The study population consisted of 1072 consecutive cases with ischemic heart disease who underwent cardiac catheterization (ACS, n = 216; non-ACS, n = 856). Among ACS subjects, biochemical data after acute-phase treatment were available in 91 cases, defined as ACS-remission phase (ACS-rem). Path models based on covariance structure analyses were proposed to clarify the direct contribution of B-type NP (BNP) and noradrenaline to glucose and HOMA-IR levels while eliminating confounding biases. In non-ACS and ACS-rem subjects, although noradrenaline slightly increased glucose and/or HOMA-IR levels (P < 0.03), BNP did not significantly affect them. In contrast, in ACS subjects, high noradrenaline was a significant cause of increases in glucose and HOMA-IR levels (P < 0.001), whereas high BNP was a significant cause of decreases in both parameters (P < 0.005). These findings indicate that BNP and noradrenaline coordinately activate glucose metabolism during ACS, with noradrenaline increasing glucose levels, as an energy substrate, while BNP improves IR and promotes glucose utilization.

The thermogenic actions of natriuretic peptide in brown adipocytes: The direct measurement of the intracellular temperature using a fluorescent thermoprobe

In addition to the various effects of natriuretic peptides (NPs) on cardiovascular systems, increasing attention is being paid to the possibility that NPs induce adipose tissue browning and activate thermogenic program. We herein established a direct intracellular temperature measurement system using a fluorescent thermoprobe and investigated the thermogenic effects of A-type NP (ANP) on brown adipocytes. The thermoprobe was successfully introduced into rat brown adipocytes, and the temperature dependent change in fluorescence intensity ratio was measured using a fluorescence microscope. After one-hour incubation with ANP, the degree of the change in fluorescence intensity ratio was significantly higher in ANP-treated (P < 0.01) adipocytes compared to untreated controls. The ANP treatment increased uncoupling protein-1 (UCP1) mRNA levels, which is one of the markers of thermogenesis in adipocytes, while the intracellular ATP content was not changed, indicating mitochondrial uncoupled respiration. Intriguingly, these thermogenic actions of ANP were more prominent when brown adipocytes were incubated at 35 °C than at 37 °C. Moreover, the increase in the intracellular temperature and the expression of UCP1 induced by ANP were cancelled by p38MAPK inhibition. Taken together, this study directly demonstrated the thermogenic actions of ANP in brown adipocytes through the use of a novel method of intracellular temperature measurement.

245 - MANP: A Novel Aldosterone Inhibitor: Potential Molecular Mechanisms in Vitro in Human Adrenal Cells

Introduction: Aldosterone (Aldo) is synthesized and secreted by the adrenal cortex zona glomerulosa (ZG) cells. In heart failure (HF) patients Aldo is increased and plays a critical role in inducing and maintaining sodium and water retention as well as mediating myocardial remodeling and fibrosis. MANP is a novel Mayo Clinic designer natriuretic peptide (NP) which was demonstrated to inhibit circulating Aldo levels in vivo canines and in human subjects. Importantly, 3′, 5′ cyclic guanosine monophosphate (cGMP) generated by NPs activates protein kinase G (PKG) and also binds to phosphodiesterases (PDEs). Both PKG and PDEs have been suggested to play a role in the actions of NPs. To date no study has defined the direct cellular inhibitory effects of MANP on Aldo in human adrenal cells. Our goals were therefore to define the mechanisms of the inhibitory actions of MANP on Aldo in ZG cells with a special focus on cGMP and PDE's. Hypothesis: We hypothesized that MANP directly inhibits Aldo in adrenal cortex ZG cells and the inhibitory effect is mediated partially through PDEs. Methods: The ZG cell line H295R cells were cultured in 24-well plates for 24 hrs and starved overnight with serum free medium before stimulation/treatment. MANP (10−8, 10−7 or 10−6 M) was added to cells after starvation. Angiotensin II (ANG II, 10−8, 10−7 or 10−6 M) was employed to stimulate Aldo release. Supernatants were collected after 24 hrs for Aldo quantification with commercial ELISA kits. The PDE inhibitor IBMX (500 uM) and protein kinase G (PKG) specific cGMP analog 8-CPT-cGMP (100 uM) were used. Data are presented as Mean ± SEM, *P < .05 between two groups by unpaired t-test. Results: Angiotensin II stimulated Aldo secretion in a dose-dependent manner. MANP inhibited ANG II stimulated Aldo in a dose dependent manner (10−8 M MANP + ANG II 38.5 ± 2.0, 10−7 M MANP + ANG II 28.8 ± 1.8*, 10−6 M MANP + ANG II 28.0 ± 1.9* vs ANG II 40.5 ± 1.3 ng/dL). The PKG-specific analogue 8-CPT-cGMP surprisingly increased Aldo levels (50.7 ± 2.4* vs ANG II 34.9 ± 0.5 ng/dL). Non-specific PDEs inhibition with IBMX attenuated the inhibitory effect of MANP on Aldo (IBMX + MANP + ANG II 34.9 ± 0.6 vs MANP + ANG II 10−7 M 24.7 ± 2.5* vs ANG II 34.9 ± 0.5 ng/dL). Conclusion: We conclude that MANP directly inhibits Aldo in human ZG cells and the inhibition of Aldo is mediated in part through PDEs. The potent Aldo suppressing property of MANP may render it a promising new generation Aldo inhibiting drug for HF and other cardiovascular disease states of aldosterone excess.

Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition

Guanylyl cyclase-A (GC-A) signaling, a natriuretic peptide receptor, exerts renoprotective effects by stimulating natriuresis and reducing blood pressure. Previously we demonstrated massive albuminuria with hypertension in uninephrectomized, aldosterone-infused, and high salt-fed (ALDO) systemic GC-A KO mice with enhanced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in podocytes. In the present study, we examined the interaction between p38 MAPK and GC-A signaling. The administration of FR167653, p38 MAPK inhibitor, reduced systolic blood pressure (SBP), urinary albumin excretion, segmental sclerosis, podocyte injury, and apoptosis. To further investigate the local action of natriuretic peptide and p38 MAPK in podocytes, we generated podocyte-specific (pod) GC-A conditional KO (cKO) mice. ALDO pod GC-A cKO mice demonstrated increased urinary albumin excretion with marked mesangial expansion, podocyte injury and apoptosis, but without blood pressure elevation. FR167653 also suppressed urinary albumin excretion without reducing SBP. Finally, we revealed that atrial natriuretic peptide increased phosphorylation of MAPK phosphatase-1 (MKP-1) concomitant with inhibited phosphorylation of p38 MAPK in response to MAPK kinase 3 activation, thereby resulting in decreased mRNA expression of the apoptosis-related gene, Bax, and Bax/Bcl2 ratio in cultured podocytes. These results indicate that natriuretic peptide exerts a renoprotective effect via inhibiting phosphorylation of p38 MAPK in podocytes.

Urodilatin reverses the detrimental influence of bradykinin in acute ischemic stroke

Occlusion of cerebral arteries leads to ischemic stroke accompanied by subsequent brain edema. Bradykinin (BK) is involved in the formation of cerebral edema, and natriuretic peptides (NPs) potentially have beneficial effects on brain edema formation via a still unknown mechanism. The aim of this study was clarifying the mechanisms of action of NPs on BK signaling, and their interactive effects after ischemic brain injury. We used a mouse model for stroke, the middle cerebral artery (MCA) occlusion. Brain lesion and edema were measured by microcomputerized tomography volumetric measurements. To determine the effects of NPs on the BK signaling pathway in the MCAs we measured changes in vessel diameter and membrane potentials in endothelial cells. To determine the effects of NPs on BK signaling pathway in isolated astrocytes and neurons, membrane potentials and intercellular Ca2+ concentrations were measured. Urodilatin inhibited and when applied together with BK, reduced the formation of the ischemic lesion via activation of G-Protein–Signaling Protein Type 4 at the cellular (atrocities, neurons) and blood vessel (endothelial cells and isolated MCA) level as well as in in vivo experiments. The results of this study show the existence of a natural antagonist of BK in the brain, and the possible use of NPs in the treatment of stroke.

Oocyte maturation and quality: role of cyclic nucleotides.

The cyclic nucleotides, cAMP and cGMP, are the key molecules controlling mammalian oocyte meiosis. Their roles in oocyte biology have been at the forefront of oocyte research for decades, and many of the long-standing controversies in relation to the regulation of oocyte meiotic maturation are now resolved. It is now clear that the follicle prevents meiotic resumption through the actions of natriuretic peptides and cGMP - inhibiting the hydrolysis of intra-oocyte cAMP - and that the pre-ovulatory gonadotrophin surge reverses these processes. The gonadotrophin surge also leads to a transient spike in cAMP in the somatic compartment of the follicle. Research over the past two decades has conclusively demonstrated that this surge in cAMP is important for the subsequent developmental capacity of the oocyte. This is important, as oocyte in vitro maturation (IVM) systems practised clinically do not recapitulate this cAMP surge in vitro, possibly accounting for the lower efficiency of IVM compared with clinical IVF. This review particularly focuses on this latter aspect - the role of cAMP/cGMP in the regulation of oocyte quality. We conclude that clinical practice of IVM should reflect this new understanding of the role of cyclic nucleotides, thereby creating a new generation of ART and fertility treatment options.

Transient silencing of Npr3 gene expression improved the circulatory levels of atrial natriuretic peptides and attenuated β-adrenoceptor activation- induced cardiac hypertrophic growth in experimental rats

Natriuretic peptide receptor-C (NPR-C) is considered as a clearance receptor that maintains the circulatory levels of natriuretic peptides. It has been suggested that augmented expression of NPR-C as a cause for the diminished anti-hypertrophic action of natriuretic peptides in the failing heart. Hence, we sought to determine the level of Npr3 gene (coding for NPR-C) expression in the Isoproterenol (ISO) treated Wistar rats. In addition, we studied the effect of Npr3 gene silencing on the hypertrophic growth. A significant increase in heart weight-to-body weight ratio (HW/BW-24%,P<0.01), an indicator of cardiac hypertrophic growth was observed in the ISO (10mg/kg BW/day,i.p for 7 days) treated rats. As expected, the cardiac NPR-C protein expression was significantly increased by 4 fold as compared to control rats. In parallel, the circulatory atrial natriuretic peptide (ANP) level was significantly decreased (2 fold) in ISO treated rats. Upon treatment with siRNA-Npr3, a significant decrease in the cardiac NPR-C protein expression (70%,P<0.01), HW/BW ratio (70%,P<0.01) and hypertrophic marker genes (α-Sk, β-MHC, c-fos, P<0.01, respectively) mRNA expression were observed. Interestingly, the circulatory ANP level was increased by 1.5 fold in the siRNA-Npr3 treated rats as compared to ISO treated rats. Moreover, the cardiac collagen content, matrixmetalloprotinases-2 (MMP-2) and enzymatic antioxidant status (P<0.01, respectively) were found to be restored back to near normal upon siRNA-Npr3 treatment. Taken together, the results of this study indicates that specific down-regulation of Npr3 gene improves the circulatory levels of ANP and antioxidant system and there by attenuates the β-adrenoceptor over-activation mediated cardiac hypertrophic growth in experimental rats.

Current Understanding of the Compensatory Actions of Cardiac Natriuretic Peptides in Cardiac Failure: A Clinical Perspective.

Natriuretic peptides play a crucial role in maintaining cardiovascular homeostasis. Among their properties are vasodilation, natriuresis, diuresis, and inhibition of cardiac remodeling. As heart failure progresses, however, natriuretic peptides fail to compensate. Knowledge of their processing and signaling pathways has guided the development of pharmacological therapies aimed at bolstering their effects. The drugs that have achieved the most clinical success have also stirred the most controversy. Nesiritide, the synthetic B-type natriuretic peptide, yielded significant symptomatic relief and improved haemodynamics but its use was plagued with questions surrounding its possibly harmful impact on renal function. More recently, compounds containing inhibitors of neprilysin, the enzyme responsible for degrading natriuretic peptides, have demonstrated morbidity and mortality benefit, but have also been linked to possible negative side effects. Clearly, potentiating the actions of natriuretic peptides for the benefit of patients is not as simple as just raising their serum concentration. This article reviews the current understanding of the compensatory actions of cardiac natriuretic peptides in heart failure and how this knowledge is revolutionizing heart failure therapy.

ANP-ing Up Diabetes: Impaired Natriuretic Peptide Action in Muscle Forms a Mechanistic Link Between Obesity and Diabetes.

A growing body of work concerns the role of natriuretic peptides (NPs) in metabolism and insulin sensitivity, the latest addition to which is published in this issue of Diabetes (1). Three principal structurally related NPs exist in mammals: atrial natriuretic peptide (ANP), produced primarily by the cardiac atria; brain/B-type natriuretic peptide (BNP), secreted by the ventricle and brain; and C-type natriuretic peptide (CNP), originating from the vascular endothelium, central nervous system, and kidney. They were originally shown to possess potent natriuretic, diuretic, and vasodilatory activity, thus playing a significant role in the prevention of circulatory volume overload and hypertension. These peptides use plasma membrane–situated natriuretic peptide receptors (NPRs) A and B, with the A receptor showing a preference for ANP and BNP and the B receptor being specific for CNP, while a distinct C receptor is responsible for peptide clearance in tissues. Binding of peptides to NPRA leads to the activation of intracellular cyclic guanosine monophosphate (cGMP)-dependent signaling cascades involving cGMP-dependent protein kinases, phosphodiesterases, and ion channels that mediate the physiological effects of NPs (reviewed in ref. 2). Recently, parallel metabolic actions of NPs have been demonstrated in adipose tissue, with selective effects in the visceral adipose depot, expansion of which is most associated with insulin resistance (IR). ANP-stimulated cGMP-mediated phosphorylation of hormone-sensitive lipase results in lipolysis in primates/humans that is independent of β-adrenergic stimulation (3–5), thereby inhibiting visceral adipocyte hypertrophy (6). In addition, ANP treatment causes reduced adipose secretion of proinflammatory cytokines and …

Advances in the Mechanism of Action of Natriuretic Peptides at a Cellular Level

Background: Natriuretic peptides have a vast array of different actions at numerous sites throughout the human body. There have been rapid advances in understanding their mechanism of action in recent years and this review aimed to collate all available information o n this field in order to present the current evidence - base. Method: A two - step process utilising a Medline/PubMed systematic search was conducted. The initial search was undertaken using elementary phrases. The search produced over 4000 published papers on the topic of the mechanisms of action of natriuretic peptides. The resultant

Current role of neprilysin inhibitors in hypertension and heart failure

Cardiovascular diseases (CVD) continue to represent the major cause of death, morbidity and healthcare expenditure worldwide. Current medical therapy fails to effectively halt disease progression and to reduce adverse clinical outcomes, reflecting incomplete understanding of pathomechanisms as well as the need to expand current pharmacotherapeutic strategies. Hypertension and heart failure, the most important CVD entities, are associated with imbalance in neurohormonal systems activity such as the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system and the endothelin system. Blockade of the RAAS constitutes the most successful pharmacotherapeutic concept in hypertension and heart failure to date. The RAAS-opposing natriuretic peptide system constitutes the body's own BP-lowering system, and mediates a multitude of beneficial actions within cardiovascular tissues. The metallopeptidase neprilysin (NEP) hydrolyzes natriuretic peptides. Conceptually, NEP inhibition would increase salutary natriuretic peptide actions in CVD. However, stand-alone NEP inhibitors (NEPi) lacked efficacy beyond standard pharmacotherapy. Combined blockers of NEP and the endothelin system demonstrated efficacy in preclinical studies but have not been evaluated in clinical trials. A decade ago, omapatrilat and other dual-acting NEPi-ACEi (vasopeptidase-inhibitors) were promising agents for hypertension and heart failure. Despite greater efficacy, development of vasopeptidase-inhibitors was halted due to significant off-target effects in some cohorts, most notably increased frequency of angioedema in hypertensive subjects. Novel angiotensin-receptor-neprilysin-inhibitors (ARNi) seek to fully exploit clinical efficacy of combined RAAS-blockade and NEPi-mediated natriuretic peptide augmentation, and hopefully do so with improved clinical safety. We herein review current knowledge of NEPi as stand-alone and combined pharmacotherapeutic agents in hypertension and heart failure.