Palatin Technologies' novel, long-acting natriuretic peptide receptor A (NPRA) agonist, PL 3994, appears to have promise for heart failure

2008 ◽  
Vol &NA; (1658) ◽  
pp. 9
Author(s):  
&NA;
2020 ◽  
Vol 4 (6) ◽  
Author(s):  
Shravya Vinnakota ◽  
Horng H Chen

Abstract The natriuretic peptide (NP) system is composed of 3 distinct peptides (atrial natriuretic peptide or ANP, B-type natriuretic peptide or BNP, and C-type natriuretic peptide or CNP) and 3 receptors (natriuretic peptide receptor-A or NPR-A or particulate guanynyl cyclase-A natriuretic peptide receptor-B or NPR-B or particulate guanynyl cyclase-B, and natriuretic peptide receptor-C or NPR-C or clearance receptor). ANP and BNP function as defense mechanisms against ventricular stress and the deleterious effects of volume and pressure overload on the heart. Although the role of NPs in cardiovascular homeostasis has been extensively studied and well established, much remains uncertain about the signaling pathways in pathological states like heart failure, a state of impaired natriuretic peptide function. Elevated levels of ANP and BNP in heart failure correlate with disease severity and have a prognostic value. Synthetic ANP and BNP have been studied for their therapeutic role in hypertension and heart failure, and promising trials are under way. In recent years, the expression of ANP and BNP in human adipocytes has come to light. Through their role in promotion of adipocyte browning, lipolysis, lipid oxidation, and modulation of adipokine secretion, they have emerged as key regulators of energy consumption and metabolism. NPR-A signaling in skeletal muscles and adipocytes is emerging as pivotal to the maintenance of long-term insulin sensitivity, which is disrupted in obesity and reduced glucose-tolerance states. Genetic variants in the genes encoding for ANP and BNP have been associated with a favorable cardiometabolic profile. In this review, we discuss several pathways that have been proposed to explain the role of NPs as endocrine networkers. There is much to be explored about the therapeutic role of NPs in improving metabolic milieu.


Genomics ◽  
1997 ◽  
Vol 39 (3) ◽  
pp. 409-411 ◽  
Author(s):  
Bruce D. Gelb ◽  
Jian Zhang ◽  
Philip D. Cotter ◽  
Irina F. Gershin ◽  
Robert J. Desnick

Biochemistry ◽  
1996 ◽  
Vol 35 (39) ◽  
pp. 12950-12956 ◽  
Author(s):  
Normand McNicoll ◽  
Jean Gagnon ◽  
Jean-Jacques Rondeau ◽  
Huy Ong ◽  
André De Léan

2018 ◽  
Vol 50 (11) ◽  
pp. 913-928 ◽  
Author(s):  
Kailash N. Pandey

Natriuretic peptides (NPs) exert diverse effects on several biological and physiological systems, such as kidney function, neural and endocrine signaling, energy metabolism, and cardiovascular function, playing pivotal roles in the regulation of blood pressure (BP) and cardiac and vascular homeostasis. NPs are collectively known as anti-hypertensive hormones and their main functions are directed toward eliciting natriuretic/diuretic, vasorelaxant, anti-proliferative, anti-inflammatory, and anti-hypertrophic effects, thereby, regulating the fluid volume, BP, and renal and cardiovascular conditions. Interactions of NPs with their cognate receptors display a central role in all aspects of cellular, biochemical, and molecular mechanisms that govern physiology and pathophysiology of BP and cardiovascular events. Among the NPs atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and initiate intracellular signaling. The genetic disruption of Npr1 (encoding GC-A/NPRA) in mice exhibits high BP and hypertensive heart disease that is seen in untreated hypertensive subjects, including high BP and heart failure. There has been a surge of interest in the NPs and their receptors and a wealth of information have emerged in the last four decades, including molecular structure, signaling mechanisms, altered phenotypic characterization of transgenic and gene-targeted animal models, and genetic analyses in humans. The major goal of the present review is to emphasize and summarize the critical findings and recent discoveries regarding the molecular and genetic regulation of NPs, physiological metabolic functions, and the signaling of receptor GC-A/NPRA with emphasis on the BP regulation and renal and cardiovascular disorders.


2001 ◽  
Vol 281 (4) ◽  
pp. F665-F673 ◽  
Author(s):  
Shang-Jin Shi ◽  
Huong T. Nguyen ◽  
Guru Dutt Sharma ◽  
L. Gabriel Navar ◽  
Kailash N. Pandey

We have studied cardiovascular and renal phenotypes in Npr1 (genetic determinant of natriuretic peptide receptor-A; NPRA) gene-disrupted mutant mouse model. The baseline systolic arterial pressure (SAP) in 0-copy mutant (−/−) mice (143 ± 2 mmHg) was significantly higher than in 2-copy wild-type (+/+) animals (104 ± 2 mmHg); however, the SAP in 1-copy heterozygotes (+/−) was at an intermediate value (120 ± 4 mmHg). To determine whether Npr1 gene function affects the renin-angiotensin-aldosterone system (RAAS), we measured the components of RAAS in plasma, kidney, and adrenal gland of 0-copy, 1-copy, and 2-copy male mice. Newborn (2 days after the birth) 0-copy pups showed 2.5-fold higher intrarenal renin contents compared with 2-copy wild-type counterparts (0-copy 72 ± 12 vs. 2-copy 30 ± 7 μg ANG I · mg protein−1 · h−1, respectively). The intrarenal ANG II level in 0-copy pups was also higher than in 2-copy controls (0-copy 33 ± 5 vs. 2-copy 20 ± 2 pg/mg protein, respectively). However, both young (3 wk) and adult (16 wk) 0-copy mutant mice showed a dramatic 50–80% reduction in plasma renin concentrations (PRCs) and in expression of renal renin message compared with 2-copy control animals. In contrast, the adrenal renin content and mRNA expression levels were 1.5- to 2-fold higher in 0-copy adult mice than in 2-copy animals. The results suggest that inhibition of renal and systemic RAAS is a compensatory response that prevents greater increases in elevated arterial pressures in adult NPRA null mutant mice. However, the greater renin and ANG II levels seen in 0-copy newborn pups provide evidence that the direct effect of NPRA activation on renin is an inhibitory response.


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