The discovery of non-basic atrial natriuretic peptide clearance receptor antagonists. part 1

Veale, C. A.; Alford, Vernon; Aharony, David; Banville, Debra L.; Bialecki, Russell; Brown, Frederick J.; Damewood, James; Dantzman, Cathy L.; Edwards, Philip D.; Jacobs, Robert T.; Mauger, Russell C.; Murphy, Megan; Palmer, Willam E; Pine, Kara K.; Rumsey, William L.; Garcia-Davenport, Laura E; Shaw, Andrew; Steelman, Gary B.; Surian, Jean M.; Vacek, Edward P.

doi:10.1016/s0960-894x(00)00387-5

Cited by 39 publications

(32 citation statements)

References 12 publications

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“…The thesis is supported by the acute vasodilator (29,30) and hypotensive (31)(32)(33)(34) responses to exogenous CNP and the emerging signaling role of G i -coupled NPR-C in various cell types (35)(36)(37)(38)(39). CNP also produced a concentration-dependent relaxation of human vessels that was abolished in the presence of the selective NPR-C antagonist M372049 (lead compound based on AP-811; gift of C. Veale, AstraZeneca) (25,40) and following precontraction mediated by high K + (which abrogates smooth muscle hyperpolarization; Figure 2L). These data confirm that an NPR-C-triggered hyperpolarization is responsible for the vasorelaxant activity of CNP in human resistance arteries and provide proof-ofconcept that the signaling pathway we have identified is functionally important in the human cardiovascular system.…”

Section: Resultsmentioning

confidence: 94%

Endothelial C-type natriuretic peptide maintains vascular homeostasis

Moyes¹,

Khambata²,

Villar³

et al. 2014

J. Clin. Invest.

137

139

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Section: Resultsmentioning

confidence: 94%

Endothelial C-type natriuretic peptide maintains vascular homeostasis

Moyes¹,

Khambata²,

Villar³

et al. 2014

J. Clin. Invest.

137

139

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“…ANP(4 -23) can elicit a cellular response and is hence regarded as an NPR-C agonist (34). While AP-811 is a highly selective NPR-C ligand (19,38), it is not known whether it is an agonist or an antagonist.…”

Section: Resultsmentioning

confidence: 99%

“…To our knowledge, NPR-A is not coupled to a NOS/NO/sGC/HSP90-mediated pathway, whereas NPR-C is linked to activation of NOS and NO in noncardiac cells (1,5,26). The highly selective NPR-C ligand AP-811 (19,38) abolished ANP-induced pump stimulation, whereas the NPR-C agonist ANP (4 -23), in a concentration not expected to have any effect on NPR-A (19, 38), reproduced it. ANP(4 -23) also induced an increase in myocyte DAF fluorescence that was abolished by L-NAME.…”

Section: Discussionmentioning

confidence: 99%

Natriuretic peptides stimulate the cardiac sodium pump via NPR-C-coupled NOS activation

William¹,

Hamilton²,

García³

et al. 2008

American Journal of Physiology-Cell Physiology

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Natriuretic peptides (NPs) and their receptors (NPRs) are expressed in the heart, but their effects on myocyte function are poorly understood. Because NPRs are coupled to synthesis of cGMP, an activator of the sarcolemmal Na+-K+ pump, we examined whether atrial natriuretic peptide (ANP) regulates the pump. We voltage clamped rabbit ventricular myocytes and identified electrogenic Na+-K+ pump current (arising from the 3:2 Na+:K+ exchange and normalized for membrane capacitance) as the shift in membrane current induced by 100 μmol/l ouabain. Ten nanomoles per liter ANP stimulated the Na+-K+ pump when the intracellular compartment was perfused with pipette solutions containing 10 mmol/l Na+ but had no effect when the pump was at near maximal activation with 80 mmol/l Na+ in the pipette solution. Stimulation was abolished by inhibition of cGMP-activated protein kinase with KT-5823, nitric oxide (NO)-activated guanylyl cyclase with 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ), or NO synthase with NG-nitro-l-arginine methyl ester (l-NAME). Since synthesis of cGMP by NPR-A and NPR-B is not NO dependent or ODQ sensitive, we exposed myocytes to AP-811, a highly selective ligand for the NPR-C “clearance” receptor. It abolished ANP-induced pump stimulation. Conversely, the selective NPR-C agonist ANP(4-23) reproduced stimulation. The stimulation was blocked by l-NAME. To examine NO production in response to ANP(4-23), we loaded myocytes with the NO-sensitive fluorescent dye diacetylated diaminofluorescein-2 and examined them by confocal microscopy. ANP(4-23) induced a significant increase in fluorescence, which was abolished by l-NAME. We conclude that NPs stimulate the Na+-K+ pump via an NPR-C and NO-dependent pathway.

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“…Enhanced proliferation of cardiomyocytes at low concentrations of natriuretic peptides is mediated by activation of Npr3 and cAMP pathways To verify that Npr3 was involved in the induction of cardiomyocyte proliferation observed with low concentrations of ANP, we used the selective Npr3 antagonist AP-811 (Veale et al, 2000;William et al, 2008). Although AP-811 did not alter baseline cardiomyocyte proliferation across a wide range of concentrations (supplementary material Fig.…”

Section: Research Articlementioning

confidence: 99%

Differential activation of natriuretic peptide receptors modulates cardiomyocyte proliferation during development

et al. 2014

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Organ development is a highly regulated process involving the coordinated proliferation and differentiation of diverse cellular populations. The pathways regulating cell proliferation and their effects on organ growth are complex and for many organs incompletely understood. In all vertebrate species, the cardiac natriuretic peptides (ANP and BNP) are produced by cardiomyocytes in the developing heart. However, their role during cardiogenesis is not defined. Using the embryonic zebrafish and neonatal mammalian cardiomyocytes we explored the natriuretic peptide signaling network during myocardial development. We observed that the cardiac natriuretic peptides ANP and BNP and the guanylate cyclase-linked natriuretic peptide receptors Npr1 and Npr2 are functionally redundant during early cardiovascular development. In addition, we demonstrate that low levels of the natriuretic peptides preferentially activate Npr3, a receptor with Gi activator sequences, and increase cardiomyocyte proliferation through inhibition of adenylate cyclase. Conversely, high concentrations of natriuretic peptides reduce cardiomyocyte proliferation through activation of the particulate guanylate cyclase-linked natriuretic peptide receptors Npr1 and Npr2, and activation of protein kinase G. These data link the cardiac natriuretic peptides in a complex hierarchy modulating cardiomyocyte numbers during development through opposing effects on cardiomyocyte proliferation mediated through distinct cyclic nucleotide signaling pathways.

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The discovery of non-basic atrial natriuretic peptide clearance receptor antagonists. part 1

Cited by 39 publications

References 12 publications

Endothelial C-type natriuretic peptide maintains vascular homeostasis

Endothelial C-type natriuretic peptide maintains vascular homeostasis

Natriuretic peptides stimulate the cardiac sodium pump via NPR-C-coupled NOS activation

Differential activation of natriuretic peptide receptors modulates cardiomyocyte proliferation during development

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