In vitro and in vivo pharmacological profile of PL-3994, a novel cyclic peptide (Hept-cyclo(Cys-His-Phe-d-Ala-Gly-Arg-d-Nle-Asp-Arg-Ile-Ser-Cys)-Tyr-[Arg mimetic]-NH2) natriuretic peptide receptor-A agonist that is resistant to neutral endopeptidase and acts as a bronchodilator

AbstractGastric cancer (GC) ranks the third among global cancer-related mortality, especially in East Asia. Angiogenesis plays an important role in promoting tumor progression, and clinical trials have demonstrated that anti-angiogenesis therapy is effective in GC management. Natriuretic peptide receptor A (NPRA) functions significantly in promoting GC development and progression. Whether NPRA can promote angiogenesis of GC remains unclear. Tumor samples collection and immunohistochemical experiment showed that the expression of NPRA was positively correlated with the expression of CD31 and vessel density. In vivo and in vitro analysis showed that NPRA could promote GC-associated angiogenesis and tumor metastasis. Results of Co-IP/MS showed that NPRA could prevent HIF-1α from being degraded by binding to HIF-1α. Protection of HIF-1α improved VEGF levels and thus promoted angiogenesis. In summary, NPRA protected HIF-1α from proteolysis by binding to HIF-1α, increased the expression of HIF-1α, and promoted GC angiogenesis. This study has discovered a new mechanism for NPRA to promote gastric cancer development and a new regulatory mechanism for HIF-1α.

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ANP-mediated inhibition of distal nephron fractional sodium reabsorption in wild-type and mice overexpressing natriuretic peptide receptor

AJP Renal Physiology ◽

10.1152/ajprenal.00479.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. F103-F108 ◽

Cited By ~ 13

Author(s):

Di Zhao ◽

Kailash N. Pandey ◽

L. Gabriel Navar

Keyword(s):

Natriuretic Peptide ◽

Sodium Excretion ◽

Urinary Sodium Excretion ◽

Sodium Reabsorption ◽

Natriuretic Peptide Receptor ◽

Distal Nephron ◽

Peptide Receptor ◽

Natriuretic Peptide Receptor A ◽

Npr1 Gene

Atrial natriuretic peptide (ANP) elicits natriuresis; however, the relative contributions of proximal and distal nephron segments to the overall ANP-induced natriuresis have remained uncertain. This study was performed to characterize the effects of ANP on distal nephron sodium reabsorption determined after blockade of the two major distal nephron sodium transporters with amiloride (5 μg/g body wt) plus bendroflumethiazide (12 μg/g body wt) in male anesthetized C57/BL6 and natriuretic peptide receptor-A gene (Npr1) targeted four-copy mice. The lower dose of ANP (0.1 ng·g body wt−1·min−1, n = 6) increased distal sodium delivery (DSD, 2.4 ± 0.4 vs. 1.6 ± 0.2 μeq/min, P < 0.05) but did not change fractional reabsorption of DSD compared with control (86.3 ± 2.0 vs. 83.9 ± 3.6%, P > 0.05), thus limiting the magnitude of the natriuresis. In contrast, the higher dose (0.2 ng·g body wt−1·min−1, n = 6) increased DSD (2.8 ± 0.3 μeq/min, P < 0.01) and also decreased fractional reabsorption of DSD (67.4 ± 4.5%, P < 0.01), which markedly augmented the natriuresis. In Npr1 gene-duplicated four-copy mice ( n = 6), the lower dose of ANP increased urinary sodium excretion (0.6 ± 0.1 vs. 0.3 ± 0.1 μeq/min, P < 0.05) and decreased fractional reabsorption of DSD compared with control (72.2 ± 3.4%, P < 0.05) at similar mean arterial pressures (91 ± 6 vs. 92 ± 3 mmHg, P > 0.05). These results provide in vivo evidence that ANP-mediated increases in DSD alone exert modest effects on sodium excretion and that inhibition of fractional reabsorption of distal sodium delivery is requisite for the augmented natriuresis in response to the higher dose of ANP or in Npr1 gene-duplicated mice.

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A Novel Chimeric Peptide, ANG1-7/BNP, with Dual In Vitro and In Vivo Actions through the Natriuretic Peptide Receptor and Mas Receptor Systems

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2013.06.008 ◽

2013 ◽

Vol 19 (8) ◽

pp. S1

Author(s):

Ingrid A. Andersen ◽

Brenda K. Huntley ◽

Gail Harty ◽

Daniel J. McCormick ◽

John C. Burnett

Keyword(s):

Natriuretic Peptide ◽

Natriuretic Peptide Receptor ◽

Peptide Receptor ◽

Mas Receptor ◽

Chimeric Peptide

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The role of natriuretic peptide receptor-A signaling in unilateral lung ischemia-reperfusion injury in the intact mouse

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00185.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. L714-L723 ◽

Cited By ~ 15

Author(s):

Jeffrey M. Dodd-o ◽

Maria L. Hristopoulos ◽

Kathleen Kibler ◽

Jolanta Gutkowska ◽

Suhayla Mukaddam-Daher ◽

...

Keyword(s):

Lung Injury ◽

Natriuretic Peptide ◽

Ischemia Reperfusion ◽

Intracellular Camp ◽

Natriuretic Peptide Receptor ◽

Intact Mouse ◽

Peptide Receptor ◽

Natriuretic Peptide Receptor A

Ischemia-reperfusion (IR) causes human lung injury in association with the release of atrial and brain natriuretic peptides (ANP and BNP), but the role of ANP/BNP in IR lung injury is unknown. ANP and BNP bind to natriuretic peptide receptor-A (NPR-A) generating cGMP and to NPR-C, a clearance receptor that can decrease intracellular cAMP. To determine the role of NPR-A signaling in IR lung injury, we administered the NPR-A blocker anantin in an in vivo SWR mouse preparation of unilateral lung IR. With uninterrupted ventilation, the left pulmonary artery was occluded for 30 min and then reperfused for 60 or 150 min. Anantin administration decreased IR-induced Evans blue dye extravasation and wet weight in the reperfused left lung, suggesting an injurious role for NPR-A signaling in lung IR. In isolated mouse lungs, exogenous ANP (2.5 nM) added to the perfusate significantly increased the filtration coefficient sevenfold only if lungs were subjected to IR. This effect of ANP was also blocked by anantin. Unilateral in vivo IR increased endogenous plasma ANP, lung cGMP concentration, and lung protein kinase G (PKGI) activation. Anantin enhanced plasma ANP concentrations and attenuated the increase in cGMP and PKGI activation but had no effect on lung cAMP. These data suggest that lung IR triggered ANP release and altered endothelial signaling so that NPR-A activation caused increased pulmonary endothelial permeability.

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Inhibition of natriuretic peptide receptor 1 reduces itch in mice

Science Translational Medicine ◽

10.1126/scitranslmed.aav5464 ◽

2019 ◽

Vol 11 (500) ◽

pp. eaav5464 ◽

Cited By ~ 12

Author(s):

Hans Jürgen Solinski ◽

Patricia Dranchak ◽

Erin Oliphant ◽

Xinglong Gu ◽

Thomas W. Earnest ◽

...

Keyword(s):

Natriuretic Peptide ◽

Behavioral Responses ◽

In Vitro Assays ◽

Natriuretic Peptide Receptor ◽

Peptide Receptor ◽

Chronic Itch ◽

Novel Strategy ◽

Molecular Components

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch– and chronic itch–challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

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