G protein-dependent activation of smooth muscle  eNOS via natriuretic peptide clearance receptor

Murthy, Karnam S.; Teng, B.-Q.; Jin, Ji‐Guang; Makhlouf, Gabriel M.

doi:10.1152/ajpcell.1998.275.6.c1409

Cited by 103 publications

(105 citation statements)

References 30 publications

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“…The role of NOS in ANP-induced pump stimulation is supported by L-NAME and radicicol blocking stimulation and HSP90 reproducing it. 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.…”

Section: Discussionmentioning

confidence: 91%

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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Section: Discussionmentioning

confidence: 91%

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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“…Since previous work has demonstrated that NPR-B KO animals are normotensive (28), these observations as a whole provide convincing evidence that, physiologically, NPR-C is the primary receptor triggered by CNP to maintain vascular function and blood pressure. 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).…”

Section: Resultsmentioning

confidence: 99%

Endothelial C-type natriuretic peptide maintains vascular homeostasis

Moyes¹,

Khambata²,

Villar³

et al. 2014

J. Clin. Invest.

137

139

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“…37,38,44,45 In addition, NPR-C activation by C-ANP 4-23 was also reported to activate eNOS in various tissues including smooth muscle. 33 We also examined whether C-ANP 4-23 -induced attenuation of BP in SHRs is attributed to its ability to augment the levels of eNOS and NO; however, in the present in vivo study, we demonstrate that C-ANP 4-23 treatment decreased the enhanced levels of NO and eNOS in kidney and attenuated further the decreased levels of eNOS and NO in VSMC and aorta from SHRs and suggest that C-ANP 4-23 -induced decreased BP may not involve NO and NO-stimulated cGMP pathway. Furthermore, our results showing that the levels of ONOO − and nitrotyrosine were increased in VSMC, aorta, and kidney from SHRs that may be formed by the reaction of NO with O 2 − are in accordance with the studies of other investigators who have also reported an increased levels of ONOO − and nitrotyrosine content in aorta and mesenteric arteries as well as in kidney from SHRs without and with typical symptoms of metabolic syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…NPR-C activation by C-ANP [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] has been shown to activate NO synthase in various tissues including smooth muscle 33,34 resulting in the increased levels of NO that through cGMP contribute to BP regulation. Because SHRs have been shown to exhibit decreased expression of eNOS, 35 it was of interest to examine whether C-ANP 4-23 -induced decreased BP in SHRs is also attributed to its ability to augment the expression of eNOS.…”

Section: Effect Of In Vivo C-anp 4-23 Treatment On the Levels Of Enosmentioning

confidence: 99%

Natriuretic Peptide Receptor-C Attenuates Hypertension in Spontaneously Hypertensive Rats

Sarkar

Brochu

et al. 2014

Hypertension

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Abstract-C-Atrial natriuretic peptide (ANP) 4-23 , a ring deleted analog of ANP that specifically interacts with natriuretic peptide receptor-C (NPR-C), has been shown to decrease the enhanced expression of Giα proteins implicated in the pathogenesis of hypertension. In the present study, we investigated whether in vivo treatment of spontaneously hypertensive rats (SHRs) with C-ANP 4-23 could attenuate the development of high blood pressure (BP) and explored the underlying mechanisms responsible for this response. Intraperitoneal injection of C-ANP 4-23 at the concentration of 2 or 10 nmol/kg body weight to prehypertensive SHRs attenuated the development of high BP, and at 8 weeks it was decreased by ≈20 and 50 mm Hg, respectively; however, this treatment did not affect BP in Wistar-Kyoto rats. C-ANP 4-23 treatment of adult SHRs for 2 weeks also attenuated high BP, heart rate, and restored the impaired vasorelaxation toward control levels. In addition, the enhanced levels of superoxide anion (O 2 − ), peroxynitrite, NADPH oxidase activity, and the enhanced expression of Giα proteins, NOX4, p47 phox , nitrotyrosine, and decreased levels of endothelial nitric oxide synthase (eNOS or NOS3) and NO in SHRs were attenuated by C-ANP 4-23 treatment; however, the altered levels of NPR-A/NPR-C were not affected by this treatment. In conclusion, these results indicate that NPR-C activation by C-ANP 4-23 attenuates the development of high BP in SHRs through the inhibition of enhanced levels of Giα proteins and nitroxidative stress and not through eNOS/ cGMP pathway and suggest that NPR-C ligand may have the potential to be used as therapeutic agent in the treatment of Li et al NPR-C and Blood Pressure Regulation 847injection of pertussis toxin in prehypertensive rats (2-week-old SHRs) has been reported to prevent the development of BP,22 suggesting the implication of enhanced expression of Gi proteins in the pathogenesis of hypertension. C-ANP 4-23 that specifically interacts with NPR-C has been reported to decrease the levels of Giα proteins in A10 vascular smooth muscle cell (VSMC) 23 and in VSMC from SHRs. 24 In addition, C-ANP 4-23 was also shown to attenuate the enhanced oxidative stress in VSMC from SHRs 24 that contributes to the enhanced expression of Giα proteins in SHRs.25 Taken together, it may be possible that C-ANP 4-23 treatment of SHRs could also attenuate the high BP in SHRs. The present study was undertaken to investigate the effect of in vivo administration of C-ANP 4-23 on the development of high BP in SHRs. We have provided the first evidence that the treatment of prehypertensive SHRs with C-ANP 4-23 , an activator of NPR-C, attenuates the development of high BP in SHRs through the inhibition of enhanced expression of Gi proteins and oxidative stress.We have provided the first evidence that NPR-C activation by C-ANP 4-23 attenuates high BP through decreasing the enhanced oxidative stress and the augmented levels of Giα proteins. From these results it may be suggested that C-ANP [4][5][6][7][8][9][10][...

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G protein-dependent activation of smooth muscle eNOS via natriuretic peptide clearance receptor

Cited by 103 publications

References 30 publications

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

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

Endothelial C-type natriuretic peptide maintains vascular homeostasis

Natriuretic Peptide Receptor-C Attenuates Hypertension in Spontaneously Hypertensive Rats

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