scholarly journals Angiotensin II stimulates superoxide production in the thick ascending limb by activating NOX4

2012 ◽  
Vol 303 (7) ◽  
pp. C781-C789 ◽  
Author(s):  
Katherine J. Massey ◽  
Nancy J. Hong ◽  
Jeffrey L. Garvin
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Knockout Mice ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Wild Type ◽  
Outer Medulla ◽  
Catalytic Subunits ◽  
In The Wild

Angiotensin II (ANG II) stimulates production of superoxide (O2−) by NADPH oxidase (NOX) in medullary thick ascending limbs (TALs). There are three isoforms of the catalytic subunit (NOX1, 2, and 4) known to be expressed in the kidney. We hypothesized that NOX2 mediates ANG II-induced O2− production by TALs. To test this, we measured NOX1, 2, and 4 mRNA and protein by RT-PCR and Western blot in TAL suspensions from rats and found three catalytic subunits expressed in the TAL. We measured O2− production using a lucigenin-based assay. To assess the contribution of NOX2, we measured ANG II-induced O2− production in wild-type and NOX2 knockout mice (KO). ANG II increased O2− production by 346 relative light units (RLU)/mg protein in the wild-type mice ( n = 9; P < 0.0007 vs. control). In the knockout mice, ANG II increased O2− production by 290 RLU/mg protein ( n = 9; P < 0.007 vs. control). This suggests that NOX2 does not contribute to ANG II-induced O2− production ( P < 0.6 WT vs. KO). To test whether NOX4 mediates the effect of ANG II, we selectively decreased NOX4 expression in rats using an adenovirus that expresses NOX4 short hairpin (sh)RNA. Six to seven days after in vivo transduction of the kidney outer medulla, NOX4 mRNA was reduced by 77%, while NOX1 and NOX2 mRNA was unaffected. In control TALs, ANG II stimulated O2− production by 96%. In TALs transduced with NOX4 shRNA, ANG II-stimulated O2− production was not significantly different from the baseline. We concluded that NOX4 is the main catalytic isoform of NADPH oxidase that contributes to ANG II-stimulated O2− production by TALs.

scholarly journals A new mechanism for the sex differences in angiotensin II-induced hypertension: the role of macula densa NOS1β-mediated tubuloglomerular feedback

2020 ◽  
Vol 319 (5) ◽  
pp. F908-F919
Author(s):  
Jie Zhang ◽  
Larry Qu ◽  
Jin Wei ◽  
Shan Jiang ◽  
Lan Xu ◽  
...  
Keyword(s):  
Sex Differences ◽  
Angiotensin Ii ◽  
Knockout Mice ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Ang Ii ◽  
Wild Type ◽  
Induced Hypertension

Females are protected against the development of angiotensin II (ANG II)-induced hypertension compared with males, but the mechanisms have not been completely elucidated. In the present study, we hypothesized that the effect of ANG II on the macula densa nitric oxide (NO) synthase 1β (NOS1β)-mediated tubuloglomerular feedback (TGF) mechanism is different between males and females, thereby contributing to the sexual dimorphism of ANG II-induced hypertension. We used microperfusion, micropuncture, clearance of FITC-inulin, and radio telemetry to examine the sex differences in the changes of macula densa NOS1β expression and activity, TGF response, natriuresis, and blood pressure (BP) after a 2-wk ANG II infusion in wild-type and macula densa-specific NOS1 knockout mice. In wild-type mice, ANG II induced higher expression of macula densa NOS1β, greater NO generation by the macula densa, and a lower TGF response in vitro and in vivo in females than in males; the increases of glomerular filtration rate, urine flow rate, and Na+ excretion in response to an acute volume expansion were significantly greater and the BP responses to ANG II were significantly less in females than in males. In contrast, these sex differences in the effects of ANG II on TGF, natriuretic response, and BP were largely diminished in knockout mice. In addition, tissue culture of human kidney biopsies (renal cortex) with ANG II resulted in a greater increase in NOS1β expression in females than in males. In conclusion, macula densa NOS1β-mediated TGF is a novel and important mechanism for the sex differences in ANG II-induced hypertension.

Abstract 229: TNF Receptor 1 Signaling Is Critically Involved in Mediating Angiotensin II-Induced Cardiac Fibrosis and Dysfunction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Sandra B Haudek ◽  
Jeff Crawford ◽  
Erin Reineke ◽  
Alberto A Allegre ◽  
George E Taffet ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Protein A ◽  
Ang Ii ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reactive Fibrosis

Angiotensin-II (Ang-II) plays a key role in the development of cardiomyopathies, as it is associated with many conditions involving heart failure and pathologic hypertrophy. Using a murine model of Ang-II infusion, we found that Ang-II induced the synthesis of monocyte chemoattractant protein 1 (MCP-1) that mediated the uptake of CD34 + /CD45 + monocytic cells into the heart. These precursor cells differentiated into collagen-producing fibroblasts and were responsible for the Ang-II-induced development of reactive fibrosis. Preliminary in vitro data using our monocyte-to-fibroblast differentiation model, suggested that Ang-II required the presence of TNF to induce fibroblast maturation from monocytes. In vivo, they indicated that in mice deficient of both TNF receptors (TNFR1 and TNFR2), Ang-II-induced fibrosis was absent. We now assessed the hypothesis that specific TNFR1 signaling is necessary for Ang-II-mediated cardiac fibrosis. Mice deficient in either TNFR1 (TNFR1-KO) or TNFR2 (TNFR2-KO) were subjected to continuous infusion of Ang-II for 1 to 6 weeks (n=6-8/group). Compared to wild-type, we found that in TNFR1-KO, but not in TNFR2-KO mouse hearts, collagen deposition was attenuated, as was cardiac α-smooth muscle actin protein (a marker for activated fibroblasts). When we isolated viable cardiac fibroblasts and characterized them by flow cytometry, we found that Ang-II infusion in TNFR1-KO, but not in TNFR2-KO, resulted in a marked decrease of CD34 + /CD45 + cells. Quantitative RT-PCR demonstrated a striking reduction of type 1 and 3 collagen, as well of MCP-1 mRNA expression in TNFR1-KO mouse hearts. Further measurements of cardiovascular parameters indicated that TNFR1-KO animals developed lesser Ang-II-mediated LV remodeling, smaller changes in E-linear deceleration times/rates over time, and displayed a lower Tei index (a heart rate independent marker of cardiac function), indicating less stiffness in TNFR1-KO hearts compared to wild-type and TNFR2-KO hearts. The data suggest that Ang-II-dependent cardiac fibrosis requires TNF and its signaling through TNFR1 which enhances the induction of MCP-1 and uptake of monocytic fibroblast precursors that are associated with reactive fibrosis and cardiac remodeling and function.

scholarly journals NADPH oxidase 4 mediates flow-induced superoxide production in thick ascending limbs

2012 ◽  
Vol 303 (8) ◽  
pp. F1151-F1156 ◽  
Author(s):  
Nancy J. Hong ◽  
Jeffrey L. Garvin
Keyword(s):  
Nadph Oxidase ◽  
Knockout Mice ◽  
Thick Ascending Limb ◽  
Wild Type ◽  
Rt Pcr ◽  
Nacl Transport ◽  
Flow Rates ◽  
Physiological Flow ◽  
Nadph Oxidase 4 ◽  
Luminal Flow

We previously showed that luminal flow stimulates thick ascending limb (TAL) superoxide (O2−) production by stretching epithelial cells and increasing NaCl transport, and reported that the major source of flow-induced O2− is NADPH oxidase (Nox). However, the specific Nox isoform involved is unknown. Of the three isoforms expressed in the kidney—Nox1, Nox2, and Nox4—we hypothesized that Nox4 is responsible for flow-induced O2− production in TALs. Measurable flow-induced O2− production at physiological flow rates of 0, 5, 10, and 20 nl/min was 5 ± 1, 9 ± 2, 36 ± 6, and 66 ± 8 AU/s, respectively. RT-PCR detected mRNA for all three Nox isoforms in the TAL. The order of RNA abundance was Nox2 > Nox4 >>> Nox1. Since all three isoforms are expressed in TALs and pharmacological inhibitors are not selective, we used rats transduced with siRNA and knockout mice. Nox4 siRNA knocked down Nox4 mRNA expression by 63 ± 7% but did not reduce Nox1 or Nox2 mRNA. Flow-induced O2− was 18 ± 9 AU/s in TALs transduced with Nox4 siRNA compared with 77 ± 9 AU/s in tubules transduced with scrambled siRNA. Flow-induced O2− was 81 ± 5 AU/s in Nox2 knockout mice compared with 83 ± 13 AU/s in wild-type mice. In TALs transduced with Nox1 siRNA, flow-induced O2− was 82 ± 7 AU/s. We conclude that Nox4 mediates flow-induced O2− production in TALs.

scholarly journals Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase

2014 ◽  
Vol 307 (7) ◽  
pp. C634-C647 ◽  
Author(s):  
Anna Cozzoli ◽  
Antonella Liantonio ◽  
Elena Conte ◽  
Maria Cannone ◽  
Ada Maria Massari ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Calcium Homeostasis ◽  
Potassium Conductance ◽  
Mdx Mouse ◽  
Dependent Manner ◽  
Ang Ii ◽  
Concentration Dependent Manner

Angiotensin II (ANG II) plays a role in muscle wasting and remodeling; however, little evidence shows its direct effects on specific muscle functions. We presently investigated the acute in vitro effects of ANG II on resting ionic conductance and calcium homeostasis of mouse extensor digitorum longus (EDL) muscle fibers, based on previous findings that in vivo inhibition of ANG II counteracts the impairment of macroscopic ClC-1 chloride channel conductance (gCl) in the mdx mouse model of muscular dystrophy. By means of intracellular microelectrode recordings we found that ANG II reduced gCl in the nanomolar range and in a concentration-dependent manner (EC50 = 0.06 μM) meanwhile increasing potassium conductance (gK). Both effects were inhibited by the ANG II receptors type 1 (AT1)-receptor antagonist losartan and the protein kinase C inhibitor chelerythrine; no antagonism was observed with the AT2 antagonist PD123,319. The scavenger of reactive oxygen species (ROS) N-acetyl cysteine and the NADPH-oxidase (NOX) inhibitor apocynin also antagonized ANG II effects on resting ionic conductances; the ANG II-dependent gK increase was blocked by iberiotoxin, an inhibitor of calcium-activated potassium channels. ANG II also lowered the threshold for myofiber and muscle contraction. Both ANG II and the AT1 agonist L162,313 increased the intracellular calcium transients, measured by fura-2, with a two-step pattern. These latter effects were not observed in the presence of losartan and of the phospholipase C inhibitor U73122 and the in absence of extracellular calcium, disclosing a Gq-mediated calcium entry mechanism. The data show for the first time that the AT1-mediated ANG II pathway, also involving NOX and ROS, directly modulates ion channels and calcium homeostasis in adult myofibers.

Niacin stimulates adiponectin secretion through the GPR109A receptor

2009 ◽  
Vol 296 (3) ◽  
pp. E549-E558 ◽  
Author(s):  
Eric P. Plaisance ◽  
Martina Lukasova ◽  
Stefan Offermanns ◽  
Youyan Zhang ◽  
Guoqing Cao ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Surface Expression ◽  
In Vivo Studies ◽  
Serum Adiponectin ◽  
Cell Surface Expression ◽  
Wild Type ◽  
The Metabolic Syndrome ◽  
In The Wild

Niacin (nicotinic acid) has recently been shown to increase serum adiponectin concentrations in men with the metabolic syndrome. However, little is known about the mechanism(s) by which niacin regulates the intracellular trafficking and secretion of adiponectin. Since niacin appears to exert its effects on lipolysis through receptor (GPR109A)-dependent and -independent pathways, the purpose of this investigation was to examine the role of the recently identified GPR109A receptor in adiponectin secretion. Initial in vivo studies in rats demonstrated that niacin (30 mg/kg po) acutely increases serum adiponectin concentrations, whereas it decreases NEFAs. Further in vitro studies demonstrated an increase in adiponectin secretion and a decrease in lipolysis in primary adipocytes following treatment with niacin or β-hydroxybutyrate (an endogenous ligand of the GPR109A receptor), but these effects were blocked when adipocytes were pretreated with pertussis toxin. Niacin had no effect on adiponectin secretion or lipolysis in 3T3-L1 adipocytes, which have limited cell surface expression of the GPR109A receptor. To further substantiate these in vitro findings, wild-type and GPR109A receptor knockout mice were administered a single dose of niacin or placebo, and serum was obtained for the determination of adiponectin and NEFA concentrations. Serum adiponectin concentrations increased and serum NEFAs decreased in the wild-type mice within 10 min following niacin administration. However, niacin administration had no effect on adiponectin and NEFA concentrations in the GPR109A receptor knockout mice. These results demonstrate that the GPR109A receptor plays an important role in the dual regulation of adiponectin secretion and lipolysis.

scholarly journals Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase

2009 ◽  
Vol 206 (13) ◽  
pp. 2889-2896 ◽  
Author(s):  
Annemarieke E. Loot ◽  
Judith G. Schreiber ◽  
Beate Fisslthaler ◽  
Ingrid Fleming
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Tyrosine Phosphorylation ◽  
Dominant Negative ◽  
No Production ◽  
Dependent Manner ◽  
Ang Ii ◽  
Wild Type ◽  
Tyrosine Kinase 2

Proline-rich tyrosine kinase 2 (PYK2) can be activated by angiotensin II (Ang II) and reactive oxygen species. We report that in endothelial cells, Ang II enhances the tyrosine phosphorylation of endothelial NO synthase (eNOS) in an AT1-, H2O2-, and PYK2-dependent manner. Low concentrations (1–100 µmol/liter) of H2O2 stimulated the phosphorylation of eNOS Tyr657 without affecting that of Ser1177, and attenuated basal and agonist-induced NO production. In isolated mouse aortae, 30 µmol/liter H2O2 induced phosphorylation of eNOS on Tyr657 and impaired acetylcholine-induced relaxation. Endothelial overexpression of a dominant-negative PYK2 mutant protected against H2O2-induced endothelial dysfunction. Correspondingly, carotid arteries from eNOS−/− mice overexpressing the nonphosphorylatable eNOS Y657F mutant were also protected against H2O2. In vivo, 3 wk of treatment with Ang II considerably increased levels of Tyr657-phosphorylated eNOS in the aortae of wild-type but not Nox2y/− mice, and this was again associated with a clear impairment in endothelium-dependent vasodilatation in the wild-type but not in the Nox2y/− mice. Collectively, endothelial PYK2 activation by Ang II and H2O2 causes the phosphorylation of eNOS on Tyr657, attenuating NO production and endothelium-dependent vasodilatation. This mechanism may contribute to the endothelial dysfunction observed in cardiovascular diseases associated with increased activity of the renin–angiotensin system and elevated redox stress.

Angiotensin II increases the expression of the transcription factor ETS-1 in mesangial cells

2008 ◽  
Vol 294 (5) ◽  
pp. F1094-F1100 ◽  
Author(s):  
Damien D. Pearse ◽  
Run-Xia Tian ◽  
Jessica Nigro ◽  
Julian B. Iorgulescu ◽  
Leopold Puzis ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Mesangial Cells ◽  
Critical Role ◽  
Ang Ii ◽  
Specific Sequence ◽  
Cox 2

Maladaptive activation of the renin-angiotensin system (RAS) has been shown to play a critical role in the pathogenesis of chronic kidney disease. Reactive oxygen species (ROS) are critical signals for many of the nonhemodynamic effects of angiotensin II (ANG II). We have demonstrated that ANG II increases mesangial and cortical cyclooxygenase-2 (COX-2) expression and activity via NADPH oxidase-derived ROS. The transcription factor ETS-1 (E26 transformation-specific sequence) has been identified as a critical regulator of growth-related responses and inflammation. The present studies were designed to determine: 1) whether ANG II induces ETS-1 expression in vitro in cultured rat mesangial cells and in vivo in rats infused with ANG II; and 2) whether ROS and COX-2 are mediators of ETS-1 induction in response to ANG II. Mesangial cells stimulated with ANG II (10−7 M) exhibited a significant increase in ETS-1 expression that was prevented by the angiotensin type 1 receptor blocker candesartan. NADPH oxidase inhibition with dyphenilene iodinium or apocynin also prevented ETS-1 induction, establishing the role of ROS as mediators of ETS-1 expression in response to ANG II. COX-2 inhibition prevented ETS-1 expression in response to ANG II, suggesting that COX-2 is required for ETS-1 induction. By utilizing short interfering RNAs against ETS-1, we have also determined that ETS-1 is required to induce the production of fibronectin in response to ANG II. Furthermore, rats infused with ANG II manifested increased glomerular expression of ETS-1. These studies unveil novel pathways that may play an important role in the pathogenesis of renal injury when RAS is activated.

Isoflurane-induced Cerebral Hyperemia in Neuronal Nitric Oxide Synthase Gene Deficient Mice 

1997 ◽  
Vol 86 (4) ◽  
pp. 875-884 ◽  
Author(s):  
Hirotsugu Okamoto ◽  
Wei Meng ◽  
Jinya Ma ◽  
Cenk Ayata ◽  
Richard J. Roman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Knockout Mice ◽  
Compensatory Mechanism ◽  
Wild Type ◽  
Doppler Flowmetry ◽  
Anesthetic Concentration ◽  
In The Wild ◽  
Oxide Synthase ◽  
Nos Isoforms

Background Nitric oxide (NO) has been reported to play an important role in isoflurane-induced cerebral hyperemia in vivo. In the brain, there are two constitutive isoforms of NO synthase (NOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Recently, the mutant mouse deficient in nNOS gene expression (nNOS knockout) has been developed. The present study was designed to examine the role of the two constitutive NOS isoforms in cerebral blood flow (CBF) response to isoflurane using this nNOS knockout mouse. Methods Regional CBF (rCBF) in the cerebral cortex was measured with laser-Doppler flowmetry in wild-type mice (129/SV or C57BL/6) and nNOS knockout mice during stepwise increases in the inspired concentration of isoflurane from 0.6 vol% to 1.2, 1.8, and 2.4 vol%. Subsequently, a NOS inhibitor, N omega-nitro-L-arginine (L-NNA), was administered intravenously (20 mg/kg), and 45 min later, the rCBF response to isoflurane was tested again. In separate groups of wild-type mice and the knockout mice, the inactive enantiomer, N omega-nitro-D-arginine (D-NNA) was administered intravenously in place of L-NNA. Brain NOS activity was measured with radio-labeled L-arginine to L-citrulline conversion after treatment with L-NNA and D-NNA. Results Isoflurane produced dose-dependent increases in rCBF by 25 +/- 3%, 74 +/- 10%, and 108 +/- 14% (SEM) in 129/SV mice and by 32 +/- 2%, 71 +/- 3%, and 96 +/- 7% in C57BL/6 mice at 1.2, 1.8, and 2.4 vol%, respectively. These increases were attenuated at every anesthetic concentration by L-NNA but not by D-NNA. Brain NOS activity was decreased by 92 +/- 2% with L-NNA compared with D-NNA. In nNOS knockout mice, isoflurane increased rCBF by 67 +/- 8%, 88 +/- 12%, and 112 +/- 18% at 1.2, 1.8, and 2.4 vol%, respectively. The increase in rCBF at 1.2 vol% was significantly greater in the nNOS knockout mice than that in the wild-type mice. Administration of L-NNA in the knockout mice attenuated the rCBF response to isoflurane at 1.2 and 1.8 vol% but had no effect on the response at 2.4 vol%. Conclusions In nNOS knockout mice, the cerebral hyperemic response to isoflurane is preserved by compensatory mechanism(s) that is NO-independent at 2.4 vol%, although it may involve eNOS at 1.2 and 1.8 vol%. It is suggested that in wild-type mice, eNOS and nNOS contribute to isoflurane-induced increase in rCBF. At lower concentrations (1.2 and 1.8 vol%), eNOS may be involved, whereas at 2.4 vol%, nNOS may be involved.

The role of adenosine in hypercarbic hyperemia: in vivo and in vitro studies in adenosine 2A receptor knockout and wild-type mice

2009 ◽  
Vol 110 (5) ◽  
pp. 981-988 ◽  
Author(s):  
Grzegorz Miekisiak ◽  
Kristen Yoo ◽  
Adam L. Sandler ◽  
Tobias B. Kulik ◽  
Jiang-Fan Chen ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Knockout Mice ◽  
Average Diameter ◽  
In Vitro Studies ◽  
Wild Type ◽  
Doppler Flowmetry ◽  
In The Wild

Object The authors tested the hypothesis that adenosine, acting through the A2A receptor, is not involved in hypercarbic hyperemia by assessing the effects of increased PaCO2 on cerebral blood flow (CBF) in vivo in wild-type and A2A receptor knockout mice. In addition, they evaluated the effect of abluminal pH changes in vitro on the diameter of isolated perfused penetrating arterioles harvested from wild-type and A2A receptor knockout mice. Methods The authors evaluated in a blinded fashion the CBF response during transient (60-second) hypercapnic (7% CO2) hypercarbia in anesthetized, ventilated C57Bl/6 wild-type and adenosine A2A receptor knockout mice. They also evaluated the hypercarbic response in the absence and presence of the nonselective and selective adenosine antagonists. Results Cerebral blood flow was measured using laser Doppler flowmetry. There were no differences between the CBF responses to hypercarbia in the wild-type and the knockout mice. Moreover, the hypercarbic hyperemia response was not affected by the adenosine receptor antagonists. The authors also tested the response to alteration in abluminal pH in isolated perfused, pressurized, penetrating arterioles (average diameter 63.3 ± 3.6 μm) harvested from wild-type (6 mice) and knockout (5 mice) animals. Arteriolar dilation in response to a decrease in abluminal pH, simulating the change in vivo during hypercarbia, was similar in wild-type (15.9 ± 2.6%) and A2A receptor knockout (17.7 ± 1.3%) mice. With abluminal application of CGS 21680 (10−6 M), an A2A receptor agonist, wild-type arterioles dilated in an expected manner (9.8 ± 0.7%), whereas A2A receptor knockout vessels had minimal response. Conclusions The results of the in vivo and in vitro studies in wild-type and A2A receptor knockout mice support the authors' hypothesis that hypercarbic vasodilation does not involve an adenosine A2A receptor–related mechanism.

scholarly journals Local Actions of Atrial Natriuretic Peptide Counteract Angiotensin II Stimulated Cardiac Remodeling

Endocrinology ◽  
2007 ◽  
Vol 148 (9) ◽  
pp. 4162-4169 ◽  
Author(s):  
Ana Kilić ◽  
Alexander Bubikat ◽  
Birgit Gaßner ◽  
Hideo A. Baba ◽  
Michaela Kuhn
Keyword(s):  
Angiotensin Ii ◽  
Knockout Mice ◽  
Growth Response ◽  
Chronic Administration ◽  
Ang Ii ◽  
Signal Transducers ◽  
Hypertrophic Growth ◽  
Brain Natriuretic Peptides ◽  
Cardiac Hormones

The cardiac hormones atrial and brain natriuretic peptides (NPs) counteract the systemic, hypertensive, and hypervolemic actions of angiotensin II (Ang II) via their guanylyl cyclase-A (GC-A) receptor. In the present study, we took advantage of genetically modified mice with conditional, cardiomyocyte (CM)-restricted disruption of GC-A (CM GC-A knockout mice) to study whether NPs can moderate not only the endocrine but also the cardiac actions of Ang II in vivo. Fluorometric measurements of [Ca2+]i transients in isolated, electrically paced adult CMs showed that atrial NP inhibits the stimulatory effects of Ang II on free cytosolic Ca2+ transients via GC-A. Remarkably, GC-A-deficient CMs exhibited greatly enhanced [Ca2+]i responses to Ang II, which was partly related to increased activation of the Na+/H+-exchanger NHE-1. Chronic administration of Ang II to control and CM GC-A knockout mice (300 ng/kg body weight per minute via osmotic minipumps during 2 wk) provoked significant cardiac hypertrophy, which was markedly exacerbated in the later genotype. This was concomitant to increased cardiac expression of NHE-1 and enhanced activation of the Ca2+/calmodulin-dependent prohypertrophic signal transducers Ca2+/calmodulin-dependent kinase II and calcineurin. On the basis of these results, we conclude that NPs exert direct local, GC-A-mediated myocardial effects to antagonize the [Ca2+]i-dependent hypertrophic growth response to Ang II.

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