Defective nitric oxide production impairs angiotensin II-induced Na-K-ATPase regulation in spontaneously hypertensive rats

Angiotensin (ANG) II via ANG II type 1 receptors (AT1R) activates renal sodium transporters including Na-K-ATPase and regulates sodium homeostasis and blood pressure. It is reported that at a high concentration, ANG II either inhibits or fails to stimulate Na-K-ATPase. However, the mechanisms for these phenomena are not clear. Here, we identified the signaling molecules involved in regulation of renal proximal tubular Na-K-ATPase at high ANG II concentrations. Proximal tubules from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were incubated with low concentrations of ANG II (pM), which activated Na-K-ATPase in both the groups; however, the stimulation was more robust in SHR. A high concentration of ANG II (μM) failed to stimulate Na-K-ATPase in WKY rats. However, in SHR ANG II (μM) continued to stimulate Na-K-ATPase, which was sensitive to the AT1R antagonist candesartan. In the presence of NG-nitro-l-arginine methyl ester (l-NAME), a nitric oxide (NO) synthase (NOS) inhibitor, ANG II (μM) caused stimulation of Na-K-ATPase in proximal tubules of WKY rats while having no further stimulatory effect in SHR. ANG II (μM), via AT1R, increased proximal tubular NO levels in WKY rats but not in SHR. In SHR, NOS was uncoupled as incubation of proximal tubules with ANG II and l-arginine, a NOS substrate, caused superoxide generation only in SHR and not in WKY rats. The superoxide production in SHR was sensitive to l-NAME. There was exaggerated proximal tubular AT1R-G protein coupling and NAD(P)H oxidase activation in response to ANG II (μM) in proximal tubules of SHR compared with WKY rats. In SHR, inhibition of NADPH oxidase restored NOS coupling and ANG II-induced NO accumulation. In conclusion, at a high concentration ANG II (μM) activates renal NO signaling, which prevents stimulation of Na-K-ATPase in WKY rats. However, in SHR ANG II (μM) overstimulates NADPH oxidase, which impairs the NO system and leads to continued Na-K-ATPase activation.

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The effects of angiotensin-(1–7) on the exchanger NHE3 and on [Ca2+]i in the proximal tubules of spontaneously hypertensive rats

AJP Renal Physiology ◽

10.1152/ajprenal.00557.2016 ◽

2017 ◽

Vol 313 (2) ◽

pp. F450-F460 ◽

Cited By ~ 3

Author(s):

Regiane Cardoso Castelo-Branco ◽

Deise C. A. Leite-Dellova ◽

Fernanda Barrinha Fernandes ◽

Gerhard Malnic ◽

Margarida de Mello-Aires

Keyword(s):

Plasma Level ◽

Spontaneously Hypertensive Rats ◽

High Plasma ◽

Proximal Tubules ◽

Ang Ii ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Wky Rats ◽

High Plasma Level ◽

Wistar Kyoto

The acute effects of angiotensin-1–7 [ANG-(1–7)] on the reabsorptive bicarbonate flow (J[Formula: see text]) were evaluated using stationary microperfusion in vivo in the proximal tubules of spontaneously hypertensive rats (SHR) and their normotensive controls, Wistar-Kyoto (WKY) rats, using a microelectrode sensitive to H+. In WKY rats, the control J[Formula: see text] was 2.40 ± 0.10 nmol·cm−2·s−1 ( n = 120); losartan (10−7 M) or A779 (10−6 M, a specific Mas antagonist), alone or in combination with losartan, decreased the J[Formula: see text]. ANG-(1–7) had biphasic effects on J[Formula: see text]: at 10−9 M, it inhibited, and at 10−6, it stimulated the flow. S3226 [10−6 M, a specific Na+-H+ exchanger 3 (NHE3) antagonist] decreased J[Formula: see text] and changed the stimulatory effect of ANG-(1–7) to an inhibitory one but did not alter the inhibitory action of ANG-(1–7). In SHR, the control J[Formula: see text] was 2.04 ± 0.13 nmol·cm−2·s−1 ( n = 56), and A779 and/or losartan reduced the flow. ANG-(1–7) at 10−9 M increased J[Formula: see text], and ANG-(1–7) at 10−6 M reduced it. The effects of A779, losartan, and S3226 on the J[Formula: see text] were similar to those found in WKY rats, which indicated that in SHR, the ANG-(1–7) action on the NHE3 was via Mas and ANG II type 1. The cytosolic calcium in the WKY or SHR rats was ~100 nM and was increased by ANG-(1–7) at 10−9 or 10−6 M. In hypertensive animals, a high plasma level of ANG-(1–7) inhibited NHE3 in the proximal tubule, which mitigated the hypertension caused by the high plasma level of ANG II.

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Role of nitric oxide as a key mediator on cardiovascular actions of atrial natriuretic peptide in spontaneously hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00488.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. H778-H786 ◽

Cited By ~ 16

Author(s):

María A. Costa ◽

Rosana Elesgaray ◽

Carolina Caniffi ◽

Andrea Fellet ◽

Myriam Mac Laughlin ◽

...

Keyword(s):

Nitric Oxide ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Spontaneously Hypertensive Rats ◽

System Response ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Wky Rats ◽

Calmodulin Inhibitors ◽

Atrial Natriuretic

The objective was to study atrial natriuretic peptide (ANP) effects on mean arterial pressure (MAP) and cardiovascular nitric oxide (NO) system in spontaneously hypertensive rats (SHRs), investigating the receptors and signaling pathways involved. In vivo, SHRs and Wistar-Kyoto (WKY) rats were infused with saline (0.05 ml/min) or ANP (0.2 μg·kg−1·min−1) for 1 h. MAP and nitrites and nitrates excretion (NOx) were determined. NO synthase (NOS) activity and endothelial (eNOS), neuronal (nNOS) and inducible (iNOS) NOS expression were measured in the heart and aorta. In vitro, heart and aortic NOS activity induced by ANP was determined in the presence of iNOS and nNOS inhibitors, natriuretic peptide receptor (NPR)-A/B blocker, Gi protein, and calmodulin inhibitors. As a result, ANP diminished MAP and increased NOx in both groups. Cardiovascular NOS activity was higher in SHRs than in WKY rats. ANP increased NOS activity, but the activation was lower in SHRs than in WKY rats. ANP had no effect on NOS isoform expression. NOS activity induced by ANP was not modified by iNOS and nNOS inhibitors. NPR-A/B blockade blunted NOS stimulation via ANP in ventricle and aorta but not in atria. Cardiovascular NOS response to ANP was reduced by Gi protein and calmodulin inhibitors in both groups. In conclusion, in atria, ventricle, and aorta, ANP interacts with NPR-C receptors, activating Ca2+-calmodulin eNOS through Gi protein. In ventricle and aorta, NOS activation also involves NPR-A/B. The NOS response to ANP was impaired in heart and aorta of SHRs. The impaired NO-system response to ANP in hypertensive animals, involving alterations in the signaling pathway, could participate in the maintenance of high blood pressure in this model of hypertension.

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Inhibition of nitric oxide causes exaggerated natriuresis in spontaneously hypertensive rats

AJP Renal Physiology ◽

10.1152/ajprenal.1994.266.5.f762 ◽

1994 ◽

Vol 266 (5) ◽

pp. F762-F766 ◽

Cited By ~ 2

Author(s):

A. A. Khraibi

Keyword(s):

Nitric Oxide ◽

Arterial Pressure ◽

Spontaneously Hypertensive Rats ◽

Competitive Inhibition ◽

High Dose ◽

Sprague Dawley ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Wky Rats ◽

Fractional Excretion Of Sodium

Competitive inhibition of the conversion of L-arginine to nitric oxide by a high dose of NG-monomethyl-L-arginine (L-NMMA) leads to significant increases in arterial pressure, natriuresis, and diuresis in Sprague-Dawley rats. The purpose of this study was to determine the extent of the natriuretic and diuretic responses and the possible role of arterial pressure and renal interstitial hydrostatic pressure (RIHP) elevations with the infusion of L-NMMA in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Intravenous infusion of L-NMMA (15 mg/kg bolus followed by 500 micrograms.kg-1.min-1 continuous infusion) in WKY rats (n = 8) resulted in a significant increase in mean arterial pressure (MAP, 122 +/- 3 to 152 +/- 2 mmHg), RIHP (4.7 +/- 0.4 to 6.7 +/- 0.5 mmHg), fractional excretion of sodium (FENa, 0.76 +/- 0.21 to 4.74 +/- 0.70%), and urine flow rate (V, 27.7 +/- 5.0 to 161.3 +/- 19.6 microliters/min). Increases in RIHP and sodium and water excretions are abolished when renal perfusion pressure is prevented from increasing with L-NMMA infusion in a group of WKY rats (n = 6). In SHR (n = 6) administration of the same dose of L-NMMA resulted in no significant changes in MAP (172 +/- 3 to 178 +/- 2 mmHg) or RIHP (3.3 +/- 0.4 to 3.5 +/- 0.6 mmHg), but significantly higher increases in FENa (1.19 +/- 0.26 to 7.52 +/- 0.68%) and V (47.1 +/- 10.0 to 248.3 +/- 25.7 microliters/min) compared with WKY rat.(ABSTRACT TRUNCATED AT 250 WORDS)

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Exercise Training Enhances Flow-Mediated Dilation in Spontaneously Hypertensive Rats

Physiological Research ◽

10.33549/physiolres.932166 ◽

2011 ◽

pp. 589-597 ◽

Cited By ~ 15

Author(s):

F. GÜNDÜZ ◽

G. KOÇER ◽

S. ÜLKER ◽

H. J. MEISELMAN ◽

O. K. BAŞKURT ◽

...

Keyword(s):

Nitric Oxide ◽

Exercise Training ◽

Spontaneously Hypertensive Rats ◽

Flow Mediated Dilation ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Wky Rats ◽

Significant Attenuation ◽

Isolated Arteries ◽

Oxide Synthase

This study investigated the effect of exercise training on the flow-mediated dilation (FMD) in gastrocnemius muscle arteries from spontaneously hypertensive rats (SHR). SHR and WKY rats were divided into sedentary and exercised groups. After swimming exercise for eight weeks, the isolated arteries were mounted on pressurized myograph and FMD responses examined. The role of nitric oxide (NO), prostaglandins (PGs) and endothelium derived hyperpolarizing factor (EDHF) on FMD were assessed by obtaining dilation responses in the presence and absence of pharmacological antagonists. Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin (INDO) and tetraethylamonium (TEA) were used to inhibit nitric oxide synthase, cyclooxygenase and EDHF-mediated responses, respectively. The FMD response was significantly blunted in arteries of SHR compared with WKY rats, and, improved by exercise training in SHR (SHR-ET) group. In SHR arteries, L NAME and TEA did not affect dilation responses to flow, while INDO led to a significant enhancement in this response. Although dilation response was not altered by L-NAME in arteries obtained from trained SHR, TEA caused a significant attenuation and INDO led to significant increases. These results demonstrate that exercise training improves FMD in SHR, and, this enhancement induced by exercise training occurs through EDHF-mediated mechanism(s).

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Ventrolateral medulla in spontaneously hypertensive rats: role of angiotensin II

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.264.2.r388 ◽

1993 ◽

Vol 264 (2) ◽

pp. R388-R395 ◽

Cited By ~ 23

Author(s):

H. Muratani ◽

C. M. Ferrario ◽

D. B. Averill

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Spontaneously Hypertensive Rats ◽

Pressor Response ◽

Ventrolateral Medulla ◽

Ang Ii ◽

Gamma Aminobutyric Acid ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Wky Rats

We investigated whether angiotensin II (ANG II), endogenous to the ventrolateral medulla (VLM), contributes to cardiovascular regulation in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The action of ANG II endogenous to the VLM was examined by microinjection of 100 pmol of [Sar1,Thr8]ANG II into either the rostral (R) or caudal (C) VLM. This ANG II antagonist caused depressor and bradycardic responses in the RVLM and pressor and tachycardic responses in the CVLM. The magnitude of the blood pressure responses was significantly greater (P < 0.01 in RVLM and P < 0.05 in CVLM) in SHRs (-27 +/- 3 mmHg in RVLM and 29 +/- 4 mmHg in CVLM) than in WKY rats (-17 +/- 1 and 17 +/- 2 mmHg, respectively). Suppression of tonic activity of RVLM neurons by bilateral injection of muscimol in the RVLM showed that the pressor response produced by ANG II antagonist injection in the CVLM required the integrity of rostral pressor neurons. The present data suggest that ANG II endogenous to RVLM and CVLM acts as a tonic excitatory agent on vasomotor neurons of the VLM. The contribution of ANG II in the RVLM and CVLM to the prevailing level of blood pressure was significantly (P < 0.01) larger in SHRs vs. WKY rats when the effect of ANG II blockade was measured as the change in blood pressure. Blockade of gamma-aminobutyric acid (GABA)A receptors in the RVLM showed that inhibitory GABAergic input to the RVLM was not diminished in this strain.(ABSTRACT TRUNCATED AT 250 WORDS)

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Renal dopamine DA1 receptor coupling with G(S) and G(q/11) proteins in spontaneously hypertensive rats

AJP Renal Physiology ◽

10.1152/ajprenal.1997.272.3.f339 ◽

1997 ◽

Vol 272 (3) ◽

pp. F339-F346 ◽

Cited By ~ 25

Author(s):

T. Hussain ◽

M. F. Lokhandwala

Keyword(s):

G Protein ◽

Spontaneously Hypertensive Rats ◽

Sch 23390 ◽

Hypertensive Rats ◽

G Protein Coupling ◽

Spontaneously Hypertensive ◽

Protein Coupling ◽

Basolateral Membranes ◽

Wky Rats ◽

Stimulation Of

The dopamine DA1 receptor transduces its signal via adenylyl cyclase and phospholipase C in the renal proximal tubule, which has been suggested to be defective at the level of receptor-G protein coupling in spontaneously hypertensive rats (SHR). We prepared basolateral membranes from Wistar-Kyoto (WKY) rats and SHR to determine the coupling of DA1 receptor with G proteins, especially G(q/11). Fenoldopam, a DA1-receptor agonist, produced a time- and concentration-dependent stimulation in 35S-labeled guanosine 5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding in WKY rats. Fenoldopam-induced (10 microM) stimulation was significantly inhibited by a DA1-receptor antagonist, Sch-23390. Specific antibodies against COOH terminals of G(S)alpha and G(q/11)alpha produced 50-60% and 40-50% inhibition, respectively, in fenoldopam stimulation of [35S]GTPgammaS binding. Western analysis of basolateral membranes with these antibodies revealed the presence of G(S)alpha (45 kDa) and G(q/11)alpha (42 kDa). Fenoldopam stimulation of [35S]GTPgammaS binding was significantly attenuated in SHR compared with WKY rats. Parathyroid hormone stimulation of [35S]GTPgammaS binding was similar in SHR and WKY rats, whereas stimulation by phenylephrine was significantly reduced in SHR. Densitometric quantification of 42-kDa band showed a reduced amount in SHR, whereas the density of 45-kDa band was not significantly different compared with WKY rats. We provide the direct evidence showing the coupling of DA1 receptor with G(q/11)alpha and G(S)alpha and propose that, in addition to a defect in the receptor-G protein coupling, a reduced amount of G(q/11)alpha observed in the hypertensive animals may also contribute to the diminished dopamine-induced inhibition of Na+-K+-adenosinetriphosphatase in SHR.

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Angiotensin stimulates respiration in spontaneously hypertensive rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.5.r1125 ◽

2000 ◽

Vol 278 (5) ◽

pp. R1125-R1133 ◽

Cited By ~ 10

Author(s):

Donald B. Jennings ◽

Heather J. Lockett

Keyword(s):

Spontaneously Hypertensive Rats ◽

Circumventricular Organs ◽

Ang Ii ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Average Decrease ◽

Wky Rats ◽

Receptor Block ◽

Wistar Kyoto ◽

Peripheral Arterial

Spontaneously hypertensive rats (SHR) have an activated brain angiotensin system. We hypothesized 1) that ventilation (V˙) would be greater in conscious SHR than in control Wistar-Kyoto (WKY) rats and 2) that intravenous infusion of the ANG II-receptor blocker saralasin would depress respiration in SHR, but not in WKY. Respiration and oxygen consumption (V˙o 2) were measured in conscious aged-matched groups ( n = 16) of adult female SHR and WKY. For protocol 1, rats were habituated to a plethysmograph and measurements obtained over 60–75 min. After installation of chronic intravenous catheters, protocol 2consisted of 30 min of saline infusion (∼14 μl ⋅ kg− 1 ⋅ min− 1) followed by 40 min of saralasin (1.3 μg ⋅ kg− 1 ⋅ min− 1).V˙, tidal volume (VT), inspiratory flow [VT/inspiratory time (Ti)], breath expiratory time, and V˙o 2 were higher, and breath Ti was lower in “continuously quiet” SHR. In SHR, but not in WKY rats, ANG II-receptor block decreasedV˙, VT, and VT/Ti and increased breath Ti. During ANG II-receptor block, an average decrease in V˙o 2 in SHR was not significant. About one-half of the higherV˙ in SHR appears to be accounted for by an ANG II mechanism acting either via peripheral arterial receptors or circumventricular organs.

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