scholarly journals Augmentation of endogenous intrarenal angiotensin II levels in Val5-ANG II-infused rats

2009 ◽  
Vol 296 (5) ◽  
pp. F1067-F1071 ◽  
Author(s):  
Weijian Shao ◽  
Dale M. Seth ◽  
L. Gabriel Navar
Keyword(s):  
Angiotensin Ii ◽  
De Novo ◽  
Excretion Rate ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Osmotic Minipump ◽  
Relative Contribution ◽  
Sprague Dawley Rats ◽  
Induced Hypertension ◽  
Stimulation Of

In angiotensin II (ANG II)-induced hypertension, intrarenal ANG II levels are increased by AT1 receptor-mediated ANG II internalization and endogenous ANG II generation. The objective of the present study was to determine the relative contribution of de novo formation of endogenous ANG II. Male Sprague-Dawley rats were divided into three groups: sham operated ( n = 6), Val5-ANG II infused ( n = 16), and Ile5-ANG II infused ( n = 6). Val5-ANG II and Ile5-ANG II were infused at 80 ng/min via subcutaneous osmotic minipump for 13 days, followed by harvesting of blood and kidney samples. In six Val5-ANG II-infused rats, urine was collected on the day before infusion and on day 12 of infusion. Extracted samples were subjected to HPLC to separate Val5-ANG II from Ile5-ANG II followed by RIA. Systolic blood pressure increased significantly from 121 ± 2 to 206 ± 4 mmHg in the Val5-ANG II-infused rats and from 124 ± 3 to 215 ± 5 mmHg in the Ile5-ANG II-infused rats. In the Val5-ANG II-infused rats, the plasma Ile5-ANG II levels increased 196.2 ± 70.1% compared with sham plasma Ile5-ANG II concentration. Val5-ANG II levels were 150.0 ± 28.2 fmol/ml which accounted for 53.5 ± 10.1% of the total ANG II in plasma. The kidney Ile5-ANG II levels in the Val5-ANG II-infused rats increased 69.9 ± 30.7% compared with sham kidney Ile5-ANG II concentrations. Intrarenal accumulation of Val5-ANG II accounted for 52.5 ± 5.3% of the total kidney ANG II during Val5-ANG II infusion while endogenous Ile5-ANG II accounted for 47.5 ± 8.6%. The urinary Ile5-ANG II excretion rate on day 12 increased 93.2 ± 32.1% compared with preinfusion level indicating increased formation of endogenous ANG II. Thus, the increases in intrarenal ANG II levels during chronic ANG II infusions involve substantial stimulation of endogenous ANG II formation which contributes to overall augmentation of intrarenal ANG II.

Abstract 493: Impact of Renal Vasoconstriction on the Relationship Between Blood Pressure and Renal Injury in Angiotensin II-induced Hypertensive Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Aaron J Polichnowski ◽  
Maria Picken ◽  
Jianrui Long ◽  
Geoffrey Williamson ◽  
Karen Griffin ◽  
...  
Keyword(s):  
Renal Injury ◽  
Left Kidney ◽  
Separate Experiment ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Osmotic Minipump ◽  
Renal Vasoconstriction ◽  
Sprague Dawley Rats ◽  
Induced Hypertension ◽  
The Relationship

Ang II is thought to play a prominent role in the development of hypertension-induced renal disease via BP dependent and independent pathways; however the quantitative relationships between BP and renal injury have not been rigorously examined in Ang II-induced hypertension. The major goals of the present study were to assess: 1) the relationship between BP and renal injury in rats with hypertension induced by Ang II vs. renal mass reduction (RMR) and 2) the pressure-flow relationships in conscious Ang II-infused rats. One group of male Sprague-Dawley rats (Charles River) were implanted with a BP radiotransmitter and 10 days later administered Ang II (n=12; 500 ng/kg/min via osmotic minipump) or subjected to 3/4 RMR via right uninephrectomy + infarction of ∼ 1/2 of the left kidney (RKI, n=5). BP was measured continuously and kidneys were perfused fixed at 6 weeks for the assessment of renal injury. In a separate experiment, MAP and RBF (Transonic) were measured in conscious chronically instrumented rats. After recovery from surgery (∼7 days), baseline MAP and RBF were assessed (∼4 hours @ 200 Hz) on 2 consecutive days. Subsequently, rats were administered Ang II (n=6; 500 ng/kg/min) or saline (n=7; sham) via osmotic minipump and MAP and RBF were again assessed every 2-3 days for 10 days. Despite a higher average systolic BP over 6 weeks in Ang II (174±3 mmHg) vs. RKI (165±6 mmHg) rats, glomerulosclerosis (GS) was higher (p<0.05) in RKI (15±7% out of 100 glomeruli) vs. Ang II (6±1% out of 100 glomeruli) rats. Moreover, the slope of the relationship between BP and %GS (Δ%GS/ΔmmHg) was greater in RKI vs. Ang II rats. Both MAP (98±2 vs. 99±3 mmHg) and RBF (8.1±1vs. 8.2±1 ml/min) were similar at baseline in Ang II and sham rats, respectively. MAP was elevated by day 3 (123±6 mmHg) and further increased to 157±5 mmHg by day 10 in Ang II rats. Conversely, RBF was decreased at day 3 (6.6±0.6 ml/min) and the vasoconstriction persisted over the experimental protocol as RBF further decreased to 5.6±0.7 ml/min at day 10 in Ang II rats. In conclusion, Ang II-induced hypertension is associated with a diminished susceptibility to renal injury as compared to rats with RMR likely due, in part, to the AngII-induced vasoconstriction, which reduces BP transmission to the renal microvasculature.

scholarly journals Down-regulation of Brain Gα12 attenuates Angiotensin II Dependent Hypertension

2019 ◽  
Author(s):  
Juan Gao ◽  
Ian Denys ◽  
Amir Shahien ◽  
Jane Sutphen ◽  
Daniel R Kapusta
Keyword(s):  
Angiotensin Ii ◽  
Baroreflex Sensitivity ◽  
Pressor Response ◽  
Ang Ii ◽  
Protein Signaling ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Induced Hypertension ◽  
Chronic Infusion

Abstract Background Angiotensin II (Ang II) activates central Angiotensin II type 1 receptors (AT1R) to increase blood pressure (BP) via multiple pathways. However, whether central Gα proteins contribute to Ang II induced hypertension remains unknown. We hypothesized that AT1R couple with Gα12 and/or Gαq to produce sympatho-excitation and increase BP and downregulation of these Gα subunit proteins will attenuate Ang II dependent hypertension. Methods & Results After chronic infusion of Ang II (s.c. 350 ng/kg/min) or vehicle for 2-weeks, Ang II evoked an increase in Gα12 expression, but not Gαq in the RVLM of Sprague-Dawley rats. In other studies, rats that received Ang II or vehicle infusion s.c. were simultaneously infused i.c.v. with a scrambled (SCR) or Gα12 oligodeoxynucleotide (ODN; 50 μg/day). Central Gα12 ODN infusion lowered mean BP in Ang II infused rats compared with SCR ODN infusion (14- day peak; 133 ± 12 vs 176 ± 11 mmHg). Compared to the SCR ODN group, Ang II infused rats that received i.c.v. Gα12 ODN showed a greater increase in heart rate to atropine, an attenuated reduction in BP to chlorisondamine, and an improved baroreflex sensitivity. In addition, central Gα12 and Gαq ODN pretreatment blunted the pressor response to an acute i.c.v. injection of Ang II (i.c.v., 200 ng). Conclusions These findings suggest that central Gα12 protein signaling pathways play an important role in the development of chronic AngII-dependent hypertension in rats.

Contribution of the subfornical organ to angiotensin II-induced hypertension

2005 ◽  
Vol 288 (2) ◽  
pp. H680-H685 ◽  
Author(s):  
Michael D. Hendel ◽  
John P. Collister
Keyword(s):  
Angiotensin Ii ◽  
Chronic Phase ◽  
Circumventricular Organs ◽  
Subfornical Organ ◽  
Saline Control ◽  
Sham Operation ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Induced Hypertension

Previous studies clearly demonstrated acute actions of angiotensin II (ANG II) at one of the central circumventricular organs, the subfornical organ (SFO), but studies demonstrating a role for the SFO in the chronic actions of ANG II remain uncertain. The purpose of this study was to examine the role of the SFO in the chronic hypertensive phase of ANG II-induced hypertension. We hypothesized that the SFO is necessary for the full hypertensive response observed during the chronic phase of ANG II-induced hypertension. To test this hypothesis, male Sprague-Dawley rats were subjected to sham operation (sham rats) or electrolytic lesion of the SFO (SFOx rats). After 1 wk, the rats were instrumented with venous catheters and radiotelemetric transducers for intravenous administration of ANG II and measurement of blood pressure and heart rate, respectively. Rats were then allowed 1 wk for recovery. After 3 days of saline control infusion (7 ml of 0.9% NaCl/day), sham and SFOx rats were infused with ANG II at 10 ng·kg−1·min−1 iv for 10 consecutive days and then allowed to recover for 3 days. A 0.4% NaCl diet and distilled water were provided ad libitum. At day 5 of ANG II infusion, mean arterial pressure increased 11.7 ± 3.0 mmHg in sham rats ( n = 9) but increased only 3.7 ± 1.4 mmHg in SFOx rats ( n = 9). This trend continued through day 10 of ANG II treatment. These results support the hypothesis that the SFO is necessary for the full hypertensive response to chronic ANG II administration.

Abstract 41: Fructose Stimulates Na/H Exchanger 3 Activity and Enhances the Ability of Angiotensin II to Activate Na/H Exchanger 3 in the Proximal Tubule

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pablo Cabral ◽  
Nancy Hong ◽  
Jeffrey Garvin
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Physiological Saline ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Basal Rate ◽  
Low Concentrations ◽  
Sprague Dawley Rats ◽  
High Fructose ◽  
Salt Sensitive Hypertension

Consumption of high-fructose corn syrup as a sweetener has increased dramatically. Fructose has been implicated in the epidemic of diabetes, obesity and hypertension including salt-sensitive hypertension. However, the mechanisms are poorly understood. The proximal nephron reabsorbs 60-70% of the fluid and Na, and most of the filtered bicarbonate via Na/H exchanger 3. Enhanced proximal nephron transport has been implicated in several forms of hypertension. We hypothesized that fructose stimulates NHE3 activity and enhances the ability of angiotensin II (ANG II) to activate NHE3 in the proximal tubule. To test our hypothesis we isolated and perfused proximal tubules from Sprague Dawley rats. NHE3 activity was measured as the recovery of intracellular pH after an NH4Cl acid pulse using the pH sensitive dye BCECF. The rate of pH recovery was measured in Fluorescent Units per second (FU/sec). In the presence of a 5.5 mM glucose-containing physiological saline the basal rate of pH recovery was 3.1 ± 0.8 FU/sec. When the luminal solution was exchanged to a 0.6 mM glucose + 5 mM fructose-containing physiological saline in a second period, the rate of pH recovery increased to 5 ± 1 FU/sec (p<0.03, n=8).To study whether this effect was due to the addition of fructose or the removal of glucose to the lumen, we performed a separate set of experiments where 5 mM glucose was substituted for 5 mM fructose. In the presence of 0.6 mM glucose the basal rate of pH recovery was 3.6 ± 1.5 FU/sec. When 5 mM fructose was added the rate of pH recovery increased to 5.9 ± 2 FU/sec (p<0.02, n=5). Control experiments showed no differences between periods when 5 mm glucose was added back to the luminal perfusate. Finally, we tested the effect of low concentrations of ANG II in the presence or absence of luminal fructose. In the presence of 5.5 mM glucose, ANG II 10-12 M did not affect the rate of pH recovery (change: -1.1 ± 0.5 FU/sec, n=9). However, in the presence of 5 mM fructose, ANG II increased the rate of pH recovery (change: 4.0 ± 2.2 FU/sec, p< 0.03 n=6). We conclude that acute treatment with fructose stimulates NHE3 activity and enhances the ability of ANG II to activate NHE3 in the proximal tubule. These results may partially explain the mechanism by which a fructose diet induces hypertension.

Mechanism of the biphasic arteriolar response to angiotensin II

1984 ◽  
Vol 247 (1) ◽  
pp. H88-H94 ◽  
Author(s):  
J. T. Fleming ◽  
I. G. Joshua
Keyword(s):  
Angiotensin Ii ◽  
Prostaglandin Synthesis ◽  
Krebs Solution ◽  
Ang Ii ◽  
Cremaster Muscle ◽  
Sprague Dawley ◽  
Third Order ◽  
Sprague Dawley Rats ◽  
Before And After ◽  
Alpha Chloralose

Male Sprague-Dawley rats (140-180 g) were anesthetized with alpha-chloralose and urethan. The cremaster muscle with intact blood supply and neural innervation was suspended in a tissue bath containing a modified Krebs solution. With the use of television microscopy the luminal diameters of third-order arterioles (14-32 micron) were measured before and after adding angiotensin II (ANG II, bath concn 10(-6) M). The arterioles responded to ANG II with an initial, transient constriction followed by a more prolonged dilation to a diameter larger than the control diameter. Pretreating the muscle with [Sar1, Ile8]ANG II significantly attenuated both the arteriolar constriction and subsequent dilation induced by ANG II. Treatment of the cremaster muscle with mefenamic acid or indomethacin, inhibitors of prostaglandin synthesis, produced a significant reduction in the diameter of the arterioles and abolished the dilator phase of the arteriolar response to ANG II without preventing the ANG II-induced constriction. These results demonstrate that within the intact microcirculation, ANG II produces both an arteriolar constriction and a dilation that are mediated by specific ANG II receptors. The ANG II-induced dilation of the arterioles appears to be caused by increased prostaglandin synthesis and release.

Mechanism of prostaglandin E2-induced increase of proximal sodium reabsorption in the rat

1990 ◽  
Vol 258 (1) ◽  
pp. R82-R86 ◽  
Author(s):  
Y. Kinoshita ◽  
F. G. Knox
Keyword(s):  
Angiotensin Ii ◽  
Prostaglandin E2 ◽  
Rat Kidney ◽  
Sodium Reabsorption ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Convoluted Tubules ◽  
Stimulation Of ◽  
Interstitial Infusion

Prostaglandin E2, when infused directly into the renal interstitium, enhances sodium reabsorption by the superficial proximal convoluted tubules of anesthetized Sprague-Dawley rats. The present study was designed to investigate the role of angiotensin II in the prostaglandin E2-induced stimulation of proximal sodium reabsorption. Micropuncture at the superficial late proximal tubule demonstrated a significant increase in the fractional reabsorption of sodium from 39.9 +/- 2.3% in control conditions to 51.8 +/- 3.0% (n = 9, P less than 0.01) during the renal interstitial infusion of prostaglandin E2. The stimulatory effect of prostaglandin E2 on proximal sodium reabsorption was markedly attenuated by pretreatment with saralasin. During intravenous saralasin infusion, prostaglandin E2 did not significantly change the fractional reabsorption of sodium from 42.2 +/- 5.8 to 45.4 +/- 6.0% (n = 7, NS). In summary, the stimulatory effect of renal interstitial infusion of prostaglandin E2 on proximal sodium reabsorption was attenuated by pretreatment with saralasin. Therefore renal interstitial infusion of prostaglandin E2 may enhance proximal sodium reabsorption, at least in part, through stimulation of angiotensin II production in the rat kidney.

Regulation of angiotensin II binding sites in neuronal cultures by catecholamines

1989 ◽  
Vol 257 (4) ◽  
pp. C706-C713 ◽  
Author(s):  
L. M. Myers ◽  
C. Sumners
Keyword(s):  
Angiotensin Ii ◽  
Binding Sites ◽  
Phorbol Esters ◽  
De Novo ◽  
Specific Binding ◽  
Physiological Mechanism ◽  
Neuronal Cultures ◽  
Ang Ii ◽  
Specific Binding Sites ◽  
Stimulation Of

Previous studies determined that direct activation of protein kinase C (PKC) with phorbol esters increases the number of angiotensin II (ANG II)-specific binding sites in neuronal cultures prepared from the hypothalamus and brain stem of 1-day-old rats. In the physiological situation, PKC is activated by diacylglycerol, which can be produced by multiple pathways, such as stimulation of inositol phospholipid (IP) hydrolysis, phosphatidylcholine hydrolysis, or by de novo synthesis. In the present study we have examined whether stimulation of IP hydrolysis, and presumably activation of PKC, can mimic the actions of phorbol esters on ANG II-specific binding. We have incubated neuronal cultures with agents that increase IP hydrolysis and have determined the effects on ANG II-specific binding. Incubation of neuronal cultures with norepinephrine (NE) at concentrations (greater than 5 microM) and for times (15-60 min) that cause large increases in IP hydrolysis caused increases in the number of ANG II-specific binding sites, mimicking the actions of phorbol esters. The return of IP hydrolysis to control values was associated with a return of ANG II-specific binding to control levels. The upregulatory action of NE was abolished by prazosin, demonstrating the involvement of alpha 1-adrenergic receptors. In addition, this effect was blunted by the PKC antagonist H 7, suggesting PKC involvement in the response. Thus we have determined a potential physiological mechanism by which stimulation of IP hydrolysis by NE, and possible subsequent activation of PKC, leads to upregulation of ANG II-specific binding sites in neuronal cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive effect of dietary calcium loading in angiotensin II-salt rats

1991 ◽  
Vol 261 (5) ◽  
pp. R1070-R1074 ◽  
Author(s):  
K. Ando ◽  
Y. Sato ◽  
A. Ono ◽  
K. Takahashi ◽  
T. Shimosawa ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Antihypertensive Effect ◽  
Hypotensive Effect ◽  
Plasma Catecholamine ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Calcium Loading ◽  
Sprague Dawley Rats ◽  
Salt Sensitive Hypertension ◽  
Do So

To clarify the hypotensive effect of high dietary Ca intake on salt-sensitive hypertension, 7-wk-old Sprague-Dawley rats, 3.15% Na and/or 4.07% Ca diet loaded, were administered 125 ng/ml of angiotensin II (ANG II) intraperitoneally for 12 days. Compared with control rats (mean blood pressure 108 +/- 2 mmHg), ANG II administration caused hypertension (131 +/- 4 mmHg, P less than 0.05). Na loading enhanced the hypertensive effect of ANG II (161 +/- 4 mmHg, P less than 0.01). Dietary Ca loading did not significantly inhibit the pressor effect of ANG II alone (119 +/- 4 mmHg). However, Ca loading suppressed hypertension in ANG II-salt rats (126 +/- 4 mmHg, P less than 0.01). Plasma total catecholamine (norepinephrine + epinephrine) was increased in ANG II-salt rats (176 +/- 14 vs. 290 +/- 23 pg/ml, P less than 0.05), but Ca loading decreased plasma catecholamine (182 +/- 13 pg/ml, P less than 0.05). In contrast, plasma catecholamine was not significantly different between ANG II-treated rats with and without Ca loading. Ca loading increased serum Ca in ANG II rats (10.9 +/- 0.1 vs. 11.7 +/- 0.1 mg/dl, P less than 0.05) but did not do so significantly in ANG II-salt rats (10.8 +/- 0.2 vs. 10.9 +/- 0.1 mg/dl). Thus Ca loading exclusively ameliorated salt-sensitive hypertension, which was induced with ANG II administration and Na loading in rats, probably through suppression of the increased sympathetic activity. In addition, these effects of Ca loading were not mediated through an increased blood level of Ca.

Abstract 600: Intrarenal Ghrelin Receptor Antagonism Inhibits cAMP Mediated Angiotensin II Sodium Reabsorption in Normal Rats

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Brandon A Kemp ◽  
Nancy L Howell ◽  
Shetal H Padia
Keyword(s):  
Angiotensin Ii ◽  
Collecting Duct ◽  
Sodium Reabsorption ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Ghrelin Receptor ◽  
Sprague Dawley Rats ◽  
Ghrelin Receptors ◽  
Messenger System

An interaction between angiotensin II (Ang II) and ghrelin has been established in many tissues relevant to cardiovascular control, but nothing is known about their relationship within the kidney. Intrarenal ghrelin receptors (GRs) localize to the collecting duct (CD) where they couple to an adenylyl cyclase second messenger system to increase cAMP and ENaC-dependent Na+ reabsorption. Ang II also stimulates the activity of ENaC in the CD (independent of aldosterone), via actions at AT1Rs. The following studies seek to determine whether CD GRs are an important mechanism of Ang II-induced antinatriuresis. Uninephrectomized Sprague-Dawley rats received 3 cumulative 1h renal interstitial (RI) infusions of vehicle 5% dextrose in water (D5W, N=8), Ang II (2 ng/kg/min, N=8), Ang II + D-LYS-GHRP-6, a highly selective GR antagonist (D-LYS, 2, 4, 6 μg/min, N=8) or D-LYS alone (N=8). Urine Na+ excretion rate (UNaV) was measured each hour and compared to baseline, during which only vehicle was infused. RI fluid was collected each hour for cAMP determinations. RI Ang II induced a significant antinatriuresis (UNaV was reduced by 34% at 1h, P<0.01; by 46% at 2h, P<0.001; and by 56% at 3h, P<0.001 from baseline). Ang II-induced antinatriuresis was accompanied by a significant increase in RI cAMP levels from a baseline value of 2.97±0.56 pmol/mL to 10.9±2.2, 13.4±2.2, and 15.3±2.7 pmol/mL after 1h, 2h, and 3h respectively (all P<0.01). However, each of these effects of RI Ang II infusion was abolished by concurrent GR blockade with D-LYS. These data suggest that intact intrarenal GR activity is necessary for Ang II-induced Na+ reabsorption in vivo. Furthermore, since cAMP fails to increase in response to Ang II when GRs are blocked, (and GRs are known to signal via cAMP in the kidney), these data strongly suggest that one of the mechanisms of Ang II-induced Na+ reabsorption in the kidney is via GR-induced increases in cAMP.

scholarly journals Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs

2016 ◽  
Vol 310 (8) ◽  
pp. F748-F754 ◽  
Author(s):  
Vanesa D. Ramseyer ◽  
Pablo A. Ortiz ◽  
Oscar A. Carretero ◽  
Jeffrey L. Garvin
Keyword(s):  
Nitric Oxide ◽  
Pde5 Inhibitor ◽  
Cell Types ◽  
No Production ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
No Donor ◽  
Induced Hypertension ◽  
Stimulation Of

In thick ascending limbs (THALs), nitric oxide (NO) decreases NaCl reabsorption via cGMP-mediated inhibition of Na-K-2Cl cotransporter (NKCC2). In angiotensin (ANG II)-induced hypertension, endothelin-1 (ET-1)-induced NO production by THALs is impaired. However, whether this alters NO's natriuretic effects and the mechanisms involved are unknown. In other cell types, ANG II augments phosphodiesterase 5 (PDE5)-mediated cGMP degradation. We hypothesized that NO-mediated inhibition of NKCC2 activity and stimulation of cGMP synthesis are blunted via PDE5 in ANG II-induced hypertension. Sprague-Dawley rats were infused with vehicle or ANG II (200 ng·kg−1·min−1) for 5 days. ET-1 reduced NKCC2 activity by 38 ± 13% ( P < 0.05) in THALs from vehicle-treated rats but not from ANG II-hypertensive rats (Δ: −9 ± 13%). A NO donor yielded similar results as ET-1. In contrast, dibutyryl-cGMP significantly decreased NKCC2 activity in both vehicle-treated and ANG II-hypertensive rats (control: Δ−44 ± 15% vs. ANG II: Δ−41 ± 10%). NO increased cGMP by 2.08 ± 0.36 fmol/μg protein in THALs from vehicle-treated rats but only 1.06 ± 0.25 fmol/μg protein in ANG II-hypertensive rats ( P < 0.04). Vardenafil (25 nM), a PDE5 inhibitor, restored NO's ability to inhibit NKCC2 activity in THALs from ANG II-hypertensive rats (Δ: −60 ± 9%, P < 0.003). Similarly, NO's stimulation of cGMP was also restored by vardenafil (vehicle-treated: 1.89 ± 0.71 vs. ANG II-hypertensive: 2.02 ± 0.32 fmol/μg protein). PDE5 expression did not differ between vehicle-treated and ANG II-hypertensive rats. We conclude that NO-induced inhibition of NKCC2 and increases in cGMP are blunted in ANG II-hypertensive rats due to PDE5 activation. Defects in the response of THALs to NO may enhance NaCl retention in ANG II-induced hypertension.

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