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 Intrarenal ghrelin receptor inhibition ameliorates angiotensin II-dependent hypertension in rats

2018 ◽  
Vol 315 (4) ◽  
pp. F1058-F1066 ◽  
Author(s):  
Brandon A. Kemp ◽  
Nancy L. Howell ◽  
Shetal H. Padia
Keyword(s):  
Angiotensin Ii ◽  
Collecting Duct ◽  
Sodium Balance ◽  
Sodium Reabsorption ◽  
Sodium Retention ◽  
Sprague Dawley ◽  
Systemic Delivery ◽  
Ghrelin Receptor ◽  
Receptor Inhibition ◽  
Sprague Dawley Rats

The intrarenal ghrelin receptor (GR) is localized to collecting duct (CD) cells, where it increases epithelial Na+ channel (αENaC)-dependent sodium reabsorption in rodents. We hypothesized that chronic GR inhibition with intrarenal GR siRNA lowers blood pressure (BP) in angiotensin II-dependent hypertension via reductions in αENaC-dependent sodium reabsorption. Uninephrectomized Sprague-Dawley rats ( n = 121) received subcutaneous osmotic pumps for chronic systemic delivery of angiotensin II or vehicle (5% dextrose in water). Rats also received intrarenal infusion of vehicle, GR siRNA, or scrambled (SCR) siRNA. In rats receiving intrarenal vehicle or intrarenal SCR siRNA, systemic angiotensin II infusion increased sodium retention and BP on day 1, and BP remained elevated throughout the 5-day study. These rats also demonstrated increased CD GR expression after 5 days of infusion. However, intrarenal GR siRNA infusion prevented angiotensin II-mediated sodium retention on day 1, induced a continuously negative cumulative sodium balance compared with angiotensin II alone, and reduced BP chronically. Glomerular filtration rate and renal blood flow remained unchanged in GR siRNA-infused rats. Systemic angiotensin II infusion also increased serum aldosterone levels, CD αENaC, and phosphorylated serum and glucocorticoid-inducible kinase 1 expression in rats with intrarenal SCR siRNA; however, these effects were not observed in the presence of intrarenal GR siRNA, despite exposure to the same systemic angiotensin II. These data demonstrate that chronic inhibition of intrarenal GR activity significantly reduces αENaC-dependent sodium retention, resulting in a negative cumulative sodium balance, thereby ameliorating angiotensin II–induced hypertension in rats. Renal GRs represent a novel therapeutic target for the treatment of hypertension and other sodium-retaining states.

Increased AQP2 targeting in primary cultured IMCD cells in response to angiotensin II through AT1 receptor

2007 ◽  
Vol 292 (1) ◽  
pp. F340-F350 ◽  
Author(s):  
Yu-Jung Lee ◽  
In-Kyung Song ◽  
Kyung-Jin Jang ◽  
Jakob Nielsen ◽  
Jørgen Frøkiær ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Angiotensin Ii ◽  
Collecting Duct ◽  
Receptor Activation ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Water Reabsorption ◽  
Sprague Dawley Rats ◽  
Medullary Collecting Duct ◽  
Camp Levels

Vasopressin and angiotensin II (ANG II) play a major role in renal water and Na+ reabsorption. We previously demonstrated that ANG II AT1 receptor blockade decreases dDAVP-induced water reabsorption and AQP2 levels in rats, suggesting cross talk between these two peptide hormones ( Am J Physiol Renal Physiol 288: F673–F684, 2005). To directly address this issue, primary cultured inner medullary collecting duct (IMCD) cells from male Sprague-Dawley rats were treated for 15 min with 1) vehicle, 2) ANG II, 3) ANG II + the AT1 receptor blocker candesartan, 4) dDAVP, 5) ANG II + dDAVP, or 6) ANG II + dDAVP + candesartan. Immunofluorescence microscopy revealed that 10−8 M ANG II or 10−11 M dDAVP ( protocol 1) was associated with increased AQP2 labeling of the plasma membrane and decreased cytoplasmic labeling, respectively. cAMP levels increased significantly in response to 10−8 M ANG II and were potentiated by cotreatment with 10−11 M dDAVP. Consistent with this finding, immunoblotting revealed that this cotreatment significantly increased expression of phosphorylated AQP2. ANG II-induced AQP2 targeting was blocked by 10−5 M candesartan. In protocol 2, treatment with a lower concentration of dDAVP (10−12 M) or ANG II (10−9 M) did not change subcellular AQP2 distribution, whereas 10−12 M dDAVP + 10−9 M ANG II enhanced AQP2 targeting. This effect was inhibited by cotreatment with 10−5 M candesartan. ANG II-induced cAMP accumulation and AQP2 targeting were inhibited by inhibition of PKC activity. In conclusion, ANG II plays a role in the regulation of AQP2 targeting to the plasma membrane in IMCD cells through AT1 receptor activation and potentiates the effect of dDAVP on AQP2 plasma membrane targeting.

Abstract 344: Intrarenal Ghrelin Receptors Mediate Sodium Reabsorption via an ENaC-Dependent Pathway

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Brandon A Kemp ◽  
Nancy L Howell ◽  
John J Gildea ◽  
Susanna R Keller ◽  
Shetal H Padia
Keyword(s):  
Collecting Duct ◽  
Sodium Reabsorption ◽  
Na Channel ◽  
Cortical Collecting Duct ◽  
Distal Nephron ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Nephron Segment ◽  
Ghrelin Receptors ◽  
Excretion Rates

Intrarenal ghrelin infusion stimulates distal nephron-dependent sodium (Na+) reabsorption in normal rats, but the mechanism is unknown. The main Na+ transporters of the distal nephron segment are the Na+-Cl- co-transporter (NCC) and the epithelial Na+ channel (ENaC). To determine which of these transporters is involved in the antinatriuretic actions of intrarenal ghrelin receptors, uninephrectomized Sprague-Dawley rats received 3 cumulative 1h renal interstitial (RI) infusions of ghrelin (0.3-3 μg/min, N=8) or vehicle (5% dextrose in water, D5W, N=8), prior to harvesting the infused kidney for determination of NCC and ENaC protein expression. Ghrelin-infused rats demonstrated significantly reduced Na+ excretion rates (UNaV) compared to D5W-infused rats (66.7±7.1% of baseline, P<0.01) and significantly increased cortical collecting duct ENaC expression (2.46±0.17 and 1.56±0.19 densitometric units respectively, P<0.01). Renal NCC expression did not change in response to either ghrelin or D5W infusion (4.21±0.58 and 4.13±0.44 densitometric units respectively, P=NS). To test whether the ghrelin-induced increase in collecting duct ENaC expression was responsible for the antinatriuretic actions of ghrelin, we infused ghrelin into the kidney in the presence of amiloride, a selective inhibitor of ENaC activity. Following uninephrectomy, rats were implanted with either a subcutaneous osmotic minipump which systemically delivered amiloride (1.4 ng/min) for 72h to block ENaC activity (N=6), or a minipump that was filled with D5W (N=6). On the day of the study, RI ghrelin (0.3-3 μg/min) or D5W infusion was initiated. RI ghrelin infusion (in the absence of amiloride) significantly reduced UNaV to 58.9±7.2% of baseline, P<0.01; however, in the presence of amiloride, RI ghrelin failed to reduce UNaV, demonstrating values identical to rats that did not receive RI ghrelin. In contrast, studies carried out in the presence of chlorothiazide pumps (to block NCC activity, 1.1 μg/min, N=6), continued to demonstrate ghrelin-induced antinatriuresis (UNaV decreased to 65.3±8.8% of baseline, P<0.01). Mean arterial pressures did not change during any of the acute RI infusions. Thus, intact ENaC function is necessary for ghrelin-induced Na+ reabsorption.

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.

Abstract P301: Renal Expression of Collectrin (TMEM27) is Downregulated During Angiotensin II-induced Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sylvia Cechova ◽  
Pei-Lun Chu ◽  
Joseph Gigliotti ◽  
Thu H Le
Keyword(s):  
Angiotensin Ii ◽  
Catalytic Domain ◽  
Collecting Duct ◽  
Amino Acid Transporters ◽  
Ang Ii ◽  
Salt Loading ◽  
Transmembrane Glycoprotein ◽  
First Time ◽  
Renal Expression

Collectrin ( Tmem27 ) is transmembrane glycoprotein with homology to ACE-2, but lacks any catalytic domain. It plays a key role as a chaperone of amino acid transporters, and is abundantly expressed in the kidney in the proximal tubules and collecting duct. Deletion of collectrin in the mouse results in hypertension (HTN) at baseline and augmented salt-sensitivity that are associated with decreased renal nitric oxide and increased superoxide levels. During high salt diet, renal expression of collectrin is upregulated, suggesting an adaptive homeostatic response to salt loading. Here, we queried whether the expression of collectrin is regulated by angiotensin II (Ang II). Wild-type 129S6 mice were made hypertensive with Ang II osmotic minipump @ 600 ng/kg/min x 2 weeks, and were compared to age-matched untreated WT 129 mice. Shown in Fig. 1 , renal mRNA expression of collectrin is significantly reduced after 2 weeks of Ang II (Panel A). Immunostaining shows collectrin protein level is also significantly diminished to near undetectable level (Panel B). We show for the first time that Ang II regulates the expression of collectrin, suggesting that the action of Ang II on blood pressure may be mediated, in part, through the downregulation of collectrin. Further studies are needed to determine the effect of AT 1 and AT 2 receptor signaling on renal expression of collectrin during Ang II-HTN in vivo.

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.

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.

Effect of angiotensin II and norepinephrine on isolated rat afferent and efferent arterioles

1990 ◽  
Vol 258 (3) ◽  
pp. F741-F750 ◽  
Author(s):  
B. H. Yuan ◽  
J. B. Robinette ◽  
J. D. Conger
Keyword(s):  
Angiotensin Ii ◽  
Dose Response ◽  
Rat Kidney ◽  
Differential Sensitivity ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Response Curves ◽  
Dose Response Curves ◽  
Isolated Rat

Differential sensitivity of the pre- and postglomerular arterial vessels to vasoconstrictor activity of angiotensin II (ANG II) and norepinephrine (NE) is controversial. To avoid the complex extravascular neurohumoral variables that may have accounted for different results in the intact rat kidney, an isolated arteriole technique was used to examine the dose responses of ANG II and NE on afferent (AA) and efferent arterioles (EA) from Sprague-Dawley rats. EA were more sensitive than AA to ANG II (EC50 = 3.2 +/- 1.8 x 10(-11) and 1.0 +/- 1.6 x 10(-9) M, respectively, P less than 0.001), whereas EC50 of both AA and EA to NE were similar (3.4 +/- 2.3 x 10(-8) and 1.4 +/- 2.6 x 10(-8) M, respectively). The dose-response curves of AA to ANG II were not different when perfused at different luminal pressures (90 and 30 mmHg). In contrast, EA were more sensitive to ANG II at 30 than at 90 mmHg (3.0 +/- 1.2 x 10(-11) and 5.0 +/- 1.8 x 10(-10) M, respectively, P less than 0.005). The EC50 of EA to NE was unaffected by similar changes in luminal pressures. The mean dose-response curves of AA to ANG II were the same with and without the addition of 10(-5) M indomethacin; however, in arterioles displaying a focal constriction pattern to ANG II the response became uniform. It is concluded that, in the isolated rat glomerular arterioles, EA are more sensitive to ANG II than AA, but both vessels respond similarly to NE. The decreased ANG II sensitivity in AA is not related to the higher in vivo pressure, and the attenuated response in AA does not appear to be mediated primarily through ANG II-stimulated vasodilator prostanoid activity. EA sensitivity to ANG II appears to be inversely related to lumen pressure.

Circulating angiotensin II and drinking behavior in rats

1990 ◽  
Vol 259 (3) ◽  
pp. R531-R538 ◽  
Author(s):  
C. M. Pawloski ◽  
G. D. Fink
Keyword(s):  
Angiotensin Ii ◽  
Water Intake ◽  
Dose Range ◽  
Drinking Behavior ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Physiological Conditions ◽  
Water Drinking ◽  
Sprague Dawley Rats ◽  
Before And After

This study was designed to investigate the effects on water drinking of acute and chronic increases in circulating angiotensin II (ANG II) concentrations in rats. Experiments were conducted in male Sprague-Dawley rats chronically instrumented with femoral arterial and venous catheters and permanently housed in metal metabolism cages. ANG II was infused intravenously either acutely (30 min-2 h) or chronically (3 days) in a dose range of 10-60 ng/min. In no instance did such infusions cause a statistically significant increase in water intake. Other experiments examined the influence of ANG II (10 ng/min iv) on drinking elicited by infusion of hypertonic sodium chloride (1.5 M at 3.5 microliters/min). ANG II administration did not increase drinking to a hypertonic saline stimulus or lower the osmotic threshold for drinking. Nitroprusside (12 micrograms/min) was infused for 30 min to produce hypotension and drinking. Water intake associated with this stimulus was not changed by blocking ANG II formation with enalapril (2 mg/kg iv) or by concomitant infusion of ANG II (10 ng/min iv). Finally, plasma ANG II concentrations were measured before and after 1-h intravenous infusion of saline or ANG II to determine the levels of circulating ANG II produced by the infusion rates used here. It is concluded that the range of circulating ANG II concentrations found under most physiological conditions in rats does not directly stimulate drinking or participate importantly in osmotic or hypotension-induced drinking.

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