Renal renin-angiotensin system.
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Angiotensin II↗
Biomedical subjects
L Gabriel Navar
Publications and source records attributed to L Gabriel Navar.
The legacy of Homer W. Smith: mechanistic insights into renal physiology.
In 1945, Homer W. Smith published an article in the JCI that clearly demonstrated that para-aminohippuric acid is the most suitable agent for the evaluation of renal plasma flow in both humans and dogs; in addition, the paper provided detailed methodology that is still in use today. This paper is but one of many outstanding works performed by Smith and his colleagues that clearly established the clearance technique as a powerful noninvasive approach to gain mechanistic insights into intrarenal function.
Animals↗
T-type calcium channels in the regulation of afferent and efferent arterioles in rats.
L-type Ca2+ channels predominantly influence preglomerular arterioles, but there is less information regarding the role of T-type Ca2+ channels in regulating the renal microvasculature. We compared the effects of T- and L-type channel blockade on afferent and efferent arterioles using the in vitro blood-perfused juxtamedullary nephron preparation. Single afferent or efferent arterioles of Sprague-Dawley rats were visualized and superfused with solutions containing Ca2+ channel blockers. We confirmed that L-type channel blockade with diltiazem dilates afferent arterioles but has no significant effects on efferent arterioles. In contrast, T-type channel blockade with pimozide (10 micromol/l) or mibefradil (1 micromol/l) dilated both afferent (26.8 +/- 3.4 and 24.6 +/- 1.9%) and efferent (19.2 +/- 2.9 and 19.1 +/- 4.8%) arterioles. Adding diltiazem did not significantly augment the dilation of afferent arterioles elicited by pimozide and mibefradil, and adding pimozide after diltiazem likewise did not elicit further vasodilation. Diltiazem blocked the depolarization-induced afferent arteriolar constriction elicited by 55 mM KCl; however, the constrictor response to KCl remained intact during treatment with 10 microM pimozide. Pimozide also prevented the afferent arterioles from exhibiting autoregulatory-mediated constrictor responses to increases in perfusion pressure. We conclude that T-type channel blockers dilate efferent arterioles as well as afferent arterioles and diminish afferent arteriolar autoregulatory responses to changes in perfusion pressure. To the extent that these agents exert their effects primarily on T-type Ca2+ channels in our experimental setting, these results indicate that T-type channels are functionally expressed in juxtamedullary afferent and efferent arterioles and may act cooperatively with L-type channels to regulate afferent arteriolar resistance. Because L-type channels are not functionally expressed in efferent arterioles, T-type channels may be particularly significant in the regulation of efferent arteriolar function.
Animals↗
Natriuretic peptide receptor A mediates renal sodium excretory responses to blood volume expansion.
The deficiency of Npr1 [genetic determinant of natriuretic peptide receptor A (NPRA)] increases arterial pressures and causes hypertensive heart disease in mice similar to those seen in untreated human hypertensive patients. However, the quantitative role of NPRA in mediating the renal responses to blood volume expansion remains uncertain. To determine the specific contribution of NPRA in mediating the signaling mechanisms responsible for natriuretic and diuretic responses to nondilutional intravascular expansion, we administered whole blood to anesthetized Npr1 homozygous null mutant (0-copy), wild-type (2-copy), and gene-duplicated (4-copy) mice. In wild-type (2-copy) animals, urinary flow (microl x min-1 x g kidney wt-1) increased from 4.9 +/- 1.0 to 14.4 +/- 1.8 and sodium excretion (microeq x min-1 x g kidney wt-1) from 1.15 +/- 0.22 to 3.11 +/- 0.60, associated with a rise in glomerular filtration rate (GFR; ml x min-1 x g kidney wt-1) from 0.63 +/- 0.03 to 0.82 +/- 0.09 and renal plasma flow (RPF; ml x min-1. g kidney wt-1) from 2.96 +/- 0.17 to 4.36 +/- 0.41, whereas arterial pressure did not significantly increase. After volume expansion, 0-copy mice showed significantly lesser increases in urinary flow (P < 0.001) and sodium excretory (P < 0.001) responses even though the increases in arterial pressures were greater (P < 0.001) compared with 2-copy mice. The 4-copy mice showed augmented responses in urinary flow (P < 0.01) and sodium excretion (P < 0.001) along with rises in both GFR (P < 0.01) and RPF (P < 0.01) compared with 2-copy wild-type mice. These results establish that NPRA activation is the predominant mechanism mediating the natriuretic, diuretic, and renal hemodynamic responses to acute blood volume expansion.
Animals↗
Human proximal tubular cell responses to angiotensin II analyzed using DNA microarray.
Angiotensin II has been shown to exert complex effects on proximal tubular cell function and growth. To assess some of the direct effects on proximal tubular cells, changes in gene expression of selected cellular pathways were determined after exposure to angiotensin II. We used DNA microarrays to analyze multiple gene expression responses to increasing angiotensin II concentrations. Human proximal tubular cells were grown in flasks, and the presence of angiotensin type 1 receptor was confirmed by Western blot analysis. At passages 4-6, these cells were exposed to angiotensin II and harvested 4 h later and mRNA of the cells was extracted; 2 microg of mRNA was fluorescently conjugated for cDNA microarray hybridization. A custom-made DNA microarray was designed by selecting 300 human genes from 10 different functional systems and amplifying clones using polymerase chain reaction. Cells were subjected to 10 and 100 nM angiotensin II with paired untreated cells as controls. RNA was isolated, reverse transcribed, labeled and hybridized to the arrays and the ratios calculated. Ratios of > or =2.0 and < or =0.5 were considered significant. Coordinated changes were observed in genes of the hepatocyte nuclear factor 3 family (NHF3; HNF3A, HNF3B and HNF3G), in the E2F genes (E2F1, E2F3) and the interferon regulatory factors IRF1 and IRF5. Induction of the expression of transcription factors points towards complex regulation of gene expression upon angiotensin II exposure. Three genes involved in the dampening of oxidative stress were enhanced. Taken together, brief exposure of human tubular epithelial cells to angiotensin II elicited a marked induction of nuclear factors, antioxidant genes and hormones and hormone receptor genes. The quick activation of transcription factors by angiotensin II indicates that angiotensin II can directly initiate a cascade of expressional events in proximal tubular cells.
Angiotensin II↗
Enhancement of intrarenal angiotensinogen in Dahl salt-sensitive rats on high salt diet.
This study was performed to examine whether there is an inappropriate regulation of intrarenal angiotensinogen in Dahl-salt sensitive rats (DS) fed a high salt diet (HS). Dahl salt-resistant rats (DR) and DS were maintained on HS (8% NaCl) or low salt diet (LS, 0.3% NaCl) for 4 weeks. Systolic blood pressure (SBP), measured by tail-cuff plethysmography, was unaltered in DR (DR+HS, 127+/-3 mm Hg, n=5; DR+LS, 126+/-3, n=5); however, SBP was significantly increased in DS+HS (208+/-7, n=9) compared with DS+LS (134+/-2, n=5). HS suppressed plasma renin activity in both strains (0.7+/-0.2 ng of angiotensin I/mL per hour in DS+HS, 3.1+/-0.5 in DS+LS, 0.8+/-0.2 in DR+HS, 5.1+/-0.7 in DR+LS). Plasma angiotensinogen levels, measured by Western blot analysis, were also suppressed by HS in both strains (36 919+/-2170 integrated densitometric unit in DS+HS, 53 028+/-2752 in DS+LS, 44 722+/-1721 in DR+HS, 55782+/-3785 in DR+LS). However, kidney angiotensinogen levels were significantly increased in DS+HS (75 850+/-4171, integrated densitometric unit) compared with DS+LS (47 232+/-3470), DR+HS (44 748+/-8236), and DR+LS (42 504+/-4052). Urinary excretion of angiotensinogen, measured by radioimmunoassay of angiotensin I after incubation with excess renin, had a similar profile. Urinary excretion of angiotensinogen was significantly increased in DS+HS (2958+/-531 pmol/d) compared with DS+LS (56+/-4), DR+HS (31+/-12), and DR+LS (21+/-7). These data indicate that intrarenal angiotensinogen is enhanced in DS+HS, which is reflected by the increased urinary excretion of angiotensinogen. The results suggest that DS on HS have an inappropriate augmentation of intrarenal angiotensinogen, which may contribute to impaired sodium excretion during a high salt diet and the development of hypertension in this strain.
Angiotensinogen↗
Intrarenal angiotensin II and hypertension.
Elevations in intrarenal angiotensin II (Ang II) cause reductions in renal function and sodium excretion that contribute to progressive hypertension and lead to renal and vascular injury. Augmentation of intrarenal Ang II occurs by several processes, leading to levels much greater than can be explained from the circulating levels. In Ang II-dependent hypertension, Ang II is internalized via an AT1 receptor mechanism, but there is also sustained intrarenal production of Ang II. Ang II exerts a positive feedback action on intrarenal angiotensinogen (AGT) mRNA and protein. The increased intrarenal AGT production is associated with increased intrarenal and intracellular Ang II contents and urinary AGT excretion rates. The increased urinary AGT indicates spillover of AGT into distal nephron segments supporting enhanced distal Ang II formation and sodium reabsorption. The augmentation of intrarenal Ang II provides the basis for sustained actions on renal function, sodium excretion, and maintenance of hypertension.
Angiotensin II↗
Proximal tubular fluid angiotensin II levels in angiotensin II-induced hypertensive rats.
BACKGROUND: It has been shown that infusions of low-dose angiotensin II (Ang II) for 2 weeks lead to impaired pressure natriuresis and autoregulatory capability. Although intrarenal renin content and renin mRNA levels are markedly reduced, whole-kidney Ang II content has been shown to be increased. However, the intrarenal distribution of the increased intrarenal Ang II has not been established. OBJECTIVE: To determine the concentrations of Ang II in the proximal tubule fluid achieved in hypertensive rats (n = 16) infused with Ang II, previously prepared by infusion with Ang II at 60 ng/min via osmotic minipump for 13 days. METHODS: Rats were anesthetized with pentobarbital sodium and prepared for micropuncture, and then several free-flow proximal tubular fluid collections were obtained and pooled for each rat. At the end of each experiment, a blood sample was collected and the micropunctured kidney was excised and homogenized in chilled methanol. All samples were extracted immediately after collection and stored at 20 degrees C until the day of Ang II radioimmunoassay. RESULTS: Mean arterial blood pressure averaged 179 +/- 3 mmHg, renal plasma flow was 1.89 +/- 0.15 ml/min per g, and glomerular filtration rate averaged 0.58 +/- 0.04 ml/min per g. The Ang II concentration in proximal tubular fluid averaged 4.5 +/- 1.1 pmol/ml, a value substantially greater than the Ang II concentrations in plasma (0.17 +/- 0.03 pmol/ml), urine (0.06 +/- 0.01 pmol/ml), or total kidney tissue (0.40 +/- 0.10 pmol/g). Plasma renin activity (1.0 +/- 0.21 ng Ang I/ml per h) was markedly suppressed, as observed previously. CONCLUSIONS These findings indicate that Ang II concentrations in proximal tubular fluid collected from kidneys of anesthetized hypertensive rats infused with Ang II are in the nanomolar range, similar to those observed in normotensive rats. The inappropriate maintenance of nanomolar concentrations of Ang II in proximal tubular fluid of Ang II-infused hypertensive rats, even at markedly increased arterial pressures, may contribute to the impaired pressure natriuresis capability previously reported and, thereby, to the development and maintenance of hypertension in this model.
Angiotensin II↗
Angiotensin II type 1 receptor-mediated augmentation of renal interstitial fluid angiotensin II in angiotensin II-induced hypertension.
BACKGROUND: Angiotensin II (Ang II)-dependent hypertension is associated with augmented intrarenal concentrations of Ang II; however, the distribution of the increased intrarenal Ang II has not been fully established. OBJECTIVE: To determine the changes in renal interstitial fluid Ang II concentrations in Ang II-induced hypertension and the consequences of treatment with an angiotensin II type 1 (AT1) receptor blocker. DESIGN AND METHODS: Rats were selected to receive vehicle (5% acetic acid subcutaneously; n = 6), Ang II (80 ng/min subcutaneously, via osmotic minipump; n = 7) or Ang II plus an AT1 receptor antagonist, candesartan cilexetil (10 mg/kg per day, in drinking water; n = 6) for 13-14 days, at which time, experiments were performed on anesthetized rats. Microdialysis probes were implanted in the renal cortex and were perfused at 2 microl/min. The effluent dialysate concentrations of Ang I and Ang II were measured by radioimmunoassay and reported values were corrected for the equilibrium rates at this perfusion rate. RESULTS: Ang II-infused rats developed greater mean arterial pressures (155 +/- 7 mmHg) than vehicle-infused rats (108 +/- 3 mmHg). Ang II-infused rats showed greater plasma (181 +/- 30 fmol/ml) and kidney (330 +/- 38 fmol/g) Ang II concentrations than vehicle-infused rats (98 +/- 14 fmol/ml and 157 +/- 22 fmol/g, respectively). Renal interstitial fluid Ang II concentrations were much greater than plasma concentrations, averaging 5.74 +/- 0.26 pmol/ml in Ang II-infused rats - significantly greater than those in vehicle-infused rats (2.86 +/- 0.23 pmol/ml). Candesartan treatment prevented the hypertension (87 +/- 3 mmHg) and led to increased plasma Ang II concentrations (441 +/- 27 fmol/ml), but prevented increases in kidney (120 +/- 15 fmol/g) and renal interstitial fluid (2.15 +/- 0.12 pmol/ml) Ang II concentrations. CONCLUSIONS: These data indicate that Ang II-infused rats develop increased renal interstitial fluid concentrations of Ang II, which may contribute to the increased vascular resistance and reduced sodium excretion. Furthermore, the augmentation of renal interstitial fluid Ang II is the result of an AT1 receptor-mediated process and can be dissociated from the plasma concentrations.
Angiotensin I↗
Urinary angiotensinogen as an indicator of intrarenal Angiotensin status in hypertension.
Angiotensin II (AngII) infusions augment renal angiotensinogen mRNA and protein and urinary angiotensinogen excretion (U(AGT)). Further experiments were performed in 4 groups of rats: normal salt diet with sham operation, NS+Sham, n=6; NS with AngII infusion at 40 ng/min via osmotic minipump, NS+AngII(40), n=9; NS with AngII infusion at 80 ng/min, NS+AngII(80), n=9; high-salt diet with deoxycorticosterone acetate salt pellet (100 mg), HS+DOCA, n=4. These experiments sought to determine whether enhanced U(AGT) is specifically associated with increased kidney AngII levels or is a nonspecific consequence of the hypertension. Systolic BP (SBP) was significantly increased to 131+/-2 and 162+/-2 mm Hg at day 11 in NS+AngII(40) and NS+AngII(80), respectively, compared with NS+Sham (110+/-1). Regression analysis demonstrated a positive relationship (R=0.49) between SBP and U(AGT) for NS+Sham (1.1+/-0.3 nmol AngI/d), NS+AngII(40) (2.5+/-0.9), and NS+AngII(80) (5.5+/-1.5). U(AGT) was also highly correlated (R=0.70) with kidney AngII content for NS+Sham (49+/-6 fmol/g), NS+AngII(40) (215+/-49), and NS+AngII(80) (347+/-47); but not with plasma AngII (R=0.12). HS+DOCA rats also exhibited increased SBP to 134+/-1 mm Hg, but U(AGT) (1.4+/-0.4 nmol AngI/d) and intrarenal AngII content (13+/-2 fmol/g) were not increased despite the hypertension. Infused human angiotensinogen could not be detected in urine of sham-operated or AngII-infused rats (n=4 each). These data demonstrate that U(AGT) increases in AngII-dependent hypertension in a dose- and time-dependent manner, but not in hypertension elicited by HS+DOCA. The results support the hypothesis that AngII-dependent hypertension results in elevated intrarenal AngII and angiotensinogen levels, reflected by increased U(AGT), which does not occur in an AngII-independent hypertensive model.
Angiotensin II↗
In memoriam. Arthur C. Guyton (1919-2003).
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History, 20th Century↗
Urinary excretion of angiotensinogen reflects intrarenal angiotensinogen production.
BACKGROUND: In rats maintained on a high salt diet (H/S) to suppress basal renal angiotensinogen levels, angiotensin II (Ang II) infusion for 13 days increased renal angiotensinogen mRNA and protein, thus providing a mechanism for further augmentation of intrarenal Ang II levels. The present study tested the hypothesis that enhanced intrarenal angiotensinogen formation during Ang II infusion is reflected by secretion into the tubular fluid leading to increased urinary excretion of angiotensinogen (UAGT). METHODS: The effects of chronic Ang II infusion were examined on kidney and plasma Ang II levels and UAGT in male Sprague-Dawley rats maintained on an 8% salt diet for three weeks (N=10). Following one week on the H/S diet, Ang II (40 ng/min) was administered for two weeks via an osmotic minipump to one group (H/S + Ang II, N=5), while the remaining rats were sham-operated (H/S + Sham, N=5). Additionally, a control group was prepared with normal salt diet and sham-operation (N/S + Sham, N=5). RESULTS: H/S alone did not alter systolic blood pressure (BP) (103 +/- 2 vs. 104 +/- 2 mm Hg), while Ang II infusion to H/S rats significantly increased systolic BP from 103 +/- 2 to 154 +/- 2 after two weeks. Intrarenal Ang II content in H/S + Ang II was significantly greater than H/S + Sham (435 +/- 153 vs. 65 +/- 14 fmol/g). Ang II infusion significantly increased UAGT (4.0 +/- 0.5 vs. 1.0 +/- 0.2 nmol Ang I/day by radioimmunoassay of generated Ang I; 57 +/- 15 vs. 14 +/- 2 densitometric units by Western blotting analysis) compared to Sham. UAGT by radioimmunoassay was highly correlated with kidney Ang II content (r=0.79); but not with plasma Ang II concentration (r=0.20). CONCLUSIONS: These data demonstrate that chronic Ang II infusion increases urinary excretion rate of angiotensinogen, and suggest that UAGT provides a specific index of intrarenal angiotensinogen production in Ang II-dependent hypertension.
Angiotensin II↗
Renal interstitial fluid angiotensin I and angiotensin II concentrations during local angiotensin-converting enzyme inhibition.
It was recently demonstrated that angiotensin II (AngII) concentrations in the renal interstitial fluid (RIF) of anesthetized rats were in the nanomolar range and were not reduced by intra-arterial infusion of an angiotensin-converting enzyme (ACE) inhibitor (enalaprilat). This study was performed to determine changes in RIF AngI and AngII concentrations during interstitial administration of ACE inhibitors (enalaprilat and perindoprilat). Studies were also performed to determine the effects of enalaprilat on the de novo formation of RIF AngII elicited by interstitial infusion of AngI. Microdialysis probes (cut-off point, 30,000 D) were implanted in the renal cortex of anesthetized rats and were perfused at 2 micro l/min. The effluent dialysate concentrations of AngI and AngII were measured by RIA, and reported values were corrected for the equilibrium rates at this perfusion rate. Basal RIF AngI (0.74 +/- 0.05 nM) and AngII (3.30 +/- 0.17 nM) concentrations were much higher than plasma AngI and AngII concentrations (0.15 +/- 0.01 and 0.14 +/- 0.01 nM, respectively; n = 27). Interstitial infusion of enalaprilat through the microdialysis probe (1 or 10 mM in the perfusate; n = 5 and 8, respectively) significantly increased RIF AngI concentrations but did not significantly alter AngII concentrations. However, perindoprilat (10 mM in the perfusate, n = 7) significantly decreased RIF AngII concentrations by 22 +/- 4% and increased RIF AngI concentrations. Interstitial infusion of AngI (100 nM in the perfusate, n = 7) significantly increased the RIF AngII concentration to 8.26 +/- 0.75 nM, whereas plasma AngI and AngII levels were not affected (0.15 +/- 0.02 and 0.14 +/- 0.02 nM, respectively). Addition of enalaprilat to the perfusate (10 mM) prevented the conversion of exogenously added AngI. These results indicate that addition of AngI in the interstitial compartment leads to low but significant conversion to AngII via ACE activity (blocked by enalaprilat). However, the addition of ACE inhibitors directly into the renal interstitium, via the microdialysis probe, either did not reduce RIF AngII levels or reduced levels by a small fraction of the total basal level, suggesting that much of the RIF AngII is formed at sites not readily accessible to ACE inhibition or is formed via non-ACE-dependent pathways.
Angiotensin I↗
ATP mediates tubuloglomerular feedback.
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Adenosine Triphosphate↗
Intrarenal AT(1) receptor and ACE binding in ANG II-induced hypertensive rats.
The intrarenal expression of angiotensin II (ANG II) type 1 (AT(1)) receptors and angiotensin-converting enzyme (ACE) was determined in ANG II-induced hypertensive rats (80 ng/min; 2 wk). Systolic blood pressure averaged 184 +/- 3 and 125 +/- 1 mmHg in ANG II-infused compared with Sham rats on day 12. Total kidney AT(1) receptor protein levels were not altered significantly. AT(1) receptor binding mapped by quantitative in vitro autoradiography was significantly decreased in glomeruli (172 +/- 25 vs. 275 +/- 34 disintegrations. min(-1). mm(-2)) and the inner stripe of the outer medulla (121 +/- 17 vs. 178 +/- 19 disintegrations. min(-1). mm(-2)), but not proximal convoluted tubules (48 +/- 9 vs. 58 +/- 6 disintegrations. min(-1). mm(-2)) of ANG II-infused compared with Sham rats. Proximal tubule ACE binding was significantly augmented (132 +/- 4 vs. 97 +/- 3 disintegrations. min(-1). mm(-2)) in ANG II-infused rats. In summary, during ANG II-induced hypertension, glomeruli and inner stripe of the outer medulla have reduced AT(1) receptor binding. Proximal convoluted tubules exhibit maintained AT(1) receptor density and increased ACE binding, which together with the elevated ANG II levels suggest that ANG II exerts a sustained influence on tubular reabsorption and consequently contributes to the development and maintenance of ANG II-dependent hypertension.
Angiotensin II↗
Essential role of AT1A receptor in the development of 2K1C hypertension.
The aims of this study were to delineate the relative contribution of angiotensin II (ANG II) subtype 1A (AT1A) and 1B (AT1B) receptors to the development of two-kidney, one-clip (2K1C) Goldblatt hypertension in mice, to examine if increased nitric oxide synthase (NOS) activity counteracts the vasoconstrictor influences of ANG II in 2K1C hypertensive mice, and to determine the role of ANG II type 2 (AT2) receptors in 2K1C hypertension in mice. AT(1A) ANG II receptor knockout (AT1A-/-) and wild-type (AT1A+/+) mice underwent clipping of the right renal artery. Systolic blood pressure (SBP) was significantly lower in AT1A-/- compared with AT1A+/+ mice, and neither clip placement nor AT2 receptor blockade with PD 123319 (PD) altered SBP in AT1A-/- mice. A significant and sustained rise in SBP from 119+/-5 to 163+/-6 mm Hg was observed in the 2K1C AT1A+/+ mice from day 10 to day 26. Chronic PD infusion did not alter the course of hypertension in 2K1C/AT1A+/+. Acute PD infusion did not alter mean arterial pressure (MAP) in AT1A+/+, PD/AT1A+/+, 2K1C/AT1A+/+, PD/2K1C/AT1A+/+, AT1A-/-, PD/AT1A-/-, and PD/2K1C/AT1A-/- mice compared with basal levels. In contrast, acute PD infusion caused significant increases in MAP in 2K1C/AT1A-/- mice. The subsequent acute NOS inhibition caused greater increases in MAP in 2K1C/AT1A+/+ and PD/2K1C/AT1A+/+ mice than in AT1A+/+ and PD/AT1A+/+ mice. These results support the essential role of AT1A receptors in mediating 2K1C hypertension and support the hypothesis that augmented NO production serves as a counteracting system in this model of hypertension.
Angiotensin Receptor Antagonists↗
Renal interstitial fluid concentrations of angiotensins I and II in anesthetized rats.
Previous studies have indicated that angiotensin II (Ang II) concentrations in renal interstitial fluid are much higher than plasma levels. In the present study, we performed experiments to explore renal interstitial fluid concentrations of Ang I and Ang II further and to determine whether these levels are altered by acute arterial infusion of an ACE inhibitor (enalaprilat) or by volume expansion. Microdialysis probes (molecular weight cutoff point: 30 000 Da) were implanted in the renal cortex of anesthetized rats and were perfused at a rate of 2 microL/min. Using relative equilibrium rates, the basal renal interstitial fluid Ang II concentration averaged 3.07+/-0.43 nmol/L, a value much higher than the plasma Ang II concentration of 107+/-8 pmol/L (n=7). Interstitial fluid Ang I concentrations (0.84+/-0.04 nmol/L) were consistently lower than the Ang II concentrations but higher than the plasma Ang I concentrations (112+/-14 pmol/L). Intra-arterial infusion of enalaprilat (7.5 micromol/kg/min, n=5) for 120 minutes resulted in a significant decrease in mean arterial pressure (from 114+/-4 to 68+/-4 mm Hg) along with reductions in plasma and renal ACE activity (by -99% and -52%, respectively). Enalaprilat resulted in a significant increase in plasma Ang I from 133+/-21 to 1167+/-328 pmol/L and a decrease in plasma Ang II from 110+/-12 to 67+/-9 pmol/L. During enalaprilat infusion, interstitial fluid concentration of Ang I was significantly increased from 0.78+/-0.06 to 0.97+/-0.08 nmol/L; however, Ang II concentrations were not altered significantly (3.67+/-0.28 versus 3.67+/-0.25 nmol/L). Acute volume loading with Ringer's solution containing 1% bovine serum albumin at a rate of 150 microL/min for 2 hours (6% to 7% of body weight) lowered plasma concentrations of Ang I from 110+/-23 to 16+/-2 pmol/L and Ang II from 100+/-23 to 36+/-6 pmol/L; however, renal interstitial fluid concentrations of Ang I and Ang II were not altered significantly during volume expansion (Ang I, from 0.77+/-0.05 to 0.69+/-0.03 nmol/L; Ang II, from 3.76+/-0.43 to 3.59+/-0.39 nmol/L, n=5). These data indicate that renal interstitial fluid concentrations of Ang I and Ang II are substantially higher than the corresponding plasma concentrations. Furthermore, the fact that the high interstitial fluid concentrations of Ang II are not responsive to acute ACE inhibition or volume expansion suggests the compartmentalization and independent regulation of renal interstitial fluid Ang II.
Anesthesia↗
Ang II accumulation in rat renal endosomes during Ang II-induced hypertension: role of AT(1) receptor.
Hypertension induced by long-term infusion of angiotensin II (Ang II) is associated with augmented intrarenal Ang II levels to a greater extent than can be explained on the basis of the circulating Ang II levels. Although part of this augmentation is due to AT(1) receptor-dependent internalization, the intracellular compartments involved in this Ang II accumulation remain unknown. In the present study, we sought to determine whether Ang II trafficking into renal cortical endosomes is increased during Ang II hypertension, and if so, whether the AT(1) receptor antagonist, candesartan, prevents this accumulation. Compared with controls (n=12; 114+/-2 mm Hg), Ang II-infused rats (n=12; 80 ng/kg/min, SC, for 13 days) developed hypertension with systolic blood pressure rising to 185+/-4 mm Hg by Day 12. In Ang II hypertensive rats, plasma renin activity was suppressed, whereas plasma and kidney Ang II levels were increased by 3-fold (348+/-58 versus 119+/-16 fmol/mL) and 2-fold (399+/-39 versus 186+/-26 fmol/g). Intracellular endosomal Ang II levels were increased by more than 10-fold (1100+/-283 versus 71+/-12 fmol/mg protein), whereas intermicrovillar cleft Ang II levels were increased by more than 2-fold (88+/-22 versus 37+/-7 fmol/mg protein). Flow cytometric analysis detected significant increases in AT(1A) receptor antibody binding in endosomal and intermicrovillar clefts of Ang II-infused rats. The hypertension induced by Ang II was prevented in rats treated concurrently with candesartan (2 mg/kg/d, 119+/-3 mm Hg). Candesartan treatment (n=8) also prevented increases in kidney (215+/-19 fmol/g), endosomal (96+/-29 fmol/mg protein), and intermicrovillar cleft Ang II levels (11+/-2 fmol/mg protein). These results indicate that there is substantial intracellular accumulation of angiotensin peptides in renal cortical endosomes during Ang II-dependent hypertension via an AT(1) receptor-mediated process.
Angiotensin I↗