Biomedical subjects

L Gabriel Navar

Publications and source records attributed to L Gabriel Navar.

40 records · Page 3Linked to original sources

PubMed2002

Regulation of intrarenal angiotensin II in hypertension.

Intrarenal angiotensin II (Ang II) is regulated by several complex processes involving formation from both systemically delivered and intrarenally formed substrate, as well as receptor-mediated internalization. There is substantial compartmentalization of intrarenal Ang II, with levels in the renal interstitial fluid and in proximal tubule fluid being much greater than can be explained from the circulating levels. In Ang II--dependent hypertension, elevated intrarenal Ang II levels occur even when intrarenal renin expression and content are suppressed. Studies in Ang II--infused rats have demonstrated that augmentation of intrarenal Ang II is due, in part, to uptake of circulating Ang II via an Ang II type 1 (AT(1)) receptor mechanism and also to sustained endogenous production of Ang II. Some of the internalized Ang II accumulates in the light and heavy endosomes and is therefore potentially available for intracellular actions. The enhanced intrarenal Ang II also exerts a positive feedback action to augment intrarenal levels of angiotensinogen (AGT) mRNA and protein, which contribute further to the increased intrarenal Ang II in hypertensive states. In addition, renal AT(1) receptor protein and mRNA levels are maintained, allowing increased Ang II levels to elicit progressive effects. The increased intrarenal Ang II activity and AGT production are associated with increased urinary AGT excretion rates. The urinary AGT excretion rates show a clear relationship to kidney Ang II content, suggesting that urinary AGT may serve as an index of Ang II--dependent hypertension. Collectively, the data support a powerful role for intrarenal Ang II in the pathogenesis of hypertension.

Angiotensin II↗

PubMed2002

Renal nuclear angiotensin II receptors in normal and hypertensive rats.

Accumulation of Angiotensin II (Ang II) in the kidneys of hypertensive rats infused chronically with Ang II occurs by AT1 receptor mediated internalization of Ang II, which may interact with intracellular targets, including nuclear binding sites. The aims of this study were to determine if kidney cell nuclei have specific Ang II binding sites and if chronic infusion of Ang II (70 ng/min; n=9) influences the nuclear Ang II binding capacity. Kidneys were harvested from control and Ang II infused rats and the renal cortexes were homogenized to obtain crude membrane preparations and nuclear fractions. Ang II binding sites were measured with a single point assay by incubating each fraction with 10 nM 125I-Sar-Ile-Ang II in the absence (total binding sites) or presence of either 2.5 M Sar-Leu-Ang II or 25 microM losartan to detect specific AT or AT1 binding sites. Both fractions exhibited specific Ang II binding sites that were displaced by both saralasin and losartan. In control rats, crude membrane preparations had 792 +/- 218 and the nuclear fraction had 543 +/- 222 fmol/mg protein AT1 receptors. AT1 receptor levels in membrane (885 +/- 170 fmol/mg protein) and nuclear fractions (610 +/- 198 fmol/mg protein) were not significantly different in Ang II infused rats. These data support the presence of nuclear Ang II receptors predominantly of the AT1 subtype in renal cells. Chronic Ang II infusion did not alter overall Ang II receptor densities.

Angiotensin II↗

PubMed2001

Expression of angiotensinogen mRNA and protein in angiotensin II-dependent hypertension.

Chronic elevations in circulating angiotensin II (AngII) levels produce sustained hypertension and increased intrarenal AngII contents through multiple mechanisms, which may include sustained or increased local production of AngII. This study was designed to test the hypothesis that chronic AngII infusion increases renal angiotensinogen mRNA and protein levels, thus contributing to the increase in intrarenal AngII levels. AngII (80 ng/min) was infused subcutaneously for 13 d into Sprague-Dawley rats, using osmotic minipumps. Control rats underwent sham operations. By day 12, systolic arterial BP increased to 184 +/- 3 mmHg in AngII-treated rats, whereas values for sham-treated rats remained at control levels (125 +/- 1 mmHg). Plasma renin activity was markedly suppressed (0.2 +/- 0.1 versus 5.3 +/- 1.2 ng AngI/ml per h); however, renal AngII contents were significantly increased in AngII-treated rats (273 +/- 29 versus 99 +/- 18 fmol/g). Western blot analyses of plasma and liver protein using a polyclonal anti-angiotensinogen antibody demonstrated two specific immunoreactive bands, at 52 and 64 kD, whereas kidney tissue exhibited one band, at 52 kD. Densitometric analyses demonstrated that AngII infusion did not alter plasma (52- or 64-kD), renal (52-kD), or hepatic (52-kD) angiotensinogen protein levels; however, there was a significant increase in hepatic expression of the highly glycosylated 64-kD angiotensinogen protein, of almost fourfold (densitometric value/control value ratios of 3.79 +/- 1.16 versus 1.00 +/- 0.35). Renal and hepatic expression of angiotensinogen mRNA, which was examined by semiquantitative reverse transcription-PCR, was significantly increased in AngII-treated rats, compared with shamtreated rats (kidney, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 0.82 +/- 0.11 versus 0.58 +/- 0.04; liver, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 2.34 +/- 0.07 versus 1.32 +/- 0.15). These results indicate that increases in circulating AngII levels increase intrarenal angiotensinogen mRNA levels, which may contribute to the sustained renal AngII-generating capacity that paradoxically occurs in AngII-treated hypertensive rats.

Angiotensin II↗

PubMed2000

Inducible nitric oxide synthase attenuates endothelium-dependent renal microvascular vasodilation.

Previous studies have demonstrated that inducible nitric oxide synthase (iNOS) plays a key pathophysiologic role during sepsis. The present study was designed to delineate the consequences of iNOS activation on renal microvascular function. Male Sprague-Dawley rats were given intraperitoneal injections of lipopolysaccharide (LPS; 4 mg/kg) at 16 h and 4 h before experimentation. Afferent and efferent arteriolar diameters from LPS-treated and control rats were assessed in vitro with the use of the blood perfused juxtamedullary nephron technique. Basal afferent and efferent arteriolar diameters of LPS-treated rats averaged 19.7 +/- 0.9 (n = 7) and 18.3 +/- 1.0 microm (n = 5), respectively, and were similar to those of control rats (20.8 +/- 0.3 [n = 6] and 18.4 +/- 0.6 microm [n = 6], respectively). Superfusion with the selective iNOS inhibitor S,S'-(1,3-phenylenebis[1,2-ethanediyl]) bisisothiourea (PBIT), at the doses of 0.01, 0.1, and 1 microM, significantly decreased afferent and efferent arteriolar diameters in a dose-dependent manner, whereas afferent or efferent arteriolar diameters of control rats were not altered in response to the same doses of PBIT. In the second series of experiments, superfusion with 10 microM acetylcholine (ACh) significantly increased afferent and efferent arteriolar diameters of LPS-treated rats by 14.9 +/- 1.6% (n = 9) and 6.6 +/- 1.1% (n = 6), respectively. The ACh-induced afferent and efferent arteriolar dilator responses were inhibited by superfusion with the nonselective NOS inhibitor N:(omega)-nitro-L-arginine (100 microM). However, afferent and efferent arteriolar dilator responses to ACh were significantly enhanced during selective iNOS inhibition with 1 microM PBIT (40.1 +/- 0.7% and 25.2 +/- 1.3%, respectively). These results suggest that activation of iNOS by LPS increases the influence of nitric oxide on afferent and efferent arteriolar tone and impairs endothelium-dependent nitric oxide effects.

Acetylcholine↗