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Biomedical subjects

L G Navar

Publications and source records attributed to L G Navar.

At least 37 records · Page 2Linked to original sources
PubMed2000

Roles of ANG II and bradykinin in the renal regional blood flow responses to ACE inhibition in sodium-depleted dogs.

The relative contributions of ANG II and bradykinin (BK) to the renal regional blood flow responses during angiotensin-converting enzyme (ACE) inhibition remain unclear. This study was performed to evaluate renal cortical (CBF) and medullary blood flow (MBF) responses to intrarterial administration of enalaprilat (33 microg. kg(-1). min (-1)) after blockade of the ANG II AT(1 )receptors with candesartan (100 microg) in 7 dogs fed a low-salt diet (0.01%) for 5 days. Laser-Doppler flowmetry was used to measure relative changes in CBF and MBF. Candesartan alone increased CBF (+20 +/- 2%) and MBF (+22 +/- 7%). Enalaprilat infusion after candesartan administration resulted in further increases in both CBF (+21 +/- 5%) and MBF (+41 +/- 8%). However, the relative changes in MBF were significantly greater (P < 0.01) than those in CBF. Administration of the BK B(2) receptor blocker icatibant (300 microg) after enalaprilat returned CBF and MBF to values seen with candesartan alone. These data support a substantive role for BK potentiation during ACE inhibitor-induced renal vasodilation in dogs maintained on a low-sodium diet, with a relatively greater effect on MBF compared to CBF.

Adrenergic beta-Antagonists↗
PubMed2000

Impairment of pressure-natriuresis and renal autoregulation in ANG II-infused hypertensive rats.

Chronic infusions of initially subpressor doses of angiotensin II (ANG II) lead to progressive hypertension over a 2-wk period and to augmented intrarenal ANG II levels. The present study was performed to investigate total renal blood flow (RBF) and medullary blood flow (MBF) autoregulatory behavior and pressure-natriuresis in ANG II-infused hypertensive rats and how these are modified by concomitant treatment with an ANG II AT(1) receptor antagonist. ANG II-infused rats (n = 27) were prepared by administration of ANG II at 60 ng/min via osmotic minipump for 13 days. Twelve of the ANG II-infused hypertensive rats were treated with losartan in the drinking water (30 mg. kg.(-1) day(-1)). Rats were anesthetized with pentobarbital sodium (50 mg/kg, ip) and prepared for renal function measurements. An aortic clamp was placed above the junction of the left renal artery to reduce renal arterial pressure. Autoregulatory responses for renal plasma flow, overall RBF, and glomerular filtration rate were impaired in ANG II-infused hypertensive rats; however, MBF autoregulation was not disrupted. Most strikingly, pressure-natriuresis was markedly suppressed in ANG II-infused hypertensive rats. Chronic treatment with losartan prevented the impairment of the pressure-natriuresis relationship caused by chronic ANG II infusion. These findings demonstrate that chronic ANG II infusion leads to marked impairment of sodium excretion and suppression of the pressure-natriuresis relationship, which may contribute to the progressive hypertension that occurs in this model. These renal effects are prevented by simultaneous treatment with an AT(1) receptor blocker.

Angiotensin II↗
PubMed2000

Dynamic interaction between myogenic and TGF mechanisms in afferent arteriolar blood flow autoregulation.

The dynamic activity of afferent arteriolar diameter (AAD) and blood flow (AABF) responses to a rapid step increase in renal arterial pressure (100-148 mmHg) was examined in the kidneys of normal Sprague-Dawley rats (n = 11) before [tubuloglomerular feedback (TGF)-intact] and after interruption of distal tubular flow (TGF-independent). Utilizing the in vitro blood-perfused juxtamedullary nephron preparation, fluctuations in AAD and erythrocyte velocity were sampled by using analog-to-digital computerized conversion, video microscopy, image shearing, and fast-frame, slow-frame techniques. These assessments enabled dynamic characterization of the autonomous actions and collective interactions between the myogenic and TGF mechanisms at the level of the afferent arteriole. The TGF-intact and TGF-independent systems exhibited common initial (0-24 vs. 0-13 s, respectively) response slope kinetics (-0.53 vs. -0.47% DeltaAAD/s; respectively) yet different maximum vasoconstrictive magnitude (-11.28 +/- 0.1 vs. -7. 02 +/- 0.9% DeltaAAD; P < 0.05, respectively). The initial AABF responses similarly exhibited similar kinetics but differing magnitudes. In contrast, during the sustained pressure input (13-97 s), the maximum vasoconstrictor magnitude (-7.02 +/- 0.9% DeltaAAD) and kinetics (-0.01% DeltaAAD/s) of the TGF-independent system were markedly blunted whereas the TGF-intact system exhibited continued vasoconstriction with slower kinetics (-0.20% DeltaAAD/s) until a steady-state plateau was reached (-25.9 +/- 0.4% DeltaAAD). Thus the TGF mechanism plays a role in both direct mediation of vasoconstriction and in modulation of the myogenic response.

Animals↗
PubMed2000

Intrarenal angiotensin II augmentation in angiotensin II dependent hypertension.

In several models of angiotensin II (ANG II) dependent hypertension, intrarenal ANG II levels increase to a much greater extent than the circulating levels even though the renal renin levels are decreased. The 2-kidney-1-clip (2K1C) Goldblatt rat model is particularly intriguing because hypertension develops in the presence of an intact kidney which would be expected to maintain sodium balance and protect against hypertension. Although the non-clipped kidney becomes renin depleted, it exhibits enhanced microvascular reactivity and increased tubular fractional sodium reabsorption. The non-clipped kidney ANG II content is either elevated or unchanged and proximal tubular fluid ANG II concentrations are not suppressed compared to the nanomolar concentrations found in normal rats. These results suggest that intrarenal ANG II content can be regulated independently of renal renin content. A similar hypertensive process occurs in rats infused chronically with low doses of ANG II. Renal ANG II content increases over 14 days to a greater extent than the circulating concentrations. Functionally, ANG II infused rats demonstrate reduced sodium excretion and marked suppression of pressure natriuresis. These ANG II dependent influences on kidney function contribute to the maintenance of hypertension. Renal augmentation of ANG II, hypertension, and suppressed sodium excretion are blocked by AT1 receptor blockers. To study the mechanisms responsible for intrarenal ANG II augmentation, we infused a different form of ANG II (Val5 ANG II), that can be separated from endogenous ANG II by HPLC. These results indicated that the increased renal ANG II content was due to accumulation of circulating ANG II in addition to continued production of endogenous ANG II. The renal accumulation of Val5-ANG II was markedly reduced by concomitant treatment with the AT1 receptor blocker, losartan. In addition, we found an unchanged overall ANG II-AT1 receptor protein which probably contributes to the maintained ANG II dependent influences. Collectively, the data support the concept that there is internalization of ANG II through an AT1 receptor mediated process and that some of the internalized ANG II is protected from degradation. The augmented intrarenal ANG II coupled with sustained levels of AT1 receptors contribute to the continued ANG II dependent suppression of renal function and sodium excretion thereby maintaining the hypertension.

Angiotensin II↗
PubMed1999

Renal function in the AT1A receptor knockout mouse during normal and volume-expanded conditions.

BACKGROUND: Genetically altered mice lacking the AT1A angiotensin II (Ang II) receptor were used to examine the role of AT1A receptors in regulating renal hemodynamics, sodium excretion, glomerulotubular balance, and Ang II levels in plasma and kidney during normal and volume-expanded conditions. METHODS: AT1A receptor-deficient mice and their wild-type controls were anesthetized with inactin and ketamine, and were prepared to allow intravenous infusions of solutions and measurements of aortic pressure and urine collections. Inulin and para-aminohippurate (PAH) solutions were infused intravenously for clearance determinations under conditions of euvolemia (2.5 microliter/min infusion of isotonic saline) or volume-expansion conditions (12.5 microliter/min). After three 30-minute urine collections, blood samples were collected, and kidneys were harvested. Plasma and kidney Ang II measurements were made by radioimmunoassay. RESULTS: In the euvolemic state, mean arterial pressures (MAPs) were significantly lower in the AT1A receptor-deficient mice (68 +/- 4 mm Hg) compared with wild-type controls (89 +/- 3 mm Hg). Despite the lower MAP, the glomerular filtration rate (GFR), renal plasma flow (RPF), absolute sodium excretion, and fractional sodium excretion were not significantly different between wild-type and AT1A-/- mice. Volume expansion did not alter MAP in wild-type mice, but significantly increased MAP in the AT1A-/- mice (68 +/- 4 to 83 +/- 5 mm Hg). Similar increases in GFR, RPF, absolute sodium excretion, and fractional sodium excretion in AT1A+/+ and AT1A-/- mice were observed. Glomerulotubular balance was not disrupted by the absence of AT1A receptors. During euvolemia, plasma Ang II concentrations were significantly higher in the AT1A-/- mice compared with wild-type mice (536 +/- 172 vs. 198 +/- 36 fmol/ml). Although volume expansion had no effect on plasma Ang II levels in the AT1A+/+ group, plasma Ang II concentrations were markedly suppressed in the AT1A-/- mice to levels that were not different from those in wild-type mice. In contrast, kidney tissue Ang II contents were reduced in the AT1A-/- mice and were not significantly altered during volume expansion in either the AT1A-/- or the AT1A+/+ mice. CONCLUSIONS: The absence of AT1A receptors does not impair chronic regulation of renal blood flow, GFR, or glomerulotubular balance. The prompt restoration of MAP following volume expansion suggests that low blood pressure in the AT1A receptor-deficient mice is primarily due to reduced effective plasma and extracellular fluid volume. Normalization of plasma Ang II levels with volume expansion demonstrates a dominant effect of extracellular fluid volume and blood pressure over AT1A receptor-mediated short-loop feedback in the regulation of plasma Ang II levels.

Angiotensin II↗
PubMed1999

Kinin influences on renal regional blood flow responses to angiotensin-converting enzyme inhibition in dogs.

The relative roles of ANG II and bradykinin (BK) in the regulation of renal medullary circulation have remained unclear. We compared the contributions of ANG II and BK to the renal medullary blood flow (MBF) responses to angiotensin-converting enzyme (ACE) inhibition (enalaprilat, 33 micrograms . kg-1. min-1) in dogs maintained on a normal-salt diet (0.63%, 3 days, n = 14; group 1) with those fed a low-salt diet (0.01%, 5 days, n = 14; group 2), which upregulates both the kallikrein-kinin and the renin-angiotensin systems. MBF responses to ACE inhibition were evaluated either before (n = 7) or after (n = 7) treatment with the BK B2 receptor blocker icatibant (100-300 micergrams) in both groups. Laser-Doppler needle flow probes were used to determine relative changes in MBF and cortical blood flow (CBF). ACE inhibition increased MBF (group 1, 33 +/- 9%, P </= 0.01; group 2, 24 +/- 9%, P </= 0.005) as well as CBF (group 1, 23 +/- 2%, P </= 0.006; group 2, 28 +/- 10%, P </= 0.05). These responses were prevented by prior blockade of B2 receptors in group 2, but not in group 1. These data indicate that under normal sodium intake, increases in MBF and CBF caused by ACE inhibition are primarily due to reduced intrarenal ANG II levels. In contrast, the renal vasodilatory responses to ACE inhibition in dogs on low salt intake were markedly dependent on the activation of BK B2 receptors.

Angiotensin II↗
PubMed1999

Neuronal NOS contributes to biphasic autoregulatory response during enhanced TGF activity.

To assess the afferent arteriolar autoregulatory response during increased activity of the tubuloglomerular feedback (TGF) mechanism and to delineate the contribution of neuronal nitric oxide synthase (nNOS) to this response, afferent arteriolar diameter responses to changes in renal perfusion pressure (RPP) were monitored in vitro using the blood-perfused rat juxtamedullary nephron preparation. At RPP of 100 mmHg, basal afferent arteriolar diameter averaged 21.1 +/- 1.4 micrometer (n = 9). The initial and sustained constrictor responses of afferent arterioles to a 60-mmHg increase in RPP averaged 14.8 +/- 1.4% and 13.3 +/- 1.3%, respectively. Acetazolamide treatment, which enhances TGF responsiveness by increasing distal nephron volume delivery, significantly decreased basal afferent arteriolar diameter by 8.2 +/- 0.5% and enhanced the initial response (25.5 +/- 2.3%) to a 60-mmHg increase in RPP but did not alter the sustained response (14.3 +/- 1.5%). In another series of experiments, nNOS inhibition with 10 microM S-methyl-L-thiocitrulline (L-SMTC) significantly decreased afferent arteriolar diameter from 20.3 +/- 1.3 to 18.3 +/- 1.1 micrometer (n = 7) and enhanced both the initial (34.4 +/- 3.5%) and sustained constrictor responses (27.6 +/- 2.9%) to a 60-mmHg increase in RPP. Treatment with acetazolamide further enhanced both initial (56.4 +/- 3.0%) and sustained responses (54.6 +/- 2.7%). Interruption of distal delivery by transection of the loops of Henle prevented the enhanced responses to increases in RPP elicited with either acetazolamide or L-SMTC. These results indicate that nNOS contributes to the counteracting resetting process of biphasic afferent arteriolar constrictor responses to increases in RPP through a TGF-dependent mechanism.

Acetazolamide↗
PubMed1999

Renal endosomes contain angiotensin peptides, converting enzyme, and AT(1A) receptors.

Kidney cortex and proximal tubular angiotensin II (ANG II) levels are greater than can be explained on the basis of circulating ANG II, suggesting intrarenal compartmentalization of these peptides. One possible site of intracellular accumulation is the endosomes. In the present study, we tested for endosomal ANG I, ANG II, angiotensin type 1A receptor (AT(1A)), and angiotensin converting enzyme (ACE) activity and determined whether these levels are regulated by salt intake. Male Sprague-Dawley rats were fed chow containing either high or low dietary sodium for 10-14 days. Blood and kidneys were harvested and processed for measurement of plasma, kidney, and renal intermicrovillar cleft and endosomal angiotensin levels. Kidney ANG I averaged 179 +/- 20 fmol/g and ANG II averaged 258 +/- 36 fmol/g in rats fed a high-sodium diet and were significantly higher, averaging 347 +/- 58 fmol/g and 386 +/- 55 fmol/g, respectively, in rats fed a low-salt diet. Renal intermicrovillar clefts and endosomes contained ANG I and ANG II. Intermicrovillar cleft ANG I and ANG II levels averaged 8.4 +/- 2.6 and 74 +/- 26 fmol/mg, respectively, in rats fed a high-salt diet and 7.6 +/- 1.7 and 70 +/- 25 fmol/mg in rats fed a low-salt diet. Endosomal ANG I and ANG II levels averaged 12.3 +/- 4.4 and 43 +/- 19 fmol/mg, respectively, in rats fed a high-salt diet, and these levels were similar to those observed in rats fed a low-salt diet. Renal endosomes from rats fed a low-salt diet demonstrated significantly more AT(1A) receptor binding compared with rats fed a high-salt diet. ACE activity was detectable in renal intermicrovillar clefts and was 2.5-fold higher than the levels observed in renal endosomes. Acute enalaprilat treatment decreased ACE activity in renal intermicrovillar clefts by 90% and in renal endosomes by 84%. Likewise, intermicrovillar cleft and endosomal ANG II levels decreased by 61% and 52%, respectively, in enalaprilat-treated animals. These data demonstrate the presence of intact angiotensin peptides and ACE activity in renal intermicrovillar clefts and endosomes, indicating that intact angiotensin peptides are formed and/or trafficked through intracellular endosomal compartments and are dependent on ACE activity.

Angiotensin II↗
PubMed1999

Increased activity and expression of Ca(2+)-dependent NOS in renal cortex of ANG II-infused hypertensive rats.

We have previously demonstrated that nitric oxide (NO) exerts a greater modulatory influence on renal cortical blood flow in ANG II-infused hypertensive rats compared with normotensive rats. In the present study, we determined nitric oxide synthase (NOS) activities and protein levels in the renal cortex and medulla of normotensive and ANG II-infused hypertensive rats. Enzyme activity was determined by measuring the rate of formation of L-[(14)C]citrulline from L-[(14)C]arginine. Western blot analysis was performed to determine the regional expression of endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) isoforms in the renal cortex and medulla of control and ANG II-infused rats. Male Sprague-Dawley rats were prepared by the infusion of ANG II at a rate of 65 ng/min via osmotic minipumps implanted subcutaneously for 13 days and compared with sham-operated rats. Systolic arterial pressures were 127 +/- 2 and 182 +/- 3 mmHg in control (n = 13) and ANG II-infused rats (n = 13), respectively. The Ca(2+)-dependent NOS activity, expressed as picomoles of citrulline formed per minute per gram wet weight, was higher in the renal cortex of ANG II-infused rats (91 +/- 11) than in control rats (42 +/- 12). Likewise, both eNOS and nNOS were markedly elevated in the renal cortex of the ANG II-treated rats. In both groups of rats, Ca(2+)-dependent NOS activity was higher in the renal medulla than in the cortex; however, no differences in medullary NOS activity were observed between the groups. Also, no differences in medullary eNOS levels were observed between the groups; however, medullary nNOS was decreased by 45% in the ANG II-infused rats. For the Ca(2+)-independent NOS activities, the renal cortex exhibited a greater activity in the control rats (174 +/- 23) than in ANG II-infused rats (101 +/- 10). Similarly, cortical iNOS was greater by 47% in the control rats than in ANG II-treated rats. No differences in the activity were found for the renal medulla between the groups. There was no detectable signal for iNOS in the renal medulla for both groups. These data indicate that there is a differential distribution of NOS activity, with the Ca(2+)-dependent activity and protein expression higher in the renal cortex of ANG II-infused rats compared with control rats, and support the hypothesis that increased constitutive NOS activity exerts a protective effect in ANG II-induced hypertension to maintain adequate renal cortical blood flow.

Angiotensin II↗
PubMed1999

Proximal tubular angiotensin II levels and renal functional responses to AT1 receptor blockade in nonclipped kidneys of Goldblatt hypertensive rats.

-Previous studies have shown that whereas the nonclipped kidney in two-kidney, one clip (2K1C) rats undergoes marked depletion of renin content and renin mRNA, intrarenal angiotensin II (Ang II) levels are not suppressed; however, the distribution and functional consequences of intrarenal Ang II remain unclear. The present study was performed to assess the plasma, kidney, and proximal tubular fluid levels of Ang II and the renal responses to intrarenal Ang II blockade in the nonclipped kidneys of rats clipped for 3 weeks. The Ang II concentrations in proximal tubular fluid averaged 9.19+/-1.06 pmol/mL, whereas plasma Ang II levels averaged 483+/-55 fmol/mL and kidney Ang II content averaged 650+/-66 fmol/g. Thus, as found in kidneys from normal rats with normal renin levels, proximal tubular fluid concentrations of Ang II are in the nanomolar range. To avoid the confounding effects of decreases in mean arterial pressure (MAP), we administered the nonsurmountable AT1 receptor antagonist candesartan directly into the renal artery of nonclipped kidneys (n=10). The dose of candesartan (0.5 microg) did not significantly decrease MAP in 2K1C rats (152+/-3 versus 148+/-3 mm Hg), but effectively prevented the renal vasoconstriction elicited by an intra-arterial bolus of Ang II (2 ng). Candesartan elicited significant increases in glomerular filtration rate (GFR) (0.65+/-0. 06 to 0.83+/-0.11 mL. min-1. g-1) and renal blood flow (6.3+/-0.7 to 7.3+/-0.9 mL. min-1. g-1), and proportionately greater increases in absolute sodium excretion (0.23+/-0.07 to 1.13+/-0.34 micromol. min-1. g-1) and fractional sodium excretion (0.38+/-0.1% to 1.22+/-0. 35%) in 2K1C hypertensive rats. These results show that proximal tubular fluid concentrations of Ang II are in the nanomolar range and are much higher than can be explained on the basis of plasma levels. Further, the data show that the intratubular levels of Ang II in the nonclipped kidneys of 2K1C rats remain at levels found in kidneys with normal renin content and could be exerting effects to suppress renal hemodynamic and glomerular function and to enhance tubular reabsorption rate.

Angiotensin I↗
PubMed1999

Regulation of angiotensin II type 1 receptor mRNA and protein in angiotensin II-induced hypertension.

Chronic elevations of circulating angiotensin II (Ang II) cause sustained hypertension and enhanced accumulation of intrarenal Ang II by an AT1 receptor-dependent process. The present study tested the hypothesis that chronic elevations in circulating Ang II regulate AT1 mRNA and protein expression in a tissue-specific manner. Sprague-Dawley rats were infused with Ang II (80 ng/min) or vehicle subcutaneously for 13 days via osmotic minipump. On day 12, systolic blood pressure averaged 186+/-12 mm Hg in Ang II-infused rats compared with rats given vehicle (121+/-2 mm Hg). Plasma renin activity was markedly suppressed in the Ang II-infused rats compared with vehicle-infused rats (0.1+/-0.01 versus 4.9+/-0.9 ng of Ang I. mL-1. h-1; P<0.05). Semiquantitative reverse transcription polymerase chain reaction using rat AT1A- and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH)-specific primers was followed by Southern blot hybridization using specific radiolabeled cDNA or oligonucleotide probes. The results showed that the ratios of AT1A/GAPDH mRNA in the kidney (0.19+/-0.05 versus 0. 26+/-0.03) and liver (2.8+/-0.9 versus 3.0+/-0.5) were comparable in Ang II- and vehicle-infused rats. In contrast, AT1A/GAPDH mRNA levels were increased in the adrenal glands of Ang II-infused rats (0.49+/-0.04 versus 0.36+/-0.02; P<0.05). Western blot analysis showed that AT1 protein levels in the kidney and liver were also similar in the two groups. Therefore, these results indicate that renal and liver AT1 receptor gene expression is maintained in Ang II-induced hypertension. The failure to downregulate AT1 receptor mRNA and protein levels thus allows the sustained effects of chronic elevations in Ang II to elicit progressive increases in arterial pressure.

Angiotensin I↗
PubMed1999

Neuronal nitric oxide synthase-dependent afferent arteriolar function in angiotensin II-induced hypertension.

This study was designed to determine the influence of neuronal nitric oxide synthase (nNOS) in tubular flow-dependent regulation of afferent arteriolar diameter in hypertensive Sprague-Dawley rats that received 60 ng/min angiotensin II (Ang II) subcutaneously for 13 days. Systolic blood pressure of control and Ang II-infused rats averaged 122+/-2 (n=23) and 194+/-2 mm Hg (n=24). Afferent arteriolar responses to the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC; 0.1 to 10 micromol/L) and the nonselective NOS inhibitor Nomega-nitro-L-arginine (L-NNA; 1 to 100 micromol/L) were assessed in vitro using the blood-perfused juxtamedullary nephron preparation. At a perfusion pressure of 160 mm Hg, afferent arteriolar diameters from control and Ang II-infused rats averaged 18.7+/-1.1 microm (n=8) and 18.1+/-1.1 microm (n=9), respectively, and decreased by 19. 9+/-1.5% and 11.8+/-1.1%, respectively, in response to 10 micromol/L L-SMTC. The L-SMTC-induced afferent arteriolar constriction was significantly greater in control than in Ang II-infused rats. In contrast, 100 micromol/L L-NNA constricted afferent arterioles similarly in both control (n=8) and Ang II-infused (n=7) rats. After transection of the loops of Henle to interrupt flow to the macula densa, the vasoconstrictor responses to L-SMTC but not to L-NNA were reversed. Increasing distal volume delivery by addition of 10 mmol/L acetazolamide to the blood perfusate significantly enhanced the afferent arteriolar constrictor responses to 10 micromol/L L-SMTC (34.5+/-4.8%, n=7) in normotensive rats. In contrast, in Ang II-infused rats, acetazolamide treatment did not enhance the responses to L-SMTC (n=8). These results indicate that chronic Ang II infusion reduces the ability of nNOS-derived nitric oxide to counteract the afferent arteriolar response to increased distal tubular flow.

Acetazolamide↗