scholarly journals Cholesterol induces renal vasoconstriction and anti-natriuresis by inhibiting nitric oxide production in anesthetized rats

2009 ◽  
Vol 297 (6) ◽  
pp. F1606-F1613 ◽  
Author(s):  
Libor Kopkan ◽  
Md Abdul H. Khan ◽  
Agnieszka Lis ◽  
Mouhamed S. Awayda ◽  
Dewan S. A. Majid
Keyword(s):  
Nitric Oxide ◽  
Sodium Reabsorption ◽  
No Production ◽  
Sprague Dawley ◽  
Appreciable Change ◽  
Renal Vasoconstriction ◽  
Sprague Dawley Rats ◽  
Nitrite Nitrate ◽  
Synthase Inhibitor ◽  
Renal Responses

Although hypercholesterolemia is implicated in the pathophysiology of many renal disorders as well as hypertension, its direct actions in the kidney are not yet clearly understood. In the present study, we evaluated renal responses to administration of cholesterol (8 μg·min−1·100 g body wt−1; bound by polyethylene glycol) into the renal artery of anesthetized male Sprague-Dawley rats. Total renal blood flow (RBF) was measured by a Transonic flow probe, and glomerular filtration rate (GFR) was determined by Inulin clearance. In control rats ( n = 8), cholesterol induced reductions of 10 ± 2% in RBF [baseline (b) 7.6 ± 0.3 μg·min−1·100 g−1], 17 ± 3% in urine flow (b, 10.6 ± 0.9 μg·min−1·100 g−1), 29 ± 3% in sodium excretion (b, 0.96 ± 0.05 μmol·min−1·100 g−1) and 24 ± 2% in nitrite/nitrate excretion (b, 0.22 ± 0.01 nmol·min−1·100 g−1) without an appreciable change in GFR (b, 0.87 ± 0.03 ml·min−1·100 g−1). These renal vasoconstrictor and anti-natriuretic responses to cholesterol were absent in rats pretreated with nitric oxide (NO) synthase inhibitor, nitro-l-arginine methylester (0.5 μg·min−1·100 g−1; n = 6). In rats pretreated with superoxide (O2−) scavenger tempol (50 μg·min−1·100 g−1; n = 6), the cholesterol-induced renal responses remained mostly unchanged, although there was a slight attenuation in anti-natriuretic response. This anti-natriuretic response to cholesterol was abolished in furosemide-pretreated rats (0.3 μg·min−1·100 g−1; n = 6) but remained unchanged in amiloride-pretreated rats (0.2 μg·min−1·100 g−1; n = 5), indicating that Na+/K+/2Cl− cotransport is the dominant mediator of this effect. These data demonstrate that cholesterol-induced acute renal vasoconstrictor and antinatriuretic responses are mediated by a decrease in NO production. These data also indicate that tubular effect of cholesterol on sodium reabsorption is mediated by the furosemide sensitive Na+/K+/2Cl− cotransporter.

scholarly journals Erythropoietin Produces a Dual Effect on Carotid Body Chemoreception in Male Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Christian Arias-Reyes ◽  
Sofien Laouafa ◽  
Natalia Zubieta-DeUrioste ◽  
Vincent Joseph ◽  
Aida Bairam ◽  
...  
Keyword(s):  
Carotid Body ◽  
No Synthase ◽  
Male Rats ◽  
High Dose ◽  
No Production ◽  
Sprague Dawley ◽  
En Bloc ◽  
No Synthase Inhibitor ◽  
Sprague Dawley Rats ◽  
Synthase Inhibitor

Erythropoietin (EPO) regulates respiration under conditions of normoxia and hypoxia through interaction with the respiratory centers of the brainstem. Here we investigate the dose-dependent impact of EPO in the CB response to hypoxia and hypercapnia. We show, in isolated “en bloc” carotid body (CB) preparations containing the carotid sinus nerve (CSN) from adult male Sprague Dawley rats, that EPO acts as a stimulator of CSN activity in response to hypoxia at concentrations below 0.5 IU/ml. Under hypercapnic conditions, EPO did not influence the CSN response. EPO concentrations above 0.5 IU/ml decreased the response of the CSN to both hypoxia and hypercapnia, reaching complete inhibition at 2 IU/ml. The inhibitory action of high-dose EPO on the CSN activity might result from an increase in nitric oxide (NO) production. Accordingly, CB preparations were incubated with 2 IU/ml EPO and the unspecific NO synthase inhibitor (L-NAME), or the neuronal-specific NO synthase inhibitor (7NI). Both NO inhibitors fully restored the CSN activity in response to hypoxia and hypercapnia in presence of EPO. Our results show that EPO activates the CB response to hypoxia when its concentration does not exceed the threshold at which NO inhibitors masks EPO’s action.

Abstract 93: Hypertension and Renal Injury Induced by Nitric Oxide Depletion are Ameliorated by Concomitant Depletion of Hydrogen Sulfide

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Sebastiaan Wesseling ◽  
Joost O Fledderus ◽  
Johanna A Dijk ◽  
Chantal Tilburgs ◽  
Marianne C Verhaar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Renal Injury ◽  
Renal Damage ◽  
No Synthase ◽  
Tubular Epithelium ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Induced Hypertension ◽  
Synthase Inhibitor

Chronic nitric oxide (NO) depletion induces hypertension and renal damage. Chronic kidney disease is associated with decreased NO availability and less renal H 2 S production. We hypothesized that combined depletion of NO and H 2 S aggravates hypertension and renal injury. Male 8-wk old Sprague Dawley rats were treated with vehicle, NO synthase inhibitor L-NG-nitroarginine (LNNA; 125 mg/L in drinking water), cystathionine-γ-lyase (CSE) inhibitor propargylglycine (PAG; 37.5 mg/kg BW ip daily) or LNNA + PAG for 1 and 4 weeks (6 rats/group). LNNA after 4w increased systolic blood pressure (SBP; 223±10 vs . 137±3 mmHg in controls; P<0.01), proteinuria (144±35 vs. 17±2 mg/d; P<0.01), uremia (16.6±4.2 vs . 7.0±0.4 mmol/L; P<0.05) and tubulo-interstitial injury (P<0.01). LNNA reduced urinary NO metabolite (NOx) excretion by ∼85% after 1w and 4w. PAG alone had no effect on SBP, renal function or injury, but did reduce urinary NOx excretion. Co-treatment with PAG ameliorated LNNA-induced hypertension (182±10 mmHg; P<0.01) and prevented proteinuria (27±3 mg/d), uremia (8.3±0.4 mmol/L) and tubulo-interstitial injury, but did not further reduce urinary NOx excretion. Renal H 2 S production was almost absent in all PAG groups after 1w and 4w (P<0.01) and was reduced in LNNA-treated rats after 4w (4.6±1.4 vs . 9.2±0.5 μmol/hr/mg; P<0.01). Renal HO-1 gene expression was strongly induced in all PAG-treated groups after 1w and 4w (4 to 19-fold; P<0.01) whereas LNNA only increased HO-1 gene expression at 4w (P<0.01). Immunohistochemistry showed that renal HO-1 protein was primarily interstitial in all PAG-treated groups at 1w and 4w. In contrast, LNNA only showed HO-1 in tubular epithelium in conjunction with protein casts. Depleting NO caused hypertension and renal damage followed by reduced renal H 2 S production and increased renal HO-1 expression. Surprisingly, concomitant inhibition of CSE ameliorated hypertension and prevented renal injury. PAG almost completely blocked renal H 2 S production and caused strong induction of renal HO-1, independently of injury, suggesting that H 2 S suppresses renal HO-1 expression. In conclusion, concomitant upregulation of HO-1 expression by inhibition of H 2 S production, prevents LNNA-induced hypertension and renal injury.

Vitamin E reduces glomerulosclerosis, restores renal neuronal NOS, and suppresses oxidative stress in the 5/6 nephrectomized rat

2007 ◽  
Vol 292 (5) ◽  
pp. F1404-F1410 ◽  
Author(s):  
You-Lin Tain ◽  
Gary Freshour ◽  
Anna Dikalova ◽  
Kathy Griendling ◽  
Chris Baylis
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Vitamin E ◽  
Kidney Cortex ◽  
Antioxidant Vitamin ◽  
No Production ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Endothelial Nitric Oxide

Chronic kidney disease is accompanied by nitric oxide (NO) deficiency and oxidative stress, which contribute to progression. We investigated whether the antioxidant vitamin E could preserve renal function and NO bioavailability and reduce oxidative stress in the 5/6th nephrectomy (NX) rat model. We studied the following three groups of male Sprague-Dawley rats: sham ( n = 6), 5/6 NX control ( n = 6), and 5/6 NX treated with vitamin E (5,000 IU/kg chow; n = 5). The 5/6 NX group showed increased severity of glomerulosclerosis vs. sham, and this was ameliorated by vitamin E therapy. Both 5/6 NX groups showed similar elevations in plasma creatinine and proteinuria and decreased 24-h creatinine clearance compared with sham. There was increased NADPH-dependent superoxide production in 5/6 NX rats vs. sham that was prevented by vitamin E. Total NO production was similarly reduced in both 5/6 NX groups. There was unchanged abundance of endothelial nitric oxide synthesis (NOS) in renal cortex and medulla and neuronal (n) NOS in medulla. However, in kidney cortex, 5/6 NX rats had lower nNOS abundance than sham, which was restored by vitamin E. An increased plasma asymmetric dimethylarginine occurred with 5/6 NX associated with decreased renal dimethylarginine dimethylaminohydrolase activity and increased type 1 protein arginine methyltransferase expression.

scholarly journals Pharmacological characterisation of arthritis induced byBothrops jararacavenom in rabbits: a positive cross talk between bradykinin, nitric oxide and prostaglandin E2

2002 ◽  
Vol 11 (1) ◽  
pp. 13-16 ◽  
Author(s):  
Suzana B. V. Mello ◽  
Maria Luiza Guzzo ◽  
Luiz Filipe Santiago Lisboa ◽  
Sandra H. P. Farsky
Keyword(s):  
Nitric Oxide ◽  
Prostaglandin E ◽  
No Production ◽  
Positive Interaction ◽  
Kinin System ◽  
Local Inflammatory Response ◽  
Griess Reaction ◽  
Hoe 140 ◽  
Nitrite Nitrate ◽  
Synthase Inhibitor

Background: Our previous results showed that nitric oxide (NO) and bradykinin (BK) mediate the arthritis induced byBothrops jararacavenom (BjV) in rabbits. In this study, we investigated the contribution of each receptor of BK as well as the inter-relationship between NO and eicosanoids in BjV-induced arthritis.Methods: The arthritis was induced in rabbits with 16 μg of BjV injected intra-articularly. Prostaglandin E2(PGE2), thromboxane B2(TxB2), leukotriene B4(LTB4) (radioimmunoassay) and nitrite/nitrate concentrations (NO2/NO3) (Griess reaction) were evaluated in the synovial fluid 4 h later. The animals were prior treated with NO synthase inhibitor (L-NAME; 20 mg/kg/day for 14 days), the B2 antagonist of BK (HOE-140) and the B1 antagonist of BK (des-Arg9[Leu8]-bradykinin), both at a dose of 0.3 mg/kg, 30 min prior to the venom injection.Results: Data show that L-NAME and HOE-140 treatment were equally able to reduce PGE2and NO2/NO3levels without interfering with TxB2and LTB4production. On the contrary, the B1 antagonist of BK inhibited TxB2and LTB4production, and did not alter PGE2and NO metabolites levels in the inflamed joint.Discussions: The results presented clarify the contribution of the kinin system, mainly through the B2 receptor, to the local inflammatory response induced by BjV, as well as its positive interaction with PGE2and NO production.

scholarly journals Augmented central nitric oxide production inhibits vasopressin release during hemorrhage in acute alcohol-intoxicated rodents

2011 ◽  
Vol 301 (5) ◽  
pp. R1529-R1539 ◽  
Author(s):  
Annie M. Whitaker ◽  
Jesse K. Sulzer ◽  
Patricia E. Molina
Keyword(s):  
Nitric Oxide ◽  
Alcohol Intoxication ◽  
Sprague Dawley ◽  
Nitric Oxide Synthase Inhibitor ◽  
Vasopressin Release ◽  
No Inhibition ◽  
Sprague Dawley Rats ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Acute alcohol intoxication (AAI) attenuates the AVP response to hemorrhage, contributing to impaired hemodynamic counter-regulation. This can be restored by central cholinergic stimulation, implicating disrupted signaling regulating AVP release. AVP is released in response to hemorrhage and hyperosmolality. Studies have demonstrated nitric oxide (NO) to play an inhibitory role on AVP release. AAI has been shown to increase NO content in the paraventricular nucleus. We hypothesized that the attenuated AVP response to hemorrhage during AAI is the result of increased central NO inhibition. In addition, we predicted that the increased NO tone during AAI would impair the AVP response to hyperosmolality. Conscious male Sprague-Dawley rats (300–325 g) received a 15-h intragastric infusion of alcohol (2.5 g/kg + 300 mg·kg−1·h−1) or dextrose prior to a 60-min fixed-pressure hemorrhage (∼40 mmHg) or 5% hypertonic saline infusion (0.05 ml·kg−1·min−1). AAI attenuated the AVP response to hemorrhage, which was associated with increased paraventricular NO content. In contrast, AAI did not impair the AVP response to hyperosmolality. This was accompanied by decreased paraventricular NO content. To confirm the role of NO in the alcohol-induced inhibition of AVP release during hemorrhage, the nitric oxide synthase inhibitor, nitro-l-arginine methyl ester (l-NAME; 250 μg/5 μl), was administered centrally prior to hemorrhage. l-NAME did not further increase AVP levels during hemorrhage in dextrose-treated animals; however, it restored the AVP response during AAI. These results indicate that AAI impairs the AVP response to hemorrhage, while not affecting the response to hyperosmolality. Furthermore, these data demonstrate that the attenuated AVP response to hemorrhage is the result of augmented central NO inhibition.

scholarly journals Involvement of tumor necrosis factor-α in natriuretic response to systemic infusion of nitric oxide synthase inhibitor in anesthetized mice

2010 ◽  
Vol 299 (1) ◽  
pp. F217-F224 ◽  
Author(s):  
Mohd Shahid ◽  
Joseph Francis ◽  
Khalid Matrougui ◽  
Dewan S. A. Majid
Keyword(s):  
Nitric Oxide ◽  
Kidney Tissue ◽  
No Synthase ◽  
Nitric Oxide Synthase Inhibitor ◽  
Renal Vasoconstriction ◽  
Tnf Α ◽  
Synthase Inhibitor ◽  
Factor Α ◽  
Oxide Synthase ◽  
Renal Responses

Systemic infusion of TNF-α exerts renal vasoconstriction but caused marked natriuresis in mice. Similar renal responses were also observed during systemic infusion of nitric oxide (NO) synthase inhibitors as opposed to their usual antinatriuretic responses when administered intrarenally. In the present study, we examined the hypothesis that acute NO blockade systemically induces TNF-α generation. which induces this natriuretic response. Renal responses to intravenous infusion of the NO synthase inhibitor nitro-l-arginine methyl ester (l-NAME; 0.2 μg·min−1·g body wt−1 for 85 min) and its impact on the plasma level of TNF-α were evaluated in anesthetized mice. Plasma TNF-α was undetected in untreated mice ( n = 7) but was elevated in l-NAME-treated mice (109 ± 22 pg/ml; P < 0.01 vs. untreated group; n = 7) along with an increase in TNF-α protein expression in kidney tissue. l-NAME infusion caused a usual increase in mean arterial pressure (MAP; 98 ± 3 to 122 ± 3 mmHg; P < 0.01) and decreases in renal blood flow (RBF; 8.6 ± 0.3 to 4.4 ± 0.2 ml·min−1·g−1; P < 0.01) and glomerular filtration rate (GFR; 1.14 ± 0.07 to 0.77 ± 0.04 ml·min−1·g−1; P < 0.01) with a marked increase in sodium excretion (UNaV; 0.48 ± 0.10 to 3.52 ± 0.85 μmol·min−1·g−1; P < 0.01). Interestingly, in mice ( n = 7) pretreated with the TNF-α blocker etanercept (5 mg/kg sc), the UNaV response to l-NAME infusion was markedly blunted (0.58 ± 0.08 to 1.22 ± 0.28 μmol·min−1·g−1; P = NS) although responses for MAP, RBF, and GFR were mostly unchanged. However, pretreatment with the superoxide scavenger tempol in mice ( n = 7) did not alter the UNaV response to l-NAME. These data demonstrate that l-NAME-induced natriuresis is mediated, at least in part, by concomitant generation of TNF-α during NO blockade.

Superoxide mediates acute renal vasoconstriction produced by angiotensin II and catecholamines by a mechanism independent of nitric oxide

2007 ◽  
Vol 292 (1) ◽  
pp. H83-H92 ◽  
Author(s):  
Armin Just ◽  
Andrea J. M. Olson ◽  
Christina L. Whitten ◽  
William J. Arendshorst
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Vascular Remodeling ◽  
Oxygen Species ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Adrenergic Agonist ◽  
Renal Vasoconstriction ◽  
Sprague Dawley Rats

NAD(P)H oxidases (NOX) and reactive oxygen species (ROS) are involved in vasoconstriction and vascular remodeling during hypertension produced by chronic angiotensin II (ANG II) infusion. These effects are thought to be mediated largely through superoxide anion (O2−) scavenging of nitric oxide (NO). Little is known about the role of ROS in acute vasoconstrictor responses to agonists. We investigated renal blood flow (RBF) reactivity to ANG II (4 ng), norepinephrine (NE, 20 ng), and α1-adrenergic agonist phenylephrine (PE, 200 ng) injected into the renal artery (ira) of anesthetized Sprague-Dawley rats. The NOX inhibitor apocynin (1–4 mg·kg−1·min−1 ira, 2 min) or the superoxide dismutase mimetic Tempol (1.5–5 mg·kg−1·min−1 ira, 2 min) rapidly increased resting RBF by 8 ± 1% ( P < 0.001) or 3 ± 1% ( P < 0.05), respectively. During NO synthase (NOS) inhibition ( Nω-nitro-l-arginine methyl ester, 25 mg/kg iv), the vasodilation tended to increase (apocynin 13 ± 4%, Tempol 10 ± 1%). During control conditions, both ANG II and NE reduced RBF by 24 ± 4%. Apocynin dose dependently reduced the constriction by up to 44% ( P < 0.05). Similarly, Tempol blocked the acute actions of ANG II and NE by up to 48–49% ( P < 0.05). In other animals, apocynin (4 mg·kg−1·min−1 ira) attenuated vasoconstriction to ANG II, NE, and PE by 46–62% ( P < 0.01). During NOS inhibition, apocynin reduced the reactivity to ANG II and NE by 60–72% ( P < 0.01), and Tempol reduced it by 58–66% ( P < 0.001). We conclude that NOX-derived ROS substantially contribute to basal RBF as well as to signaling of acute renal vasoconstrictor responses to ANG II, NE, and PE in normal rats. These effects are due to O2− rather than H2O2, occur rapidly, and are independent of scavenging of NO.

Exercise-stimulated glucose transport in skeletal muscle is nitric oxide dependent

1997 ◽  
Vol 273 (1) ◽  
pp. E220-E225 ◽  
Author(s):  
C. K. Roberts ◽  
R. J. Barnard ◽  
S. H. Scheck ◽  
T. W. Balon
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Glucose Transport ◽  
Acute Exercise ◽  
Treadmill Running ◽  
Sprague Dawley ◽  
Nitric Oxide Synthase Inhibitor ◽  
Transport Pathways ◽  
Sprague Dawley Rats ◽  
Synthase Inhibitor

It has been suggested that there are separate insulin-stimulated and contraction-stimulated glucose transport pathways in skeletal muscle. This study examined the effects of nitric oxide on glucose transport in rat skeletal muscle by use of an isolated sarcolemmal membrane preparation and the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), administered in the drinking water (1 mg/ml). Female Sprague-Dawley rats were divided into five groups: control, acute exercise, acute exercise+L-NAME, insulin stimulated, and insulin stimulated+L-NAME. Exercise (45 min of exhaustive treadmill running) increased glucose transport (37 +/- 2 to 76 +/- 5 pmol.mg-1.15 s-1) and this increase was completely inhibited by L-NAME (40 +/- 4 pmol.mg-1.15 s-1). A maximum dose of insulin increased glucose transport (87 +/- 10 pmol.mg-1.15 s-1), and adding L-NAME had no effect (87 +/- 11 pmol.mg-1.15 s-1). In addition, exercise, but not exercise+L-NAME, increased sarcolemma GLUT-4 content. This study confirms that there are separate pathways for contraction- and insulin-stimulated glucose transport. More importantly, although exercise and insulin both significantly increased glucose transport, L-NAME had no effect on insulin-stimulated glucose transport but blocked the exercise-stimulated transport. We conclude that nitric oxide is involved in the signal transduction mechanism to increase glucose transport during exercise.

scholarly journals Endothelial cell-derived nitric oxide mobilization is attenuated in copper-deficient rats

2008 ◽  
Vol 33 (6) ◽  
pp. 1073-1078 ◽  
Author(s):  
Jeff C. Falcone ◽  
David Lominadze ◽  
W. Thomas Johnson ◽  
Dale A. Schuschke
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelium ◽  
No Production ◽  
Sprague Dawley ◽  
Deficient Diet ◽  
Fluorescent Intensity ◽  
Consistent Finding ◽  
Cu Deficiency ◽  
Sprague Dawley Rats ◽  
Series Of Experiments

The attenuation of endothelium-dependent nitric oxide (NO) mediated vasodilation is a consistent finding in both conduit and resistance vessels during dietary copper (Cu) deficiency. Although the effect is well established, evidence for the mechanism remains circumstantial. This study was designed to determine the relative amount of NO produced in and released from the vascular endothelium. Using the fluorescent NO indicator, 4-amino-5-methylamino-2′,7′-difluorofluorescein (DAF-FM), we now demonstrate the effect of a Cu-deficient diet on the production of NO from the endothelium of resistance arterioles. In one group of experiments, control and Cu-chelated lung microvascular endothelial cells (ECs) were used to assay NO production and fluorescence was observed by confocal microscopy. Weanling Sprague–Dawley rats were fed purified diets that were either Cu adequate (6.3 micrograms Cu per gram of food) or Cu deficient (0.3 micrograms Cu per gram of food) for 4 weeks. In the second series of experiments, first-order arterioles were microsurgically isolated from the rat cremaster muscle, cannulated, and pressurized with (3[N-morpholino]propanesulfonic acid) physiologic salt solution (MOPS-PSS). DAF-FM (5 µmol·L–1) was added in the lumen of the vessel to measure NO release. Baseline DAF-FM fluorescence was significantly lower in Cu-chelated ECs than in controls. In response to 10−6 mol·L–1 acetylcholine, fluorescent intensity was significantly less in chelated ECs and in the lumen of Cu-deficient arterioles. The results suggest that production and release of NO by the vascular endothelium is inhibited by a restriction of Cu. This inhibition may account for the attenuated vasodilation previously reported in Cu-deficient rats.

scholarly journals Large BP-dependent and -independent differences in susceptibility to nephropathy after nitric oxide inhibition in Sprague-Dawley rats from two major suppliers

2012 ◽  
Vol 302 (1) ◽  
pp. F173-F182 ◽  
Author(s):  
Karen Griffin ◽  
Aaron Polichnowski ◽  
Hector Licea-Vargas ◽  
Maria Picken ◽  
Jianrui Long ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Linear Regression Analysis ◽  
Sprague Dawley ◽  
Glomerular Injury ◽  
Renal Vasoconstriction ◽  
Renal Autoregulation ◽  
Sprague Dawley Rats ◽  
The Relationship ◽  
Dose Dependent

The Nω-nitro-l-arginine methyl ester (l-NAME) model is widely employed to investigate the role of nitric oxide (NO) in renal injury. The present studies show that Sprague-Dawley rats from Harlan (H) and Charles River (CR) exhibit strikingly large differences in susceptibility to l-NAME nephropathy. After 4 wk of l-NAME (∼50 mg·kg−1·day−1 in drinking water), H rats ( n = 13) exhibited the expected hypertension [average radiotelemetric systolic blood pressure (BP), 180 ± 3 mmHg], proteinuria (136 ± 17 mg/24 h), and glomerular injury (GI) (12 ± 2%). By contrast, CR rats developed less hypertension (142 ± 4), but surprisingly no proteinuria or GI, indicating a lack of glomerular hypertension. Additional studies showed that conscious H, but not CR, rats exhibit dose-dependent renal vasoconstriction after l-NAME. To further investigate these susceptibility differences, l-NAME was given 2 wk after 3/4 normotensive nephrectomy (NX) and comparably impaired renal autoregulation in CR-NX and H-NX rats. CR-NX rats, nevertheless, still failed to develop proteinuria and GI despite moderate hypertension (144 ± 2 mmHg, n = 29). By contrast, despite an 80–90% l-NAME dose reduction and lesser BP increases (169 ± 4 mmHg), H-NX rats ( n = 20) developed greater GI (26 ± 3%) compared with intact H rats. Linear regression analysis showed significant ( P < 0.01) differences in the slope of the relationship between BP and GI between H-NX (slope 0.56 ± 0.14; r = 0.69; P < 0.008) and CR-NX (slope 0.09 ± 0.06; r = 0.29; P = 0.12) rats. These data indicate that blunted BP responses to l-NAME in the CR rats are associated with BP-independent resistance to nephropathy, possibly mediated by a resistance to the renal (efferent arteriolar) vasoconstrictive effects of NO inhibition.

Sign in / Sign up

Export Citation Format

Share Document