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Cisplatin is a chemotherapeutic agent used for treating solid tumors. However, nephrotoxicity is the dose-limiting factor in its clinical use. The present study was aimed to determine whether altered regulation of the local nitric oxide (NO) and natriuretic peptide (NP) systems is involved in the pathogenesis of cisplatin-induced nephropathy. Cisplatin (6 mg/kg) was injected intraperitoneally into male Sprague-Dawley rats. The control group was not treated with cisplatin. Expression levels of nitric oxide synthase (NOS), nitrotyrosine, soluble guanylyl cyclase and neutral endopeptidase (NEP) in the kidneys were determined 4 days after treatment by semiquantitative immunoblotting. mRNA expression of NPs and natriuretic peptide receptors (NPRs) was determined by real-time polymerase chain reaction. The activities of soluble and particulate guanylyl cyclase were determined by measuring the amount of cyclic 3',5'-guanosine monophosphate (cGMP) generated in responses to sodium nitroprusside and atrial natriuretic peptide (ANP), respectively. In the test rats, creatinine clearance was decreased, while sodium and water excretion were increased. The expression of inducible NOS (iNOS) and nitrotyrosine was increased in the cortex/outer stripe of outer medullar and inner medullar, while that of endothelial and neuronal NOS was decreased in the inner medullar. Excretion of NO metabolites was increased in these rats. The catalytic activity of soluble guanyly cyclase was blunted in the papilla after cisplatin was administered. The mRNA expression of ANP, brain natriuretic peptide, and C-type natriuretic peptide was increased, while that of NPR-A and NPR-C were decreased in the test rats. The catalytic activity of soluble and particulate guanylyl cyclase in the papilla was blunted after cisplatin was administered. In conclusion, increased production of NO by iNOS may contribute to cytotoxic injury, resulting in cisplatin-induced nephropathy, while the up-regulation of renal natriuretic peptide synthesis together with the down-regulation of NEP and NPR-C may contribute to the natriuresis and diuresis seen in cisplatin-induced nephropathy., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The present study was aimed to determine whether there is an altered role of local nitric oxide (NO) and atrial natriuretic peptide (ANP) systems in the kidney in association with the angiotensin (Ang) II-induced hypertension. Male Sprague-Dawley rats were used. Ang II (100 ng·min⁻¹·kg⁻¹) was infused through entire time course. Thirteenth day after beginning the regimen, kidneys were taken. The protein expression of NO synthase (NOS) and nitrotyrosine was determined by semiquantitative immunoblotting. The mRNA expression of components of ANP system was determined by real-time polymerase chain reaction. The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and ANP, respectively. There developed hypertension and decreased creatinine clearance in the experimental group. The protein expression of eNOS, nNOS and nitrotyrosine was increased in the cortex, while that of iNOS remained unaltered. The urinary excretion of NO increased in Ang II-induced hypertensive rats. The catalytic activity of soluble guanylyl cyclase was blunted in the glomerulus in Ang II-induced hypertensive rats. The mRNA expression of ANP was increased in Ang II-induced hypertensive rats. Neither the expression of NPR-A nor that of NPR-C was changed. The protein expression of neutral endopeptidase was decreased and the activity of particulate guanylyl cyclase was blunted in the glomerulus and papilla in Ang II-induced hypertensive rats. In conclusion, the synthesis of NO and ANP was increased in the kidney of Ang II-induced hypertension, while stimulated cGMP response was blunted. These results suggest desensitization of guanylyl cyclase in the kidney of Ang II-induced hypertensive rats, which may contribute to the associated renal vasoconstriction and hypertension., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The present study was aimed to determine whether there is an altered role of local nitric oxide (NO), atrial natriuretic peptide (ANP) and cyclooxygenase (COX) systems in the kidney in association with the aldosterone escape. Male Sprague-Dawley rats were used. Aldosterone (200 microg/day) was infused through entire time course. The control group was kept on a low sodium diet (0.02 mEq/day), and the experimental group was supplied with a higher sodium diet (2. /day). Four days after beginning the regimen, the kidneys were taken. The protein expression of NO synthase (NOS) and COX isoforms was determined by semiquantitative immunoblotting. The mRNA expression of components of ANP system was determined by real-time polymerase chain reaction. The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and ANP, respectively. There developed aldosterone escape in the experimental group. Accordingly, the renal content and the urinary excretion of NO increased. The expression of nNOS was increased in the inner medulla. Neither the expression of eNOS nor that of iNOS was changed. The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered. The mRNA expression of ANP was increased. Neither the expression of NPR-A or NPR-C nor the activity of particulate guanylyl cyclase was altered in the papilla. The protein expression of COX-2 was increased in the inner medulla, while that of COX-1 remained unchanged. In conclusion, the upregulation of nNOS, ANP, and COX-2 may be causally related with the aldosterone escape.

Background: Effects of gentamicin (GM) on the local natriuretic peptide (NP) and nitric oxide (NO) systems in the kidney were investigated., Methods: Male Sprague-Dawley rats (180-200 g) were intramuscularly injected with GM (100 mg/kg/day) for 5 days. The expression of NO synthase (NOS) isoforms was determined by Western blot analysis, and that of NPs by real-time polymerase chain reaction. The activity of guanylyl cyclase was also determined by the amount of guanosine 3',5'-cyclic monophosphate (cGMP) generated in responses to atrial natriuretic peptide (ANP) or sodium nitroprusside (SNP)., Results: GM treatment resulted in renal failure in association with increases in urinary flow and the fractional excretion of sodium. Accordingly, the expression of inducible NOS was increased in the cortex, while that of endothelial NOS remained unchanged. The urinary excretion of NO metabolites was increased. The expression of ANP, brain natriuretic peptide and C-type natriuretic peptide mRNA was increased in the kidney. The cGMP production provoked by either ANP or SNP was decreased in the glomerulus, but not in the papilla., Conclusion: GM-induced nephropathy may be causally related with decreased guanylyl cyclase activities in the glomerulus.

The present study was aimed at investigating whether the regulation of vascular renin-angiotensin and endothelin (ET) systems is altered by a chronic blockade of nitric oxide (NO) synthesis. Male Sprague-Dawley rats were supplemented with N(G)-nitro-L-arginine methyl ester (L-NAME, 100mgl(-1)) in drinking water for 4 weeks to inhibit the endogenous synthesis of NO. The mRNA expressions of renin, angiotensin converting enzyme (ACE), type-1 angiotensin II receptor (AT1R), ET-1, type-A ET receptor (ET(A)), and neutral endopeptidase (NEP) were determined in the thoracic aorta by reverse transcription-polymerase chain reaction. The treatment with L-NAME significantly increased the blood pressure, while it decreased the tissue levels of nitrite/nitrate. The mRNA expression of renin, ACE, and AT1R was increased in the aorta. The protein expression of AT1R assessed by Western blot analysis was also increased. The expression of ET-1 and ET(A) mRNA was increased, whereas that of NEP mRNA decreased. The increased expression of renin-angiotensin and ET system genes and the decreased expression of NEP may in part be causally related with the development of hypertension induced by a chronic blockade of NO synthesis.

1. The effects of volume depletion and NaHCO3 loading on the expression of Na+/H+ exchanger isoform 3 (NHE3), Na+ : cotransporter type 1 (NBC1) and neuronal (n) and inducible (i) isoforms of nitric oxide synthase (NOS) were determined in rat kidney. 2. Adult male Sprague-Dawley rats were used. Rats were divided into four groups: (i) euvolaemic (EC); (ii) hypovolaemic (HC); (iii) euvolaemia with NaHCO3 loading (EB); and (iv) hypovolaemia with NaHCO3 loading (HB). The expression of NHE3, NBC1, nNOS and iNOS proteins was determined in the cortex of the kidney by immunoblotting and immunohistochemistry. Tissue content of nitric oxide (NO) metabolites (NOx) were also determined in the cortex using a colourimetric assay. 3. Compared with the EC group, the expression of NHE3 and NBC1 was increased in the HC group and decreased in the EB group. Comparing the EB and HB groups, the expression of NHE3 and NBC1 was higher in the latter group. The expression of NHE3 was decreased and that of NBC1 was increased in the HB group compared with the HC group. The NOx content and nNOS expression were decreased in the hypovolaemic (HC) and NaHCO3-loaded (EB and HB) rats. Moreover, the expression of iNOS was decreased in the HB group compared with the other groups. 4. An altered volume status and NaHCO3 loading may affect the regulation of NHE3 and NBC1 in the kidney and the endogenous NO system may play a role in the observed effects. [ABSTRACT FROM AUTHOR]

1. Effects of non-steroidal anti-inflammatory drugs on the local atrial natriuretic peptide (ANP) and nitric oxide (NO) systems in the kidney were investigated. 2. Male Sprague-Dawley rats were treated with indomethacin (5 mg/kg, every 12 h, i.p.) for 2 days. The expression of ANP and natriuretic peptide receptor-A (NPR-A) mRNA was determined in the kidney, as was that of endothelial NO synthase (NOS) proteins. Particulate and soluble guanylyl cyclase activities were determined separately. 3. Following treatment with indomethacin, urinary sodium excretion decreased significantly. Although the renal expression of ANP was not changed significantly, that of NPR-A decreased significantly. The expression of NOS increased significantly. Particulate guanylyl cyclase activity was decreased, whereas the activity of soluble guanylyl cyclase was increased. The catalytic activity of Na+/K+-ATPase was increased, with no significant changes in its expression. The expression of the type 3 Na/H exchanger and Na–K−2CL cotransporters increased significantly. 4. The indomethacin-induced decrease in urinary sodium excretion may be attributed, at least in part, to decreased activity of the local ANP/cGMP system. The increased activity of the NO/cGMP system may be a compensatory response to the diminished activity of the prostaglandin system. [ABSTRACT FROM AUTHOR]

SUMMARY 1. The aim of the present study was to explore the mechanisms underlying the renal effects of caffeine. 2. Male Sprague-Dawley rats were treated with caffeine, consisting of a single oral bolus (0.2%, 20 mL/kg) followed by supplementation in drinking water (0.2%) for 1 day. Rats treated the same but given water without caffeine served as controls. 3. The expression of α 1- and β 1-subunits of Na+ /K+ -ATPase, the type 3 Na+ /H+ exchanger (NHE3) and aquaporin-1 was determined in the kidney by western blot analysis. 4. To explore possible involvement of local humoral mediators, the tissue expression of nitric oxide synthase (NOS) proteins was determined by western blot analysis and the expression of atrial natriuretic peptide (ANP) mRNA was determined by semiquantitative reverse transcription–polymerase chain reaction. 5. Following treatment with caffeine, the expression of α 1- and β 1-subunits of Na+ /K+ -ATPase, as well as that of NHE3, was decreased. Accordingly, the catalytic activity of Na+ /K+ -ATPase was decreased. In contrast, the expression of aquaporin-1 was not altered significantly. 6. The expression of the endothelial isoform of NOS was increased, along with tissue nitrite/nitrate levels. The expression of ANP mRNA was increased. 7. It is suggested that caffeine decreases Na+ /K+ -ATPase and NHE3 activities and increases nitric oxide and ANP activities in the kidney. [ABSTRACT FROM AUTHOR]

Background. Cyclosporin (CsA)-induced vascular dysfunction has been attributed to a diminished role of the nitric oxide (NO)/cGMP-mediated vasodilator mechanism. The present study was aimed at investigating whether l-arginine, the substrate of NO synthesis, ameliorates CsA-induced vascular dysfunction. [ABSTRACT FROM PUBLISHER]