nitrophenols and Kidney-Diseases

Voltage-dependent Ca channels are classified into several subtypes based on the isoform of their α1 subunits. Traditional Ca channels blockers (CCBs), including nifedipine and amlodipine, act predominantly on L-type Ca channels, whereas novel CCBs such as efonidipine, benidipine and azelnidipine inhibit both L-type and T-type Ca channels. Furthermore, cilnidipine blocks L-type and N-type Ca channels. These CCBs exert divergent actions on renal microvessels. L-type CCBs preferentially dilate afferent arterioles, whereas both L-/T-type and L-/N-type CCBs potently dilate afferent and efferent arterioles. The distinct actions of CCBs on the renal microcirculation are reflected by changes in glomerular capillary pressure and subsequent renal injury: L-type CCBs favor an increase in glomerular capillary pressure, whereas L-/T-type and L-/N-type CCBs alleviate glomerular hypertension. The renal protective action of L-/T-type CCBs is also mediated by non-hemodynamic mechanisms, i.e., inhibition of the inflammatory process and inhibition of Rho kinase and aldosterone secretion. Finally, a growing body of evidence indicates that T-type CCBs offer more beneficial action on proteinuria and renal survival rate than L-type CCBs in patients with chronic kidney disease (CKD). Similarly, in CKD patients treated with renin-angiotensin blockers, add-on therapy with N-type CCBs is more potent in reducing proteinuria than that with L-type CCBs, although no difference is found in the subgroup with diabetic nephropathy. Thus, the strategy for hypertension treatment with CCBs has entered a new era: treatment selection depends not only on blood pressure control but also on the subtypes of CCBs.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Dihydropyridines; Humans; Kidney Diseases; Nitrophenols; Organophosphorus Compounds

Since conventional Ca(2+) antagonists, with predominant blockade of L-type voltage-dependent Ca(2+) channels, elicit preferential dilation of afferent arterioles, they might ostensibly aggravate glomerular hypertension. Recently, novel Ca(2+) antagonists, with inhibitory action on L-/T-type Ca(2+) channels, have been reported to dilate both afferent and efferent arterioles. The present review attempted to characterize the renal action of these Ca(2+) antagonists and evaluated the consequences following the treatment with these agents. In contrast to conventional Ca(2+) antagonists (e.g., nifedipine), novel antagonists (e.g., benidipine, efonidipine) potently dilated afferent and efferent arterioles; their action on efferent arterioles appeared to be mediated by the T-type Ca(2+) channel blockade, probably through the inhibition of the intracellular Ca(2+) release. The comparison of the anti-proteinuric action in subtotally nephrectomized rats showed that efonidipine exerted more prominent action than nifedipine. Furthermore, Ca(2+) antagonists with T-type Ca(2+) inhibitory action inhibited renin/aldosterone release and proinflammatory process. Finally, patients with chronic renal disease given a 48-week efonidipine treatment showed reduced proteinuria, and this effect was seen even when mean arterial blood pressure failed to become less than 100 mmHg. Collectively, T-type Ca(2+) channel blockade provides beneficial action in renal injury. Various mechanisms serve to protect against renal injury, including systemic/glomerular hemodynamic action and non-hemodynamic mechanisms.

Topics: Animals; Calcium; Calcium Channel Blockers; Calcium Channels, T-Type; Dihydropyridines; Humans; Kidney; Kidney Diseases; Microcirculation; Nitrophenols; Organophosphorus Compounds; Renal Circulation; Signal Transduction

This study evaluated the impact of renal function on cardiovascular outcomes in elderly hypertensive patients enrolled in the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive patients. The patients were randomly assigned to either a strict-treatment group (target systolic blood pressure (BP) <140 mm Hg, n=2212) or a mild-treatment group (target systolic BP, 140 to <160 mm Hg, n=2206), each with efonidipine (a T/L-type Ca channel blocker)-based regimens. Cardiovascular events (stroke, cardiovascular disease and renal disease) were evaluated during the 2-year follow-up period following the prospective randomized open-blinded end-point method. Estimated glomerular filtration rate (eGFR) was elevated throughout the trial period in both the strict-treatment (59.4-62 ml min⁻¹ per 1.73 m²) and the mild-treatment group (58.8-61.4 ml min⁻¹ per 1.73 m²). This tendency was also observed in diabetic patients and patients aged ≥75 years, with baseline eGFR<60 ml min⁻¹ per 1.73 m². Baseline eGFR (<60 vs. ≥60 ml min⁻¹ per 1.73 m²) had no definite relationship with the incidence of cardiovascular events, nor did the level of BP control. Proteinuria at the time of entry into the study, however, was significantly correlated with cardiovascular event rates (7.1%), an association that was more apparent in patients with eGFR<60 ml min⁻¹ per 1.73 m² (8.2%). Furthermore, the event rate was more elevated in patients with greater declines in eGFR and was amplified when the baseline eGFR was <60 ml min⁻¹ per 1.73 m². In conclusion, the rates of decline of renal function and proteinuria constitute critical risk factors for cardiovascular events in elderly hypertensive patients, trends that are enhanced when baseline eGFR is diminished. Furthermore, the fact that efonidipine-based regimens ameliorate renal function in elderly hypertensive patients with chronic kidney disease may offer novel information on the mechanisms of cardiovascular protection.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Cardiovascular Diseases; Chronic Disease; Dihydropyridines; Female; Humans; Hypertension; Kidney; Kidney Diseases; Male; Nitrophenols; Organophosphorus Compounds; Prospective Studies

Although several lines of recent studies fail to demonstrate the beneficial action of calcium antagonists, a novel dihydropyridine efonidipine, which possesses dilatory action of both afferent and efferent arterioles and, therefore, shares the renal microvascular action with angiotensin converting enzyme (ACE) inhibitors, is reported to exhibit renal protection in experimental animals. The present study evaluated the effect of efonidipine and ACE inhibitors on blood pressure (BP) and proteinuria. Sixty-eight hypertensive patients with renal impairment (serum creatinine, >1.5 mg/dL) or chronic renal parenchymal disease were randomly assigned to efonidipine or ACE inhibitor treatment. Of the 68 patients, 23 were treated with efonidipine and 20 with ACE inhibitors; these patients were analyzed for the 48-week study. Both efonidipine and ACE inhibitors produced a similar degree of reductions in BP (efonidipine, from 161 +/- 2/93 +/- 2 to 142 +/- 5/82 +/- 2 mm Hg; ACE inhibitor, from 163 +/- 3/95 +/- 2 to 141 +/- 5/83 +/- 2 mm Hg), and maintained creatinine clearance for 48 weeks. Proteinuria tended to decrease in both groups, and a significant reduction was observed in proteinuric patients (>1 g/day) (efonidipine, from 2.7 +/- 0.3 to 2.1 +/- 0.3 g/day; ACE inhibitor, from 3.0 +/- 0.4 to 2.0 +/- 0.5 g/day). Of interest, efonidipine decreased proteinuria in proteinuric patients who failed to manifest decreases in systemic BP. Finally, the incidence of adverse effects, including hyperkalemia and cough, was less in the efonidipine-treated group. Both efonidipine and ACE inhibitors preserved renal function in hypertensive patients with renal impairment. The antiproteinuric effect was apparent in patients with greater proteinuria. The beneficial action of efonidipine, along with fewer side effects, may favor the use of this agent in the treatment of hypertension with renal impairment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Kidney; Kidney Diseases; Male; Middle Aged; Nitrophenols; Organophosphorus Compounds; Proteinuria

Topics: Aged; Antihypertensive Agents; Chronic Disease; Dihydropyridines; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Diseases; Nitrophenols; Organophosphorus Compounds; Proteinuria; Randomized Controlled Trials as Topic

Topics: Aging; Antihypertensive Agents; Chronic Disease; Dihydropyridines; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Diseases; Nitrophenols; Organophosphorus Compounds; Randomized Controlled Trials as Topic

T-type calcium channel blockers have been previously shown to protect glomeruli from hypertension by regulating renal arteriolar tone. To examine whether blockade of these channels has a role in protection against tubulointerstitial damage, we used a stereo-selective T-type calcium channel blocker R(-)-efonidipine and studied its effect on the progression of this type of renal injury in spontaneously hypertensive rats that had undergone subtotal nephrectomy. Treatment with racemic efonidipine for 7 weeks significantly reduced systolic blood pressure and proteinuria. The R(-)-enantiomer, however, had no effect on blood pressure but significantly reduced proteinuria compared to vehicle-treated rats. Both agents blunted the increase in tubulointerstitial fibrosis, renal expression of alpha-smooth muscle actin and vimentin along with transforming growth factor-beta (TGF-beta)-induced renal Rho-kinase activity seen in the control group. Subtotal nephrectomy enhanced renal T-type calcium channel alpha1G subunit expression mimicked in angiotensin II-stimulated mesangial cells or TGF-beta-stimulated proximal tubular cells. Our study shows that T-type calcium channel blockade has renal protective actions that depend not only on hemodynamic effects but also pertain to Rho-kinase activity, tubulointerstitial fibrosis, and epithelial-mesenchymal transitions.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Chronic Disease; Dihydropyridines; Hypertension; Kidney Diseases; Male; Nephrectomy; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Inbred SHR

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is an acute nephrotoxicant in rats. Our previous studies suggested that sulfate conjugation of NDPS metabolites might be a bioactivation step mediating NDPS nephrotoxicity. In this study, effects of substrates and/or inhibitors of sulfation on NDPS nephrotoxicity were examined to explore further the role of sulfation in NDPS nephrotoxicity. Male Fischer rats (4-8/group) were administered one of the following intraperitoneal (ip) pretreatment (dose, pretreatment time) prior to NDPS (0.6 mmol/kg) or NDPS vehicle (sesame oil, 2.5 ml/kg): (1) no pretreatment, (2) dehydroepiandrosterone (DHEA) (0.5 mmol/kg, 1 h), or (3) 2,6-dichloro-4-nitrophenol (DCNP) (0.04 mmol/kg, 1 h). Following NDPS or NDPS vehicle administration, renal function was monitored at 24 and 48 h. Pretreatment with DHEA, a typical substrate for and an inhibitor of hydroxysteroid (alcohol) sulfotransferase, resulted in marked protection against NDPS nephrotoxicity. A selective inhibitor of phenol sulfotransferase, DCNP, afforded little attenuation in NDPS nephrotoxicity. These results suggest that alcohol sulfate conjugates of NDPS metabolites, rather than phenolic sulfate conjugates, may be a penultimate or ultimate nephrotoxicant species mediating NDPS nephrotoxicity. The marked, but not complete, protection by DHEA also suggests that there are other metabolites or mechanisms responsible for NDPS nephrotoxicity.

Topics: Adjuvants, Immunologic; Animals; Biotransformation; Dehydroepiandrosterone; Eating; Fungicides, Industrial; Kidney Diseases; Male; Nitrophenols; Rats; Rats, Inbred F344; Succinimides; Sulfuric Acid Esters

Young adult female Sprague-Dawley (SD) rats are more susceptible to acetaminophen (APAP)-induced nephrotoxicity than are age-matched male SD rats. Mechanisms contributing to sex-dependent APAP nephrotoxicity may involve differences in APAP bioactivation via cytochrome P450-dependent metabolism to N-acetyl-p-benzoquinoneimine and/or deacetylation to para-amino-phenol. APAP bioactivation by oxidation and deacetylation was assessed by examining the effects of 1-aminobenzotriazole (ABT), a suicide substrate inhibitor of cytochrome P450, and bis-(para-nitrophenyl) phosphate (BNPP), a reversible carboxyesterase inhibitor, on covalent binding of APAP-derived radiolabel. Hepatic and renal S9 fractions prepared from naive male and female rats were incubated with [14C-ring]-APAP in the presence and absence of NADPH. There were no sex-related differences in covalent binding of APAP-derived radiolabel in hepatic or renal S9 fractions from male and female rats. In both sexes, incubation of hepatic or renal S9 fractions with 10 mM ABT significantly reduced covalent binding of APAP-derived radiolabel as compared with covalent binding in the absence of ABT. In contrast, incubation of renal and hepatic S9 fractions with 10 mM BNPP did not alter covalent binding of radiolabel derived from APAP in either males or females. Thus, at least in vitro, differences in bioactivation of APAP in liver and kidney from male and female SD rats do not seem to contribute to sex-dependent APAP toxicity. Carboxyesterases inhibited by BNPP do not seem to contribute to covalent binding of APAP-derived radiolabel in vitro in either liver or kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetaminophen; Animals; Biotransformation; Carbon Radioisotopes; Female; Kidney; Kidney Diseases; Liver; Male; Nitrophenols; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Sex Factors; Triazoles

Acetaminophen (APAP) administration (600 mg/kg, po) results in proximal tubular necrosis in 18-hr fasted, 3-month-old male CD-1 mice. This study was undertaken to determine if deacetylation of APAP to p-aminophenol (PAP) is a prerequisite to nephrotoxicity in the mouse, as it is in the Fischer rat. Administration of either APAP or PAP to mice resulted in significant elevations of plasma urea nitrogen and marked proximal tubular necrosis at 12 hr after dosing. Prior inhibition of APAP deacetylation by the carboxylesterase inhibitors bis(p-nitrophenyl) phosphate or tri-o-tolyl-phosphate did not alter APAP hepatotoxicity or nephrotoxicity. By contrast, pretreatment with the MFO inhibitor piperonyl butoxide decreased APAP nephrotoxicity but not that of PAP. Immunochemical analysis of kidneys from APAP-treated mice demonstrated covalently bound APAP but no binding was detected after mice were treated with a nephrotoxic dose of PAP. Since the antibody used has been characterized as being directed primarily against the N-acetyl moiety of bound APAP metabolite and since it did not react with kidney proteins of mice given a nephrotoxic dose of PAP, it is unlikely that APAP deacetylation preceded binding or that acetylation of bound PAP occurred. Taken together, these findings indicate that in the CD-1 mouse, APAP-induced nephrotoxicity differs from that previously described for the Fischer rat and likely involves cytochrome P450-dependent activation and subsequent covalent binding of a metabolite without prior deacetylation.

Topics: Acetaminophen; Acetylation; Aminophenols; Animals; Blood Urea Nitrogen; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Kidney Diseases; Kidney Tubular Necrosis, Acute; Kidney Tubules, Proximal; Male; Mice; Nitrophenols; Piperonyl Butoxide; Proteins; Tritolyl Phosphates

We automated two procedures for determination of urinary N-acetyl-beta-D-glucosaminidase (NAG; EC 3.2.1.30) concentrations and evaluated their reliability for detecting drug-induced tubular damage in children receiving cisplatin, methotrexate, or ifosfamide. Results for 174 patient specimens correlated well (r = 0.98), but NAG concentrations determined by the m-cresolsulfonphthaleinyl (MCP) procedure were about 40% lower than those obtained with p-nitrophenyl-N-acetyl-beta-D-glucosaminide substrate. Dialysis and assay of 50 specimens disclosed no evidence of activators or inhibitors of enzymatic activity. Drugs and metabolites added to urine had negligible effect on NAG determinations; however, NAG was unstable in alkaline urine (pH greater than 8) associated with methotrexate therapy. Both procedures detect tubular damage equally well and neither requires laborious sample treatment. The MCP procedure, being more sensitive and not requiring a sample blank, is better suited for rapid automated assays. Comparisons of clinical data obtained by the two procedures require standardization against human NAG.

Topics: Acetylglucosaminidase; Adolescent; Antineoplastic Agents; Autoanalysis; Child; Child, Preschool; Cresols; Dialysis; Hexosaminidases; Humans; Kidney Diseases; Kidney Tubules; Nitrophenols; Spectrophotometry

The binding of oxazepam and its glucuronide conjugates to human serum albumin (HSA), as well as the binding interactions of the drug and its metabolites, were examined by equilibrium dialysis and kinetic probe studies. Oxazepam and its S(+) glucuronide are bound to the HSA molecule with affinity constants of 3.5 X 10(5) M-1 and 5.5 X 10(4) M-1, respectively, which were independent of protein concentration over a range of 0.1 to 5.0 g/dl. The R(-) glucuronide bound weakly to albumin, with the binding parameter, N X K, increasing at lower albumin concentrations. Pre-acetylation of fatty acid free-HSA resulted in decreased binding of all three compounds, probably by altering the conformation of the binding sites. Kinetic probe studies with p-nitrophenyl acetate indicate that oxazepam and its S(+) glucuronide shared a common binding site on HSA, but that the R(-) glucuronide bound at another site. Oxazepam binding was unaffected by the presence of its glucuronide conjugates but was inhibited by fatty acids. The percentage of oxazepam bound to plasma proteins in patients with renal impairment (94%) was lower than in normal volunteers (97%). This lower binding can neither be attributed to lower albumin concentrations because of the large binding capacity of the protein and linearity of N X K nor to displacement by elevated concentrations of glucuronide conjugates, but it may be ascribed partly to increased plasma fatty acids.

Topics: Glucuronates; Humans; In Vitro Techniques; Kidney Diseases; Nitrophenols; Oxazepam; Protein Binding; Serum Albumin; Stereoisomerism