nitrophenols and Proteinuria

Efonidipine, a dihydropirydine calcium channel blocker, has been shown to dilate the efferent glomerular arterioles as effectively as the afferent arterioles. The present study compared the chronic effects of efonidipine and amlodipine on proteinuria in patients with chronic glomerulonephritis. The study subjects were 21 chronic glomerulonephritis patients presenting with spot proteinuria greater than 30 mg/dL and serum creatinine concentrations of or=130/85 mmHg. Efonidipine 20-60 mg twice daily and amlodipine 2.5-7.5 mg once daily were given for 4 months each in a random crossover manner. In both periods, calcium channel blockers were titrated when the BP exceeded 130/85 mmHg. Blood sampling and urinalysis were performed at the end of each treatment period. The average blood pressure was comparable between the efonidipine and the amlodipine periods (133+/-10/86+/-5 vs. 132+/-8/86+/-5 mmHg). Urinary protein excretion was significantly less in the efonidipine period than in the amlodipine period (1.7+/-1.5 vs. 2.0+/-1.6 g/g creatinine, p=0.04). Serum albumin was significantly higher in the efonidipine period than the amlodipine period (4.0+/-0.5 vs. 3.8+/-0.5 mEq/L, p=0.03). Glomerular filtration rate was not significantly different between the two periods. Plasma aldosterone was lower in the efonidipine period than in the amlodipine period (52+/-46 vs. 72+/-48 pg/mL, p=0.009). It may be concluded that efonidipine results in a greater reduction of plasma aldosterone and proteinuria than amlodipine, and that these effects occur by a mechanism independent of blood pressure reduction. A further large-scale clinical trial will be needed in order to apply the findings of this study to the treatment of patients with renal disease.

Topics: Adult; Aged; Aldosterone; Amlodipine; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Chronic Disease; Cross-Over Studies; Dihydropyridines; Female; Glomerulonephritis; Humans; Male; Middle Aged; Nitrophenols; Organophosphorus Compounds; Proteinuria

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

Angiotensin receptor blockers (ARBs) or T- and L-type calcium channel blockers (CCBs) are useful for glomerular protection; however, the protective effects of combination therapy remain unclear. In this study, Dahl salt-sensitive rats were fed a high-salt diet and were treated daily with placebo, irbesartan (60 mg kg(-1)), efonidipine (30 mg kg(-1)), irbesartan (60 mg kg(-1))+efonidipine (30 mg kg(-1)), amlodipine (3 mg kg(-1)), or irbesartan (60 mg kg(-1))+amlodipine (3 mg kg(-1)) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan-, efonidipine- and amlodipine-treated groups compared with the placebo-treated group; a further significant reduction was seen in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group. Compared with the placebo-treated group, proteinuria was significantly lower in the irbesartan- and efonidipine-treated groups, but not in the amlodipine-treated group. Furthermore, a significant attenuation of proteinuria in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group was observed; this effect was not observed in the irbesartan+amlodipine-treated group. The glomerulosclerosis index was significantly attenuated by all active treatments except amlodipine. The glomerulosclerosis index in the irbesartan+efonidipine-treated group, but not in the irbesartan+amlodipine-treated group, was significantly lower than that in the irbesartan-treated group. Significant attenuations of gene expressions of p22(phox), transforming growth factor-beta, monocyte chemoattractant protein-1 and collegen I were observed in the irbesartan- and efonidipine-treated groups, but not in the amlodipine-treated group. Values for these parameters were reduced to control levels in the irbesartan+efonidipine-treated group. Combination therapy with ARB and T- and L-type CCB might produce a powerful renal protective effect.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Chemokine CCL2; Collagen Type I; Dihydropyridines; Drug Therapy, Combination; Gene Expression; Glomerulosclerosis, Focal Segmental; Hypertension; Irbesartan; Kidney Glomerulus; Male; NADPH Oxidases; Nitrophenols; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred Dahl; Tetrazoles; Transforming Growth Factor beta

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

1. To obtain some insight into the renoprotective mechanism of the new calcium antagonist efonidipine hydrochloride, we evaluated the acute effects of efonidipine on proteinuria, glomerular haemodynamics and the tubuloglomerular feedback (TGF) mechanism in anaesthetized 24-25-week-old spontaneously hypertensive rats (SHR) with glomerular injury. 2. Efonidipine infusion at 10 micrograms/kg per h following a bolus dose of 10 micrograms/kg, i.v., reduced systemic blood pressure (BP) and renal vascular resistance, whereas renal plasma flow (RPF), glomerular filtration rate (GFR), filtration fraction, urine volume and urinary sodium excretion were unaltered. Urinary protein excretion was clearly diminished from 163 +/- 25 to 105 +/- 24 ng/min per g kidney weight. 3. Micropuncture experiments revealed that the maximal reduction of proximal stop-flow pressure (SFP), an index of glomerular capillary pressure (Pgc), induced by loop of Henle perfusion was significantly less with efonidipine treatment (6.7 +/- 1.0% of SFP with no loop flow) than in control (23.8 +/- 3.1%). In the presence of efonidipine, SFP at half-maximal reduction (SFP1/2max), which approximates Pgc at the in vivo steady state tubular flow rate, remained unchanged compared with control (36.9 +/- 0.8 vs 35.3 +/- 0.7 mmHg, respectively) and the slope of dependency on mean BP was not different between control and efonidipine. 4. These results indicate that efonidipine attenuates the TGF response in SHR by dilating the afferent arteriole, thus maintaining the level of RPF and GFR despite reduced renal perfusion pressure. Constant GFR and SFP1/2max under efonidipine suggest that single nephron GFR and Pgc remain unaltered and that a marked reduction in proteinuria is achieved without changes in single nephron GFR or Pgc of superficial nephrons.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Glomerular Filtration Rate; Kidney; Kidney Glomerulus; Kidney Tubules, Proximal; Male; Nitrophenols; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred SHR; Renal Circulation

We investigated the effects of a calcium antagonist, efonidipine, which was reported to dilate not only afferent arterioles but also efferent alterioles, on progression of renal failure in salt-loaded partially nephrectomized spontaneously hypertensive rats (SHR). Forty-four SHR's with 5 of 6 nephrectomy were divided into four groups: group 1 as control (n=20); group 2, efonidipine-treated (n=8); group 3, enalapril-treated (n=8); and group 4, nifedipine-treated (n=8). The rats were given these drugs and a high-salt diet (5% NaCl) for 8 weeks. During the experiment, systolic blood pressure (SBP) and daily urinary protein excretion were measured every 2 weeks. At the end of the study, serum creatinine was determined, and renal tissues were obtained for light microscopic examination. SBP was markedly reduced by 8-week antihypertensive treatment. (control, 267+/-7 mmHg; efonidipine, 181+/-7 mmHg; enalapril, 200+/-12 mmHg; nifedipine, 184+/-6 mmHg). Glomerular sclerosis developed markedly in the control group, but was partially prevented in all treated groups. Similarly, urinary protein excretion (UPE) was suppressed by efonidipine (180+/-16 mg/day) and enalapril (186+/-16 mg/day vs. 301+/-28 mg/day for control). In contrast, nifedipine failed to prevent the increase in urinary protein excretion (258+/-22 mg/day). In conclusion, efonidipine attenuates SBP increase and ameliorates glomerular injury as well as nifedipine and enalapril. Furthermore, beneficial effects of efonidipine, but not nifedipine, on proteinuria suggest that different mechanisms mediate the improvement of proteinuria; one possible mechanism could be efferent arteriolar dilation, not reported in nifedipine.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Progression; Hypertension; Kidney; Male; Nephrectomy; Nitrophenols; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred SHR; Systole

Previous studies have shown that antihypertensive drugs attenuate the progression of proteinuria by their treatments from young age, but few have examined their effects on impaired renal function in older age. In the present study the calcium antagonists efonidipine ((+/-)-2-[benzyl (phenyl)amino]ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3, 2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-pyridinecarboxyla te hydrochloride ethanol, CAS 111011-76-8, NZ-105) and nicardipine, and an angiotensin-converting enzyme inhibitor, captopril, were examined for their effects on heavy proteinuria in aged spontaneously hypertensive rats (SHR). Efonidipine (20 mg/kg), nicardipine (20 mg/kg) and captopril (30 mg/kg) were orally administered once a day for 4 weeks. The urinary protein excretion (UproE) increased with age (54.9 mg/kg/day at 24 weeks of age to 170.8 mg/kg/day at 36 weeks). The increased UproE was significantly suppressed by daily administration of efonidipine or captopril as compared to that in the non drug treated control group. The UproE in the nicardipine group was maintained at a slightly lower level than in the control. The histological examination showed that the damages of the kidneys were slightly suppressed by efonidipine and captopril. These findings indicate that efonidipine as well as captopril reduce proteinuria in aged SHR and the effect was stronger than that of nicardipine. This beneficial effect of efonidipine on proteinuria suggests its usefulness in antihypertensive therapy.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Calcium Channel Blockers; Captopril; Creatinine; Dihydropyridines; Heart Rate; Hypertension; Kidney; Male; Nicardipine; Nitrophenols; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred SHR

1. We investigated the renal protective effect of efonidipine hydrochloride (NZ-105) in spontaneously hypertensive rats (SHR). SHR were given a diet containing 0.075% NZ-105 from 8 weeks old for 20 weeks. 2. 24-hr urinary protein excretion in the control SHR (drug-free diet) increased with age (from 77.3 mg/kg/day at 8 weeks old to 385.4 mg/kg/day at 28 weeks old), while that in NZ-105-treated SHR was maintained at almost the same level as that in Wistar-Kyoto rats (WKY), matched control animals throughout the experimental period. 3. The histological changes of the kidney were examined by light microscopy at the end of the treatment period. In control SHR, swelling and hyalinization of glomeruli, dilatation of renal tubules containing hyaline casts and arteriolosclerosis were revealed. The long-term administration of NZ-105 markedly suppressed these changes. 4. The kidney weights and plasma creatinine concentration in control SHR were higher than those in WKY, while they were significantly reduced in NZ-105-treated SHR. The long-term administration of NZ-105 also suppressed the elevation of systolic blood pressure and the increases of plasma renin activity and aldosterone concentration. 5. These findings suggest that NZ-105 inhibits the development of proteinuria and progressive kidney damage in SHR and may become a useful antihypertensive drug with the renal protective effect.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Hypertension; Kidney; Male; Nitrophenols; Organ Size; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Enzymes; Galactosidases; Glucosephosphate Dehydrogenase; Glucuronates; Glucuronidase; Glutamate Dehydrogenase; Hexosaminidases; Hydro-Lyases; Isocitrate Dehydrogenase; Ketoglutaric Acids; Kidney; Kidney Tubules; L-Lactate Dehydrogenase; Male; NAD; NADP; Nitrophenols; Proteinuria; Pyruvate Kinase; Pyruvates; Rats; Serum Albumin, Bovine

Topics: Alkaline Phosphatase; Antigen-Antibody Reactions; Antitoxins; Blood; Histocytochemistry; Kidney Glomerulus; Nitrophenols; Proteinuria; Rats; Research; Spectrophotometry; Toxicology; Toxins, Biological

Topics: Animals; Dinitrophenols; Dogs; Humans; Kidney; Nitrophenols; Proteinuria; Renal Artery; Urinalysis