imidapril and Hypertension--Renal

Left ventricular hypertrophy is considered to be a major cardiovascular risk factor in hemodialysis patients. Not only high blood pressure but also humoral factors such as angiotensin II and aldosterone are thought to contribute to the increase in left ventricular mass. We examined the effects of an angiotensin converting enzyme (ACE) inhibitor, imidapril, on left ventricular mass in patients with end-stage renal diseases on maintenance hemodialysis. Thirty patients on chronic hemodialysis were randomly divided into 2 groups of 15 patients each and given placebo or 2.5 mg imidapril once daily for 6 months. Before and after the 6-month period, left ventricular mass was evaluated by echocardiography, and circulating factors of the renin-angiotensin-aldosterone system were measured. Background characteristics such as age, gender ratio, causes of renal failure, duration of hemodialysis, body mass index and pre-dialysis blood pressure were comparable between the placebo and the imidapril groups. Systolic and diastolic blood pressures were not significantly changed in either group during the study period. In the imidapril group, serum ACE was reduced (12 +/- 1 to 5 +/- 2 U/l, p < 0.01) and plasma renin activity was increased (3.3 +/- 0.8 to 8.1 +/- 3.2 ng/ml/h, p < 0.01), but plasma angiotensin II and aldosterone were not significantly changed after 6 months (13 +/- 3 to 17 +/- 3 pg/ml and 365 +/- 125 to 312 +/- 132 pg/ml, respectively). On the other hand, left ventricular mass index was significantly decreased in the imidapril group (132 +/- 10 to 109 +/- 6 g/m2, p < 0.05) but was unchanged in the placebo group (129 +/- 6 to 126 +/- 5 g/m2). These results suggest that an ACE inhibitor reduces left ventricular mass in hemodialysis patients by a mechanism that is independent of changes in blood pressure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Body Weight; Echocardiography; Female; Humans; Hypertension, Renal; Hypertrophy, Left Ventricular; Imidazolidines; Kidney Failure, Chronic; Male; Middle Aged; Placebos; Renal Dialysis; Treatment Outcome

It has been demonstrated that antihypertensive treatment of hypertensive diabetic patients is quite effective in preventing macrovascular and microvascular complications and improving prognosis. Nevertheless, the target blood pressure level of antihypertensive treatment in hypertensive diabetic patients with microalbuminuria (i.e., with early diabetic nephropathy) remains to be established. In this study, we evaluated the effect of intensive blood pressure control (diastolic blood pressure <80 mmHg) on urinary albumin excretion in hypertensive, type II diabetic patients with microalbuminuria. We examined the effects of a combination therapy using an angiotensin-converting enzyme (ACE) inhibitor plus a long-acting calcium channel blocker (amlodipine), and compared them with the effect of an ACE inhibitor alone. Thirty hypertensive, type II diabetic patients with microalbuminuria were treated with either an ACE inhibitor alone (group I, n=17) or an ACE inhibitor plus amlodipine (group II, n=13) for 32 weeks. With treatment, blood pressures in both groups were significantly reduced, and diastolic blood pressure was lowered to a much greater extent in group II (76 +/- 2 mmHg) than in group I (83 +/- 2 mmHg, p < 0.05). Although the urinary albumin excretion rate was decreased in both groups, the decrease attained statistical significance only in group II (from 141 +/- 25 mg/day to 69 +/- 18 mg/day, p < 0.05); the extent of reduction in microalbuminuria during antihypertensive treatment was significantly greater in group II (50 +/- 10%) than in group I (14 +/- 13%, p < 0.05). In conclusion, this study showed that in hypertensive microalbuminuric type II diabetic patients, the combination of an ACE inhibitor plus amlodipine resulted in a more pronounced decreased in blood pressure (diastolic blood pressure <80 mmHg) and a greater reduction in urinary albumin excretion than did use of an ACE inhibitor alone. This combination strategy should thus be a more effective tool for obtaining optimal blood pressure control in patients with diabetic nephropathy.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension, Renal; Imidazoles; Imidazolidines; Indoles; Male; Middle Aged

The objective of the present study was to compare the effects of imidapril hydrochloride, an angiotensin converting enzyme inhibitor, and dilazep hydrochloride, an antiplatelet agent, on urinary protein excretion and renal function in patients with chronic glomerulonephritis. Imidapril (2.5 or 5 mg/day) or dilazep (300 or 450 mg/day) was administered for 3 years. Blood pressure, proteinuria, and renal function were measured before and during the treatment. In the group administered imidapril (n = 11), urinary protein decreased by approximately 50% (2.16 +/- 1.57 versus 0.90 +/- 0.53 g/g Cr, P < 0.01) and blood pressure by 14/10 mmHg (139.6 +/- 17.4/93.6 +/- 8.7 mmHg versus 122.7 +/- 10.5/81.8 +/- 9.9 mmHg, P < 0.01) and both remained at low levels during the three years of treatment. No correlation was observed between the extent of blood pressure reduction and changes in urinary protein. Serum creatinine concentrations did not change significantly (1.3 +/- 0.3 versus 1.3 +/- 0.3 mg/dL, NS). In the dilazep group (n = 12), there were no significant changes in blood pressure, urinary protein, or serum creatinine. These findings demonstrate that imidapril reduces proteinuria and contributes to preserve renal function, suggesting its usefulness in the treatment of patients with chronic glomerulonephritis.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Dilazep; Drug Therapy, Combination; Female; Glomerulonephritis; Humans; Hypertension, Renal; Imidazolidines; Kidney; Male; Middle Aged; Proteinuria

This study was designed to investigate whether chronic angiotensin-converting enzyme (ACE) inhibition prevents hypertensive glomerular injury and inhibits increases in the mRNA levels and immunohistological expression of the apoptosis inducer caspase-3, and transforming growth factor (TGF)-beta 1 during prolonged nitric oxide synthase (NOS) inhibition with N-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR).. For 3 weeks, we studied three groups of 20-week-old male SHR: a control group, a l-NAME group, and a group treated with L-NAME and the ACE inhibitor imidapril. L-NAME rats developed severe hypertensive nephrosclerosis with significantly elevated blood pressure, markedly increased urinary protein excretion and serum creatinine levels, and more severe glomerulosclerosis and tubulo-interstitial changes. Levels of TGF-beta 1 mRNA in the renal tissue was also significantly increased in L-NAME rats compared with control SHR. Addition of imidapril significantly lowered blood pressure, inhibited nephrosclerosis and attenuated the mRNA level of TGF-beta 1 in comparison with L-NAME/SHR. Histologically, the glomerular cell apoptosis labeling index, terminal doxynucleotidil transferase-mediated dUTP nick-end labeling of fragmented DNA (TUNEL) and active caspase-3, and TGF-beta 1 positive areas were also reduced by imidapril.. These data suggest that imidapril prevents glomerular and arteriolar damages and renal functions, through inhibiting both TGF-beta 1 production and apoptosis induction.

Topics: Animals; Antihypertensive Agents; Aorta; Cardiomegaly; Caspase 3; Caspases; Enzyme Inhibitors; Hypertension, Renal; Imidazolidines; Kidney; Male; Nephrosclerosis; NG-Nitroarginine Methyl Ester; Organ Size; Rats; Rats, Inbred SHR; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

This study was carried out to characterize a novel angiotensin II-receptor antagonist, TA-606, (3-pentyloxy) carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2'(1H-tetrazole-5-yl) biphenyl-4-yl]methyl-4,5,6,7-tetrahydro imidazo [4,5-c] pyridine-4-carboxylate hydrochloride, which is a newly synthesized prodrug of 606A. In anesthetized rats, 606A inhibited angiotensin II-induced pressor response with a median inhibitory concentration (IC50) of 6 microg/kg, i.v., and was 8 times more potent than EXP3174, an active metabolite of losartan. Bioavailability of TA-606 was 11 times higher than that of 606A in Sprague-Dawley rats, with consistent hypotensive potencies in spontaneously hypertensive rats (SHRs). In conscious renal hypertensive rats (RHRs) and conscious SHRs, TA-606 lowered the blood pressure without any effects on the heart rate, and its effective dose for 30 mm Hg (ED30) values were 0.14 and 0.21 mg/kg, p.o., respectively. The effect of TA-606 lasted > 10 h in both models. Moreover, the effect of TA-606 was approximately 30 and 10 times more potent than those of losartan in RHRs and SHRs, respectively. TA-606 did not affect the blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. TA-606 given for 12 weeks attenuated the development of hypertension in stroke-prone SHRs. These results indicate that TA-606 is a potent angiotensin II-receptor antagonist with antihypertensive efficacy. Thus TA-606 is suggested to be a possible useful agent in the treatment of hypertension.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biological Availability; Blood Pressure; Desoxycorticosterone; Heart Rate; Hypertension, Renal; Imidazoles; Imidazolidines; Losartan; Male; Prodrugs; Pyridines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Tetrazoles; Time Factors

Our previous studies showed that imidapril prevented the occurrence of cerebral stroke and ameliorated biochemical parameter changes of renal dysfunction at a dose that did not inhibit the progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). To confirm these findings, a histopathological investigation was conducted on the kidney of salt-loaded (from 11 to 16 weeks of age) SHRSP, which was the subject of the preceding study. Their brains and hearts were also examined. Histopathologically, renal lesions such as fibrinoid necrosis and proliferative arteritis of small calibration arteries, necrotizing glomerulitis and tubular degeneration, and cerebral hemorrhage and slight cardial hypertrophy were observed in salt-loaded control SHRSP. The occurrence of these lesions were prevented in a dose-dependent manner by the administration of imidapril (1 and 2 mg/kg/day). Especially, the preventive effects on the renal lesions were apparently noted. Enalapril also prevented these renal lesions, but its preventive effects were weaker than those of imidapril at the same dose (2 mg/kg/day). It became evident from the results of the present and previous studies that imidapril reduced renal biochemical and histopathological injuries.

Topics: Animals; Antihypertensive Agents; Autopsy; Basilar Artery; Brain; Cerebrovascular Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart; Hypertension, Renal; Imidazoles; Imidazolidines; Kidney; Kidney Function Tests; Kidney Glomerulus; Male; Microscopy, Fluorescence; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Sodium Chloride, Dietary