imidapril and Diabetes-Mellitus--Type-2

Aim of this study was to compare the antiproteinuric effect of imidapril (I) and ramipril (R) in diabetic hypertensive patients with microalbuminuria.. One hundred and seventy-six patients were randomised to I 10 - 20 mg once daily (od) (n = 88) or R 5 - 10 mg od (n = 88) for 24 weeks. Clinic, ambulatory, central blood pressure (BP), urinary albumin excretion (UAE), plasma Angiotensin II (Ang II), bradykinin and brain natriuretic peptide (BNP) were assessed at baseline and after 6, 12 and 24 weeks.. Both I and R produced a similar decrease in clinic, ambulatory and central BP (p < 0.001 vs baseline). Both treatments significantly reduced UAE throughout the study, but the decrease in UAE associated with I was more pronounced, being evident at week 6 (p = 0.05) and maximal at week 24 end-point (-42 vs -29%, p < 0.01). BNP and Ang II levels were similarly reduced by I and R, while bradykinin increased more with R (+132 vs +86%, p < 0.05).. These findings showed that in diabetic hypertensive patients with microalbuminuria, despite equivalent BP-lowering effect, I produced a greater antiproteinuric effect than R, which might be due to different intrinsic molecular properties of the two drugs.

Topics: Adult; Aged; Albumins; Albuminuria; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bradykinin; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Ramipril; Treatment Outcome

To investigate the renoprotective effect of combination therapy with an angiotensin I converting enzyme inhibitor and an angiotensin type I receptor blocker (ARB) on diabetic kidney disease, half doses of each monotherapy were given to type 2 diabetic patients with albuminuria.. Urinary albumin index (UAI) and blood pressure (BP) were measured in a total of 27 outpatients with type 2 diabetes mellitus receiving 10 mg imidapril or 8 mg candesartan per day. Either agent was then substituted with a combination of 5 mg imidapril and 4 mg candesartan. After 3 months of combination therapy, UAI and BP were measured. Changes in the parameters were assessed by paired t test.. Although BP was not significantly different prior to and at the end of combination therapy, log-transformed UAI was significantly reduced (P = 0.003) from an initial UAI (mean log-transformed UAI +/- SD) of 79.4 (27.4-231)mg/g Cre to 52.5 (17.1-161)mg/g Cre at the end of combination therapy. The reduction was not associated with the initial UAI, initial BP, decrease in BP, pretreatment medication or other concomitant antihypertensive agents.. In patients with type 2 diabetes and nephropathy, dual blockade of the renin system with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker significantly reduces albuminuria and, thus, may be renoprotective even when the doses of the agents are reduced by one half.

Topics: Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Imidazolidines; Male; Middle Aged; Tetrazoles; 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

Kidney fibrosis is the final common pathway of progressive kidney diseases including diabetic nephropathy. Here, we report that the endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), the substrate of angiotensin-converting enzyme (ACE), is an orally available peptide drug used to cure kidney fibrosis in diabetic mice. We utilized two mouse models of diabetic nephropathy, streptozotocin- (STZ-) induced type 1 diabetic CD-1 mice and type 2 diabetic nephropathy model db/db mice. Intervention with the ACE inhibitor imidapril, oral AcSDKP, or imidapril + oral AcSDKP combination therapy increased urine AcSDKP levels. AcSDKP levels were significantly higher in the combination group compared to those of the other groups. AcSDKP oral administration, either AcSDKP alone or in addition to imidapril, ameliorated glomerulosclerosis and tubulointerstitial fibrosis. Plasma cystatin C levels were higher in both models, at euthanasia, and were restored by all the treatment groups. The levels of antifibrotic miRs, such as miR-29 or let-7, were suppressed in the kidneys of both models; all treatments, especially the combination of imidapril + oral AcSDKP, restored the antifibrotic miR levels to a normal value or even higher. AcSDKP may be an oral antifibrotic peptide drug that would be relevant to combating fibroproliferative kidney diseases such as diabetic nephropathy.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Imidazolidines; Mice; Mice, Inbred NOD; Oligopeptides; Peptidyl-Dipeptidase A

We investigated the renoprotective effects of imidapril hydrochloride ((-)-(4 S)-3-[(2 S)-2-[[(1 S)-1-ethoxycarbonyl-3-phenylpropyl] amino] propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril), an angiotensin-converting enzyme inhibitor, in a diabetic animal model. We used BKS.Cg-+Lepr(db)/+Lepr(db) (db/db) mice, a genetic animal model of obese type 2 diabetes. Diabetic db/db mice suffered from glomerular hyperfiltration, albuminuria and hypoalbuminemia. Oral administration of 5 mg/kg/day of imidapril for 3 weeks suppressed renal hyperfiltration, reduced albuminuria and normalized hypoalbuminemia. Imidapril did not influence body weights, blood pressure or blood glucose concentrations in db/db mice. Urinary excretion of heparan sulfate (HS) in non-treated 11-week-old db/db mice was significantly lower than that in age-matched non-diabetic db/+m mice. HS is a component of HS proteoglycans, which are present in glomerular basement membranes and glycocalyx of cell surfaces. Reduced urinary HS excretion indicated glomerular HS loss in db/db mice. Imidapril increased urinary excretion of HS to concentrations observed in db/+m mice, indicating that imidapril prevented the loss of renal HS. These results suggest that imidapril ameliorates renal hyperfiltration and loss of renal contents of HS. Improvement of filtration function and maintenance of HS, which is an important structural component of glomeruli, may contribute to renoprotective effects of imidapril.

Topics: Administration, Oral; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Heparitin Sulfate; Humans; Hypoalbuminemia; Imidazolidines; Kidney Glomerulus; Mice; Mice, Inbred NOD; Obesity

Angioedema due to angiotensin-converting enzyme inhibitors (ACEIs) therapy occurs not infrequently and is sometimes associated with life-threatening conditions.. A 59-year-old woman presented with recurrent angioedema of the tongue complicated by upper airway obstruction which required endotracheal intubation. Laboratory tests including complement levels were normal. ACEI-associated angioedema precipitated by NSAIDs was suspected. Her condition improved after discontinuation of imidapril and diclofenac without other specific treatment.. ACEIs, and in particular concomitant use with NSAIDs, should be avoided in patients with a history of angioedema because continuing administration tends to lead to more severe attacks.

Topics: Airway Obstruction; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Diabetes Mellitus, Type 2; Diclofenac; Drug Therapy, Combination; Female; Humans; Imidazolidines; Intubation, Intratracheal; Middle Aged; Pain; Withholding Treatment

To examine the mechanism of nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a recently developed type II diabetic model, we compared the long-term effect of angiotensin-converting enzyme (ACE) inhibitor (imidapril, 1 mg/kg/day), calcium channel blocker (amlodipine, 10 mg/kg/day), and insulin (5-10 U/kg/day) on nephropathy of OLETF rats. Both imidapril and amlodipine, but not insulin, significantly reduced blood pressure of OLETF rats. Imidapril treatment significantly decreased urinary albumin excretions and improved glomerulosclerosis of OLETF rats, while amlodipine failed to improve nephropathy of OLETF rats despite lowering of blood pressure. Insulin treatment, which significantly decreased HbA1c throughout the treatment period, did not ameliorate nephropathy of OLETF rats. Serum ACE activity in OLETF rats was significantly lower than that in genetic control nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. However, glomerular and aortic ACE activities in OLETF rats were significantly higher than those in LETO rats, and were significantly decreased by treatment with imidapril. Furthermore, immunohistochemical analysis of ACE in the kidney using specific antibodies indicated greater ACE immunostaining in the glomeruli and renal vessels of OLETF rats than in those of LETO rats. These observations demonstrate that ACE is involved in the development of nephropathy of OLETF rats and provide evidence that intrarenal ACE rather than circulating ACE may play an important role in nephropathy of this type II diabetic model.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycated Hemoglobin; Imidazoles; Imidazolidines; Insulin; Kidney; Lipids; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred OLETF; Rats, Long-Evans

Serum N-acetyl-beta-D-glucosaminidase activity (NAG) is a possible predictor of vascular injury in hypertension. We assessed whether the activity of this enzyme reflects vascular damage in a genetic rat model of non-insulin-dependent diabetes mellitus (NIDDM) in humans. Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a regular chow were treated with the angiotensin converting enzyme (ACE) inhibitor imidapril for 16 wk. Systolic blood pressure increased in a time-dependent manner in the untreated OLETF rats as compared with that in the control Long-Evans Tokushima (LET) rats. The blood pressure elevation was associated with increases in cardiac and aortic weight. Imidapril treatment significantly attenuated the blood pressure elevation and reduced the increases in cardiac and aortic weight. The untreated OLETF rats had higher plasma glucose and insulin concentrations than did the LET rats and presented with glucosuria at the age of 22 wk. Imidapril treatment strikingly decreased plasma glucose levels and the glucosuria. Plasma insulin concentrations decreased, approaching those of the non-diabetic control LET rats. ACE inhibitor treatment attenuated the nodular lesions in the glomeruli of OLETF rats and improved the kidney function. Serum NAG activity increased significantly by 35% in the untreated rats; this increase was attenuated significantly by imidapril treatment. The reduction in serum NAG activity correlated with improvement in cardiovascular injury. In contrast, there were no changes in urinary NAG excretion in the three OLETF rat groups. In addition, NAG excretion did not correlate with indices of cardiovascular injury. These data suggest that serum NAG activity is useful in predicting injury in the cardiovascular system in rats with diabetes mellitus.

Topics: Acetylglucosaminidase; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Creatinine; Diabetes Mellitus, Type 2; Glucose; Hemodynamics; Imidazoles; Imidazolidines; Kidney; Kidney Function Tests; Nitric Oxide; Organ Size; Rats; Rats, Inbred Strains