imidapril and Body-Weight

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

Rosiglitazone (RGZ) and imidapril improve cancer cachexia via different mechanisms. Therefore, we hypothesized that combination therapy of RGZ+imidapril would further attenuate cancer cachexia in vivo. After injection with colon-26 adenocarcinoma for 9 days, BALB/c mice were randomly divided into the following four treatment groups for 7 days (n = 8 per group): (1) placebo, (2) RGZ, (3) imidapril, and (4) RGZ+imidapril. Eight healthy control animals were also assessed. Body weight, tumor volume, gastrocnemius muscle and epididymal adipose mass, serum metabolic markers and cytokines, and the expression of nuclear factor-κB and two E3 ubiquitin ligases, atrogin-1 and MuRF-1, were measured. From days 14 to 16, all treatments significantly reduced tumor volume (P < 0.05). From days 10 to 16, improvements in the tumor-free body weight were observed in the RGZ and RGZ+imidapril groups. In addition, significant improvements in both gastrocnemius muscle and epididymal adipose mass were observed in all treatment groups (all, P < 0.05). Furthermore, all treatments significantly increased tumor necrosis factor alpha levels as compared to those observed in the healthy control animals (P < 0.001). Insulin levels significantly increased in the placebo group as compared to those in the healthy control group (P < 0.05), which were reduced in all the treatment groups (P < 0.05). Finally, whereas all treatments significantly reduced atrogin-1 levels as compared to the placebo group (all, P < 0.05), significant reductions in MuRF-1 levels were only observed in the RGZ and RGZ+imidapril groups (both, P < 0.05). Thus, all three treatments reduce tumor growth and alleviate cancer cachexia; however, synergistic effects of RGZ+imidapril combination therapy were not observed.

Topics: Adipose Tissue; Animals; Biomarkers; Body Weight; Cachexia; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Gene Expression Regulation; Imidazolidines; Inflammation Mediators; Insulin; Male; Mice; Muscle Proteins; Muscles; Muscular Atrophy; Neoplasms; Organ Size; Rosiglitazone; SKP Cullin F-Box Protein Ligases; Thiazolidinediones; Tripartite Motif Proteins; Tumor Burden; Ubiquitin-Protein Ligases

Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130).. Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated.. Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer.

Topics: Adrenergic beta-1 Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bisoprolol; Body Composition; Body Weight; Cachexia; Glycogen Synthase Kinase 3; Heart Failure; Imidazolidines; Liver Neoplasms; Mineralocorticoid Receptor Antagonists; Myocytes, Cardiac; Myosin Heavy Chains; Rats; Signal Transduction; Spironolactone; Survival Analysis; Ventricular Dysfunction, Left; Wasting Syndrome

It has been suggested that proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, may function as a component of the tissue renin-angiotensin system (RAS). To investigate the role of proang-12 in the production of angiotensin II (Ang II), we measured its plasma and tissue concentrations in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, with and without RAS inhibition. The 15-week-old male WKY and SHR rats were left untreated or were treated for 7 days with 30 mg kg(-1) per day losartan, an angiotensin receptor blocker, or with 20 mg kg(-1) per day imidapril, an angiotensin-converting enzyme (ACE) inhibitor. Both treatments increased renin activity and the concentrations of angiotensin I (Ang I) and Ang II in the plasma of WKY and SHR rats, but neither affected plasma proang-12 levels. In contrast to the comparatively low level of proang-12 seen in plasma, cardiac and renal levels of proang-12 were higher than those of Ang I and Ang II. In addition, despite activation of the RAS in the systemic circulation, tissue concentrations of proang-12 were significantly reduced following treatment with losartan or imidapril. Similar reductions were also observed in the tissue concentrations of Ang II in both strains, without a reduction in Ang I. These results suggest that tissue concentrations of proang-12 and Ang II are regulated independently of the systemic RAS in WKY and SHR rats, which is consistent with the notion that proang-12 is a component of only the tissue RAS.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Body Weight; Imidazolidines; Kidney; Losartan; Male; Myocardium; Organ Size; Peptide Fragments; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Renin-Angiotensin System

To examine the involvement of (pro)renin receptor in the accelerated organ damage in streptozotocin-induced diabetic male SHRsp, the rats fed a high-salt diet were divided into 5 groups: a group treated with the vehicle, a group treated with 15 mg/kg/day of imidapril (ACEi), a group treated with 60 mg/kg/day of imidapril (High ACEi), a group treated with handle region peptide (HRP), and a group treated with both ACEi and HRP (ACEi+HRP). After 8 weeks, the arterial pressure was similar in the vehicle and HRP groups and decreased in the ACEi-treated groups. The renal angiotensin II content decreased similarly in the groups treated with ACEi and/or HRP. Urinary protein excretion also decreased in the ACEi, High ACEi, and HRP groups and significantly further decreased in the ACEi+HRP group. The heart weight of the ACEi+HRP group was significantly lower than that of any other groups, although the cardiac angiotensin II levels decreased similarly in the groups treated with ACEi and/or HRP. Thus, (pro)renin receptor contributes to the accelerated pathogenesis in the heart and kidneys of diabetic SHRsp.

Topics: Angiotensin II; Animals; Blood Glucose; Blood Pressure; Body Weight; Collagen Type I; Diabetes Mellitus, Experimental; Imidazolidines; Male; Organ Size; Prorenin Receptor; Rats; Rats, Inbred SHR; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta

We have studied the effect of imidapril, an angiotensin-converting enzyme inhibitor, on streptozotocin-induced diabetic rats. A sequential euglycemic hyperinsulinemic clamp procedure was used (insulin infusion rates: 3 and 30 mU/kg BW/min) in 30 diabetic rats. The rats were divided in 6 groups: a control group, a control group with N-monomethyl-L-arginine (L-NMMA, 1 mg/kg/min, a nitric oxide synthase inhibitor) infusion, a streptozotocin-induced diabetic group, a diabetic group with L-NMMA infusion, a diabetic group involving imidapril infusion (5 microg/kg/min), and a diabetic group involving simultaneous imidapril and L-NMMA infusion. Glucose concentrations were maintained around 140 mg/dl during the clamp studies. Plasma insulin levels during the 3 and 30 mU/kg BW/min insulin infusions were 30 and 400 microU/ml, respectively. Glucose infusion rates (GIR) in STZ-induced diabetic rats showed a significant decrease compared to controls. At both insulin infusion rates, imidapril-infused diabetic rats showed an increased GIR, compared with the saline infused ones. There was no significant difference in GIR between L-NMMA and saline infusion in diabetic rats. Simultaneous infusion of imidapril and L-NMMA did not significantly decrease GIR with low-dose insulin infusion, but the increase in GIR induced by imidapril with high-dose insulin infusion was impaired by 100 % by L-NMMA infusion in diabetic rats. These results suggest that imidapril may improve insulin action, in part, via nitric oxide.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Glucose; Glucose Clamp Technique; Imidazoles; Imidazolidines; Insulin; Insulin Resistance; Male; Nitric Oxide Synthase; omega-N-Methylarginine; Rats; Rats, Wistar

We investigated effects of the angiotensin-converting enzyme (ACE) inhibitor imidapril and the angiotensin II type 1 (AT1) antagonist candesartan cilexetil on cardiac plasminogen activator inhibitor-1 (PAI-1) expression in rats. Cardiac PAI-1 mRNA levels were increased after a 7-day treatment with the nitric oxide (NO) synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). PAI-1 immunoreactivity was increased in the coronary arteries. Treatment with imidapril significantly prevented the L-NAME-induced increase in the gene expression and immunoreactivity of PAI-1, but candesartan cilexetil showed no such effect. This study provides the first evidence of differential effects of ACE inhibition and AT1 antagonism on cardiac PAI-1 expression in vivo.

Topics: Actins; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Gene Expression Regulation; Heart; Imidazoles; Imidazolidines; Immunohistochemistry; Male; Muscle, Skeletal; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; RNA, Messenger; Tetrazoles

We investigated whether the prevention of the development of diabetic nephropathy by angiotensin-converting enzyme inhibitors is associated with decreases in renal angiotensin-converting enzyme activity and/or blood pressure in diabetic mice. C57Bl/6 mice were injected with streptozotocin (200 mg/kg, i.v.) and randomized to receive either imidapril (1 and 5 mg/kg) or captopril (10 and 50 mg/kg) or vehicle by gavage for 28 days. Each assay was performed on 8-10 mice from each treatment. At 28 days after the start of drug treatment, imidapril and captopril significantly reduced blood pressure of the diabetic mice, and this effect of captopril was stronger than that of imidapril. On the other hand, inhibition of renal angiotensin-converting enzyme activity by imidapril was stronger than that by captopril. Imidapril and captopril dose-dependently inhibited urinary albumin excretion to similar extents, but they failed to inhibit the renal hypertrophy and elevation of creatinine clearance. Total renal angiotensin-converting enzyme activity was significantly reduced in diabetic mice, but immunohistochemical localization of angiotensin-converting enzyme was intensive in the vasculature and glomeruli of the diabetic kidney. In conclusion, both effects on blood pressure and angiotensin-converting enzyme activity may be involved in the prevention of development of diabetic nephropathy by imidapril and captopril in streptozotocin-induced diabetic mice. The data suggest that the degrees of contribution of their effects on blood pressure and renal angiotensin-converting enzyme activity to the inhibition of urinary albumin excretion may be different between the two angiotensin-converting enzyme inhibitors.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Blood Glucose; Blood Pressure; Body Weight; Captopril; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Imidazoles; Imidazolidines; Male; Mice; Mice, Inbred C57BL; Peptidyl-Dipeptidase A; Renal Artery; Streptozocin

Ischemic acute renal failure is associated with vascular endothelial dysfunction. We examined whether vasodilatory antihypertensive agents would improve endothelial function in rats with ischemia/reperfusion renal injury. Rat kidneys were isolated and perfused after clipping of the bilateral renal arteries for 45 min and reperfusion for 24 h, and renal perfusion pressure and nitric oxide concentration in the venous effluent (chemiluminescence assay) were monitored. Preischemic administration of celiprolol (a beta-blocker; 100 mg/kg p.o.), benidipine (a calcium channel blocker; 1 mg/kg p.o.), or imidapril (an angiotensin converting-enzyme inhibitor; 3 mg/kg p.o.) restored endothelial function in rats subjected to acute renal ischemia (deltarenal perfusion pressure [10(-8) M acetylcholine]: sham -42+/-3%, ischemia -31+/-1%, ischemia +celiprolol -39+/-1%*, ischemia+benidipine -38+/-2%*, ischemia+imidapril -42+/-2%*; *p<0.05 vs. ischemia). Serum urea nitrogen and creatinine levels were also lower in the treated groups. Furthermore, ischemia-induced decreases in the response to acetylcholine and renal excretory function were smaller in SHR than in deoxycorticosterone-salt hypertensive rats, in which endothelial damage was marked. These results suggest that preischemic endothelial function may influence the degree of ischemic renal injury. Calcium channel blockers, converting-enzyme inhibitors, and endothelial NO synthase-activating beta-blockers had beneficial effects on renovascular endothelial dysfunction due to ischemia.

Topics: Acetylcholine; Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Blood Urea Nitrogen; Body Weight; Calcium Channel Blockers; Celiprolol; Creatinine; Desoxycorticosterone; Dihydropyridines; Endothelium, Vascular; Imidazoles; Imidazolidines; Male; Nitric Oxide; Rats; Rats, Inbred SHR; Rats, Wistar; Reperfusion Injury; Vasodilator Agents

The renin-angiotensin system and endothelin are important regulators of the cardiovascular system. Although increased production of endothelin-1 (ET-1) is reported in patients with heart failure, the detailed mechanism remains to be determined. To elucidate the relationship between the renin-angiotensin system and ET-1 in hypertensive heart failure, we evaluated the effects of long-term treatment with imidapril, an angiotensin converting enzyme (ACE) inhibitor, on preproET-1, endothelin A receptor (ETAR), and ACE mRNA expression in the left ventricle and evaluated these in relation to myocardial remodeling in the failing heart of Dahl salt-sensitive (DS) hypertensive rats fed a high salt diet. In DS rats fed an 8% NaCl diet after the age of 6 weeks, a stage of concentric left ventricular hypertrophy at 11 weeks (DSLVH) was followed by a distinct stage of left ventricular failure with chamber dilatation at 18 weeks (DSHF). Imidapril (DSHF-IM, n = 8, 1 mg/kg/day, subdepressor dose) or vehicle (DSHF-V, n = 8) was given from stage DSLVH to DSHF for 7 weeks, and age-matched (18 weeks) Dahl salt-resistant rats fed the same diet served as the control group (DR-C, n = 8). In both groups, blood pressure was similar and significantly higher than in DR-C. Markedly increased left ventricular end-diastolic diameter and reduced fractional shortening in DSHF-V was significantly ameliorated in DSHF-IM using transthoracic echocardiography. The preproET-1, ETAR, and ACE mRNA levels in the left ventricle were significantly increased in DSHF-V compared with DR-C, and significantly suppressed in DSHF-IM compared with DSHF-V. DSHF-V demonstrated a significant increase in the wall-to-lumen ratio and perivascular fibrosis in coronary arterioles, and myocardial fibrosis, with all these parameters being significantly improved by imidapril. In conclusion, myocardial remodeling and heart failure in DS rats fed a high salt diet were significantly ameliorated by a subdepressor dose of imidapril, which may be attributable to a decrease in ET-1 mRNA expression and angiotensin II in the left ventricle.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Body Weight; Cardiac Output, Low; Endothelin-1; Endothelins; Gene Expression; Heart Ventricles; Hemodynamics; Hypertension; Imidazoles; Imidazolidines; Male; Myocardial Contraction; Myocardium; Organ Size; Peptidyl-Dipeptidase A; Protein Precursors; Rats; Rats, Inbred Dahl; Receptor, Endothelin A; Receptors, Endothelin; RNA, Messenger; Ventricular Remodeling

The present study was undertaken to examine the effects of the ACE (angiotensin converting enzyme) inhibitor imidapril, on the brain, when administered after the onset of stroke in a stroke-prone substrain of spontaneously hypertensive rats (SHRSP). Learning deficits and induced lesions in the brain as well as in the kidneys and heart were investigated in detail. SHRSP were divided into two groups with or without salt loading at the age of 4 weeks. The salt loading was performed for 7-9 weeks to increase the incidence of stroke. Within 24 h after the first observation of stroke, animals were subsequently treated with 5 mg/kg imidapril orally once a day or the vehicle for up to the age of 27 weeks. Imidapril attenuated progression of neurological abnormalities such as irritability, hyperkinesia and motor dysfunction, and increased survival rate. In three-panel runway testing, learning deficits did not develop significantly in the imidapril-treated group, and was comparable to that in the non-salt-loaded/non-stroke group. Imidapril reduced oedema formation in the cortex, hippocampus and striatum, and also suppressed lesion formation in the kidneys and heart. Imidapril thus suppressed progression of neurological deficits with loss of learning ability following onset of stroke, and also suppressed formation of oedema in the brain and decreased the number of lesions in other organs. Imidapril-induced reduction of cerebrovascular damage, which presumably occurs in the brain after stroke, may account for the inhibitory effects of imidapril on lesion formation and learning impairment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Brain Edema; Cerebrovascular Disorders; Imidazoles; Imidazolidines; Kidney; Learning Disabilities; Male; Myocardium; Neurologic Examination; Organ Size; Rats; Rats, Inbred SHR; Survival Rate

Imidapril, enalapril and quinapril were subcutaneously administered to aortic-banded rats by osmotic minipumps to compare the suppressive actions of these angiotensin converting enzyme (ACE) inhibitors on pressure-induced cardiac hypertrophy. Among the three drugs tested, imidapril was most potent for the prevention of cardiac hypertrophy, although equipotent hypotensive doses were used. Imidapril reduced both serum and cardiac ACE activities, while enalapril reduced only the former. Quinapril also reduced both, however, it was less potent at reducing the former compared to imidapril. Moreover, only imidapril significantly decreased left ventricular end diastolic pressure, which tended to be increased by aortic-banding. The lipophilicity of ACE inhibitors could not explain the more potent suppressive action of imidapril on cardiac hypertrophy because the lipophilicity of imidaprilat, an active metabolite of imidapril, was as low as an active metabolite of enalapril; i.e., much lower than an active metabolite of quinapril. The efficacy of ACE inhibitors on pressure-induced cardiac hypertrophy depends not only on an inhibitory effect on cardiac ACE activity, but also on other actions such as their effect on left ventricular end diastolic pressure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Cardiomegaly; Diastole; Enalapril; Heart; Imidazoles; Imidazolidines; Isoquinolines; Quinapril; Rats; Tetrahydroisoquinolines; Ventricular Function, Left

We investigated the effect of angiotensin-converting enzyme inhibition on spontaneous nephrosis in Dahl salt-sensitive (Dahl/S) rats. Dahl/S rats fed on a normal sodium diet spontaneously developed nephrosis and mild hypertension from a young age. In young Dahl/S rats, an angiotensin-converting enzyme inhibitor, imidapril, attenuated the development of proteinuria accompanied by a decrease in blood pressure. Methylprednisolone, a potent therapeutic agent for proteinuria, did not affect the development of nephrosis. An angiotensin AT1 receptor antagonist, losartan, but not a Ca2+ channel blocker, verapamil, inhibited the development of nephrosis while both agents decreased blood pressure to a similar extent as imidapril. In mature Dahl/S rats, imidapril suppressed not only the development of proteinuria but also the glomerular lesions. It is concluded that the development of spontaneous nephrosis in Dahl/S rats is mediated by angiotensin II.

Topics: Aging; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Body Weight; Calcium Channel Blockers; Cholesterol; Glucocorticoids; Hypertension; Imidazoles; Imidazolidines; Losartan; Male; Methylprednisolone; Nephrosis; Proteinuria; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Verapamil

The pharmacokinetics and pharmacodynamics (PK/PD) of imidaprilat, an active metabolite of imidapril, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated. Imidapril was infused subcutaneously for 4 weeks via an osmotic pump implanted under the skin in the back of male spontaneously hypertensive rats (SHRs). Plasma concentration of imidaprilat, systolic blood pressure (SBP), and plasma ACE activity were determined periodically. The plasma concentration of imidaprilat increased in proportion to the infusion rates and was maintained for 4 weeks. The SBP and ACE activity did not decrease in proportion to the infusion rates due to the saturation of the pharmacologic effects, but these actions also were maintained for 4 weeks. The PK/PD of imidaprilat were not influenced by aging of SHRs. The antihypertensive action in subcutaneous infusion of imidapril was as potent as that in oral administration at the same dose, although the maximum plasma concentration of imidaprilat in subcutaneous infusion was one-eightieth times of that in oral administration. The action was also maintained 28 times longer than that in oral administration, indicating that subcutaneous infusion is useful as an administration route. Furthermore, good correlation between plasma imidaprilat concentration and SBP was observed in subcutaneous infusion, indicating that plasma concentration may be a useful marker of pharmacologic action.

Topics: Administration, Oral; Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Body Weight; Hypertension; Imidazoles; Imidazolidines; Infusions, Parenteral; Male; Radioimmunoassay; Rats; Rats, Inbred SHR

Effects of isoproterenol (ISO) on the expression of cardiac angiotensinogen mRNA, angiotensin converting enzyme (ACE) activity, and mechanical functions in spontaneously hypertensive rats were investigated. In the acute phase, defined as within 24 h after the subcutaneous injection of ISO 85 mg/kg, cardiac angiotensinogen mRNA was slightly induced, but ACE activity was not. In the subacute phase, defined as within 8 d after ISO treatment on 2 successive d, both angiotensinogen mRNA expression and ACE activity in the heart were markedly induced. ACE activity in serum was not affected by ISO in either phase. In the subacute phase, ISO reduced body weight and blood pressure, increased ventricular weight and calcium content, and impaired cardiac mechanical function. Oral treatment with imidapril (10 mg/kg/d), an ACE inhibitor, 1 h before each ISO treatment and on the following 6 d, improved ventricular hypertrophy, the elevation of the left ventricular end diastolic pressure, the reduction in contractility, and the prolongation of the time constant. Imidapril significantly suppressed both serum and cardiac ACE activity but did not affect cardiac angiotensinogen mRNA expression in the subacute phase. These results indicate that enhancement of cardiac angiotensinogen mRNA and ACE activity is involved in ISO-induced cardiac dysfunction. Imidapril improved ISO-induced cardiac dysfunction, possibly by suppression of the local ACE activity as well as circulating ACE activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Body Weight; Cardiotonic Agents; Heart Rate; Hypertension; Imidazoles; Imidazolidines; Isoproterenol; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; RNA, Messenger

Magnetic resonance imaging (MRI) was used to investigate the therapeutic effects of imidapril, a newly synthesized angiotensin converting enzyme (ACE) inhibitor, on cerebral stroke lesions.. Pretreatment with ACE inhibitors is known to prevent stroke in stroke-prone spontaneously hypertensive rats, prolonging their lifespan. Malignant stroke-prone spontaneously hypertensive rats (M-SHRSP) were treated with imidapril after the onset of stroke.. M-SHRSP with proved stroke were divided into two groups. One group received 40 mg/kg per day imidapril and the other group was used as a control. For 4 weeks, neurological symptoms were scored daily, and MRI images were taken and scored once a week.. In the control group the MRI score for cerebral lesions increased during the experiment, and seven out of eight control rats died within 17 days. In rats treated with imidapril the major finding was that imidapril rapidly ameliorated the damage to the blood-brain barrier and resolved brain oedema within 1 week. At the same time the neurological symptoms observed after stroke disappeared. Furthermore, none of the rats treated with imidapril showed recurrence of stroke, and their survival rate was improved.. These results suggest that imidapril has therapeutic effects on stroke lesions, as well as prophylactic effects on the recurrence of stroke.

Topics: Animals; Antihypertensive Agents; Behavior, Animal; Blood Pressure; Body Weight; Brain; Cerebrovascular Disorders; Female; Hypertension; Imidazoles; Imidazolidines; Longevity; Magnetic Resonance Imaging; Rats; Rats, Inbred SHR

Effects of (4S)-1-methyl-3-[(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]- propionyl]-2-oxoimidazolidine-4-carboxylic acid hydrochloride (TA-6366) on morphological change and mechanical property related to sodium ion permeability in the aorta of spontaneously hypertensive rats (SHRs) were examined, as compared with those of enalapril and captopril. Ten-week oral administration of TA-6366 (1 and 5 mg/kg/d) from 4 weeks of age impeded aortic media-thickening together with a rise in blood pressure in SHRs. Concomitantly, aorta weights in both groups were markedly decreased. The higher dose of TA-6366 almost fully suppressed the accelerated tension development induced by K(+)-free medium and decreased total sodium ion content in the aorta. These vascular effects of TA-6366 was more prominent than those of enalapril and captopril at 5 mg/kg/d. The difference in potencies on the above vascular parameters between TA-6366 and these drugs seemed to be mainly related to the difference in their antihypertensive activities. These results suggest that TA-6366 has preventive effects against progression of vascular diseases, particularly atherosclerosis, accompanied with hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Body Weight; Captopril; Cardiomegaly; Dose-Response Relationship, Drug; Enalapril; Imidazoles; Imidazolidines; Male; Muscle Contraction; Muscle, Smooth, Vascular; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium