imidapril and Hypertension

Imidapril (Tanatril), through its active metabolite imidaprilat, acts as an ACE inhibitor to suppress the conversion of angiotensin I to angiotensin II and thereby reduce total peripheral resistance and systemic blood pressure (BP). In clinical trials, oral imidapril was an effective antihypertensive agent in the treatment of mild to moderate essential hypertension. Some evidence suggests that imidapril also improves exercise capacity in patients with chronic heart failure (CHF) and reduces urinary albumin excretion rate in patients with type 1 diabetes mellitus. Imidapril was well tolerated, with a lower incidence of dry cough than enalapril or benazepril, and is a first choice ACE inhibitor for the treatment of mild to moderate essential hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Heart Failure; Humans; Hypertension; Imidazolidines; Molecular Structure; Treatment Outcome

Imidapril hydrochloride (imidapril) is a long-acting, non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, which has been used clinically in the treatment of hypertension, chronic congestive heart failure (CHF), acute myocardial infarction (AMI), and diabetic nephropathy. It has the unique advantage over other ACE inhibitors in causing a lower incidence of dry cough. After oral administration, imidapril is rapidly converted in the liver to its active metabolite imidaprilat. The plasma levels of imidaprilat gradually increase in proportion to the dose, and decline slowly. The time to reach the maximum plasma concentration (T(max)) is 2.0 h for imidapril and 9.3 h for imidaprilat. The elimination half-lives (t(1/2)) of imidapril and imidaprilat is 1.7 and 14.8 h, respectively. Imidapril and its metabolites are excreted chiefly in the urine. As an ACE inhibitor, imidaprilat is as potent as enalaprilat, an active metabolite of enalapril, and about twice as potent as captopril. In patients with hypertension, blood pressure was still decreased at 24 h after imidapril administration. The antihypertensive effect of imidapril was dose-dependent. The maximal reduction of blood pressure and plasma ACE was achieved with imidapril, 10 mg once daily, and the additional effect was not prominent with higher doses. When administered to patients with AMI, imidapril improved left ventricular ejection fraction and reduced plasma brain natriuretic peptide (BNP) levels. In patients with mild-to-moderate CHF [New York Heart Association (NYHA) functional class II-III], imidapril increased exercise time and physical working capacity and decreased plasma atrial natriuretic peptide (ANP) and BNP levels in a dose-related manner. In patients with diabetic nephropathy, imidapril decreased urinary albumin excretion. Interestingly, imidapril improved asymptomatic dysphagia in patients with a history of stroke. In the same patients it increased serum substance P levels, while the angiotensin II receptor antagonist losartan was ineffective. These studies indicate that imidapril is a versatile ACE inhibitor. In addition to its effectiveness in the treatment of hypertension, CHF, and AMI, imidapril has beneficial effects in the treatment of diabetic nephropathy and asymptomatic dysphagia. Good tissue penetration and inhibition of tissue ACE by imidapril contributes to its effectiveness in preventing cardiovascular complications of hypertension. The major advantages of imidapril are

Topics: Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Cardiomegaly; Cardiovascular Diseases; Clinical Trials as Topic; Deglutition Disorders; Heart Failure; Humans; Hypertension; Imidazoles; Imidazolidines; Kidney Failure, Chronic; Myocardial Ischemia

Angiotensin-converting enzyme 2 (ACE2), a newly discovered member of renin-angiotensin-aldosterone system, counterbalances the actions of angiotensin-converting enzyme. The objective of our study was to assess the association between rs2106809 polymorphism in ACE2 gene and the blood pressure response to ACE inhibitors in untreated hypertensive patients. After a 2-week, double-blind placebo run-in period, either benazepril or imidapril was administered for 6 weeks to 497 patients with mild to moderate essential hypertension. The achieved changes in BP were analyzed for their association with genotypes at ACE2 gene loci. In female hypertensive patients, the genotype frequency of ACE2 rs2106809 was 36.7%, 45.2% and 18.1% for CC, CT and TT genotypes, respectively. After 6 weeks of treatment, the reductions in diastolic blood pressure were significantly greater in female patients carrying the CC or CT genotype compared with those carrying the TT genotype (9.62±6.83 or 10.2±7.2 versus 6.81±6.31 mm Hg, respectively; P=0.045, analysis of variance (ANOVA)). Moreover, the reductions in mean arterial pressure were significantly greater in female patients carrying the CC or CT genotype compared with those carrying the TT genotype (12.1±7.5 or 12.0±7.9 versus 8.38±6.83 mm Hg, respectively; P=0.035, ANOVA). In male hypertensive patients, the genotype frequency of ACE2 rs2106809 was 58.1% and 41.9% for C and T genotypes, respectively. However, no association could be observed in males. We conclude that ACE2 rs2106809 is an important predictive factor of the response to antihypertensive treatment with ACE inhibitors in Chinese female hypertensive patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arterial Pressure; Asian People; Benzazepines; China; Double-Blind Method; Gene Frequency; Heterozygote; Homozygote; Humans; Hypertension; Imidazolidines; Middle Aged; Peptidyl-Dipeptidase A; Pharmacogenetics; Pharmacogenomic Variants; Phenotype; Polymorphism, Single Nucleotide; Precision Medicine; Prospective Studies; Renin-Angiotensin System; Sex Factors; Time Factors; Treatment Outcome

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

The aim of this study was to evaluate the effects of imidapril and candesartan on fibrinolysis and insulin sensitivity in normoweight hypertensive patients. After a 2-week wash-out period, 61 patients with mild-to-moderate hypertension were randomized to imidapril or candesartan for 12 weeks. Blood pressure (BP), plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen activities were evaluated at baseline and during treatment. The patients underwent a euglycemic-hyperinsulinemic clamp (insulin sensitivity was evaluated as glucose infusion rate during the last 30 min) and a desmopressin test (with desmopressin infusion in the brachial artery) to evaluate endothelial ability to release t-PA. Imidapril and candesartan induced similar systolic/diastolic BP reductions (-16/12.6 and -16.1/12.2 mm Hg, respectively, P<0.001 vs. baseline). Imidapril increased glucose infusion rate (+1.1 mg min(-1) per kg, P<0.02), whereas candesartan did not change it. Both drugs decreased PAI-1 antigen activity after 4 weeks of treatment; subsequently, only the decreasing effect of imidapril was sustained throughout the 12 weeks, whereas candesartan increased PAI-1 activity at week 12 (P<0.05 vs. baseline, P<0.01 vs. imidapril). Activity of t-PA decreased with candesartan (from 0.48±0.16 to 0.43±0.14 IU ml(-1), P<0.05) but not with imidapril. Activity of t-PA in response to desmopressin was increased more by imidapril (+4.45 IU ml(-1)) than by candesartan (+2.73 IU ml(-1), P<0.01 vs. imidapril). These results indicate that in normoweight hypertensive patients, despite similar BP reduction, imidapril but not candesartan improved the fibrinolytic balance, suggesting that mechanisms other than Ang II inhibition, possibly including bradykinin-mediated effects on insulin sensitivity and endothelial function, may be responsible for these different effects.

Topics: Adolescent; Adult; Aged; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Endothelium, Vascular; Female; Fibrinolysis; Humans; Hypertension; Imidazolidines; Insulin Resistance; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Prospective Studies; Signal Transduction; Single-Blind Method; Tetrazoles; Tissue Plasminogen Activator; Treatment Outcome; Young Adult

Anti-angiotensin II receptor subtype 1 (AT1 receptor) autoantibodies have previously been shown in sera of hypertensive patients. This study assessed whether anti-AT1-receptor autoantibody in serum is correlated with the efficacy of an AT1-receptor blocker (ARB; candesartan)-based regimen in hypertensive patients after 8 weeks of treatment.. The Study of Optimal Treatment in Hypertensive Patients with Anti-AT1-Receptor Autoantibodies is a multicentre, randomised, blinded endpoint, open-label, parallel-group comparison clinical trial conducted in five centres in Wuhan, China. Treatment is designed as stepwise added-on therapy to reduce blood pressure (BP) < 140/90 mm Hg. 512 patients with moderate to severe primary hypertension were randomly assigned to an 8-week treatment with either ARB (candesartan)-based regimen (n=257) or ACE inhibitor (imidapril)-based regimen (n=255).. Systolic and diastolic BP was reduced significantly in both treatment groups. The candesartan-based regimen achieved a significantly greater systolic BP reduction than imdapril (30.8 ± 10.3 vs 28.8 ± 10.3 mm Hg, p = 0.023). In those anti-AT1 receptor autoantibody-positive hypertensive patients, the mean systolic BP at baseline was higher than in the anti-AT1 receptor autoantibody-negative group (160.5 ± 16.5 vs 156.2 ± 17.7 mm Hg; p = 0.006). The mean BP reduction was greater in the candesartan-based regimen than the imidapril-based regimen (-35.4 ± 9.8/16.9 ± 6.9 vs -29.4 ± 9.8/14.2 ± 6.9 mm Hg; p = 0.000 and 0.002, respectively), and more patients on imidapril required add-on medications to achieve BP control (94% vs 86%; p=0.03). No correlation was observed between the titre of anti-AT1 receptor autoantibody and the efficacy of candesartan-based therapy. In those anti-AT1 receptor autoantibody-negative patients similar BP lowering was reached in the candesartan and the imidapril-based regimens.. An ARB-based regimen is more effective in BP lowering than an ACE inhibitor-based regimen in the presence of anti-AT1 receptor autoantibodies. Trial registration number This trial has been registered at http://www.register.clinicaltrials.gov/ (identifier: NCT00360763).

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Autoantibodies; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Double-Blind Method; Female; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Receptor, Angiotensin, Type 1; Tetrazoles; Treatment Outcome

To evaluate the relationship between plasma plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) changes during treatment with imidapril and candesartan in hypertensive patients with metabolic syndrome. A total of 84 hypertensive patients with metabolic syndrome were randomized to imidapril 10 mg or candesartan 16 mg for 16 weeks. At weeks 4 and 8, there was a dose titration to imidapril 20 mg and candesartan 32 mg in nonresponders (systolic blood pressure (SBP) >140 and/or diastolic blood pressure (DBP) >90 mm Hg). We evaluated, at baseline and after 2, 4, 8, 12 and 16 weeks, clinic blood pressure, Ang II and PAI-1 antigen. Both imidapril and candesartan induced a similar SBP/DBP reduction (-19.4/16.8 and -19.5/16.3 mm Hg, respectively, P<0.001 vs. baseline). Both drugs decreased PAI-1 antigen after 4 weeks of treatment, but only the PAI-1 lowering effect of imidapril was sustained throughout the 16 weeks (-9.3 ng ml(-1), P<0.01 vs. baseline), whereas candesartan increased PAI-1 (+6.5 ng ml(-1), P<0.05 vs. baseline and P<0.01 vs. imidapril). Imidapril significantly decreased Ang II levels (-14.6 pg ml(-1) at week 16, P<0.05 vs. baseline), whereas candesartan increased them (+24.2 pg ml(-1), P<0.01 vs. baseline and vs. imidapril). In both groups there was a positive correlation between Ang II and PAI-1 changes (r=0.61, P<0.001 at week 16 for imidapril, and r=0.37, P<0.005 at week 16 for candesartan). Imidapril reduced plasma PAI-1 and Ang II levels, whereas candesartan increased them. This suggests that the different effect of angiotensin-converting enzyme inhibitors and Ang II blockers on Ang II production has a role in their different influence on fibrinolysis.

Topics: Adolescent; Adult; Aged; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol; Cholesterol, HDL; Female; Humans; Hypertension; Imidazolidines; Insulin; Male; Metabolic Syndrome; Middle Aged; Plasminogen Activator Inhibitor 1; Tetrazoles; Triglycerides; Young Adult

The aim of hypertension treatment is to achieve blood pressure target values; in the majority of patients this is achieved with combination therapy. ACE inhibitors and imidazoline receptor agonists have neutral effect on lipid metabolism and positive effect on glucose metabolism. They thus may significantly improve long-term prognosis of patients with hypertension and metabolic syndrome or hypertension and diabetes mellitus. The aim of our research was to evaluate physicians' approach to hypertension treatment and to ascertain the proportion of patients in general clinical practice who require combination treatment to control their hypertension. The study also aimed to assess the knowledge of the type and frequency of adverse events associated with the administered agents.. The 12-week evaluation (two 6-week visits) included 993 patients with mild to moderate hypertension above 18 years of age (20-92; mean 57; median 56) with proportional distribution of men and women (48% and 51%, respectively). Data were collected using a standard instrument and blood pressure measured in a standard manner according to guidelines. Hypertension was newly identified in 609 patients (61%), insufficiently controlled hypertension in 363 patients (37%) and data on hypertension were missing in 21 patients (2%). The initial therapy was imidapril (Tanatril) 10 mg. On the first follow up visit, it was on the physician's discretion to increase the dose (increase--imidapril 20 mg) or to prescribe a combination of lower doses [low dose combination--imidapril 10 mg + moxonidin (Cynt) 0.2 or 0.3 mg, respectively]. The second visit, scheduled at 12 weeks post study entry, was attended by 965 patients (97%).. Eleven (1.1%) patients discontinued the treatment prematurely. Dry irritant cough, occurring in 4, i.e., only 0.4%, patients was the most frequent cause of treatment discontinuation. Over the 12 weeks oftreatment, systolic blood pressure declined from 154 mm Hg to 132 mm Hg (p < 0.001); diastolic blood pressure declined from 92 mm Hg to 80 mm Hg (p < 0.001). By the second visit, normal blood pressure was achieved by 718 (74%) patients. Overweight and obese patients have profited from the treatment significantly more than patients with BMI < 25. This held true for the reduction of systolic blood pressure (p = 0.022 at the first follow up and p = 0.037 at the second follow up, respectively) as well as the reduction of diastolic blood pressure (p = 0.003 at the first follow up and p = 0.001 at the second follow up, respectively). After the first follow up visit, the majority of patients continued to take 10 mg of imidapril (610; 61%). At the second follow up visit, 808 (84%) patients continued on the study medication, 79% of patients were on imidapril (5, 10 or 20 mg) and 21% on imidapril + moxonidin combination. Imidapril monotherapy (no other antihypertensive) was prescribed to 258 (27%) patients.. Imidapril is an ACE inhibitor with one ofthe lowest incidences (less than 1% of patients) of dry irritant cough. It thus may become an alternative treatment modality in patients who experienced cough while taking other ACE inhibitors. A significant reduction of blood pressure can be expected in the majority of patients at a dose as low as 10 mg.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Young Adult

The principal means for reducing proteinuria in patients with chronic kidney disease are strong blockade of the renin-angiotensin system and strict regulation of blood pressure (BP). This study compared the efficacy of the maximum permissible doses of two common angiotensin receptor blockers (ARBs), namely valsartan (maximum dose=160 mg per day) and olmesartan (maximum dose=40 mg per day). We also investigated whether a high-dose ARB or the combination of an angiotensin-converting enzyme inhibitor with a high-dose ARB would be more renal protective. We recruited 87 poorly controlled hypertensive patients. In the first study, 50 patients without proteinuria were switched from valsartan (160 mg per day) to olmesartan (40 mg per day) for 4 months. In the second study, 37 patients with proteinuria were randomized to either switch from valsartan 160 mg per day to 40 mg per day olmesartan (n=19; Olm-G) or addition of 2.5-10 mg per day imidapril (stepped up by 2.5 mg per month) to valsartan at 160 mg per day (n=18; Imi-G). After 4 months, the BP level decreased (first study) from 157/88 mm Hg to 145/82 mm Hg (P<0.001) and (second study) from 149/86 mm Hg to 135/77 mm Hg and 145/82 mm Hg for Olm-G and Imi-G, respectively. Furthermore, in the second study, urinary protein/creatinine excretion was reduced from 2.0±1.8 g g⁻¹ to 0.8±0.8 g g⁻¹ (P=0.0242) in Olm-G and from 1.4±1.3 g g⁻¹ to 0.9±1.0 g g⁻¹ (P=0.0398) in Imi-G. The significance persisted after adjustment for BP or other risk factors. Our results suggested that the maximum dose of olmesartan was more effective than that of valsartan and comparable with the combination of valsartan and imidapril for reducing BP and proteinuria in poorly controlled hypertensive patients.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Drug Therapy, Combination; Female; Hawaii; Humans; Hypertension; Imidazoles; Imidazolidines; Kidney; Kidney Diseases; Male; Middle Aged; Proteinuria; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Aldosterone controls sodium balance and intravascular volume, and thus helps regulate blood pressure. Secretion of aldosterone is mainly regulated at the level of expression of the aldosterone synthase (CYP11B2) gene. The intron-2 conversion polymorphism of CYP11B2 was suggested to lead to overexpression of the gene, and may therefore have potential to predict the blood pressure response of patients with essential hypertension to angiotensin-converting enzyme inhibitors (ACEIs).. To investigate the association between the intron-2 conversion polymorphism and the blood pressure response to ACEIs in a hypertensive cohort.. After a 2-week, single-blind, placebo run-in period, ACEIs were administered for 6 weeks to 509 patients with mild-to-moderate essential hypertension. The intron-2 conversion polymorphism was examined by polymerase chain reaction.. The IwIw genotype was observed in 106 patients (20.8%), the IwIc genotype in 251 patients (49.3%), and the IcIc genotype in 152 patients (29.9%). After 6 weeks of treatment the reductions in diastolic blood pressure were significantly greater in patients carrying IcIc or IwIc compared with IwIw genotypes (9.2 +/- 7.2 or 9.2 +/- 7.1 versus 6.4 +/- 6.6 mmHg, respectively; analysis of variance, P = 0.001). Stepwise multiple regression analysis showed that significant predictors of diastolic blood pressure reduction at 6 weeks were baseline diastolic blood pressure (P < 0.001), intron-2 conversion genotype (P = 0.006) and sex (P = 0.030).. The intron-2 conversion polymorphism was related to the diastolic blood pressure lowering response in hypertensive patients treated with ACEIs. Interindividual variation in the efficacy of antihypertensive medications may therefore be influenced by genetic factors.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Pressure; Cytochrome P-450 CYP11B2; Female; Genotype; Humans; Hypertension; Imidazolidines; Introns; Male; Middle Aged; Polymorphism, Single Nucleotide

The dialyzability of imidaprilat, an active metabolite of the angiotensin-converting enzyme (ACE) inhibitor imidapril, was determined and compared with those of enalaprilat and quinaprilat in hypertensive patients on chronic hemodialysis. Imidapril (5 mg/d, n = 6), enalapril (2.5 mg/d, n = 6), or quinapril (2.5 mg/d, n = 6) was given for at least 8 weeks prior to the trial. During dialysis, enalaprilat, but not imidaprilat or quinaprilat, concentrations in both sides decreased significantly. Compared to enalaprilat, the dialyzabilities of imidaprilat and quinaprilat were significantly lower (dialyzer clearance [mL/min/m(2)]: enalaprilat, 41.8 +/- 7.4; imidaprilat, 19.0 +/- 7.8; quinaprilat, 8.9 +/- 1.3). The dialyzabilities of the 3 drugs were negatively correlated with their respective protein-binding rates. During hemodialysis, blood pressure did not change significantly in any group. These results suggest that imidapril provides good blood pressure control without a large fluctuation of drug concentration in hypertensive patients undergoing chronic hemodialysis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Enalapril; Female; Humans; Hypertension; Imidazolidines; Male; Quinapril; Renal Dialysis; Renal Insufficiency; Tetrahydroisoquinolines

To determine the incidence of cough secondary to (1) Cilazapril, (2) Enalapril, (3) Imidapril, and (4) Perindopril and their efficacy in the control of hypertension.. Randomized double-blind study conducted in selected medical centers in the Philippines from the first quarter of 1999 to March, 2001.. A total of 301 patients, aged 28-86 years with stage I or II hypertension were included. Patients were randomized to Cilazapril 2.5-5.0 mg/day (n=70), Enalapril 10-20 mg/day (n=82), Perindoril 4-8 mg/day (n=73), or Imidapril 10-20 mg/day (n=76). Hydrochlorothiazide 12.5 mg/day was added if needed. Using a dechallenge and rechallenge method, a strict criteria to attribute cough to angiotensin converting enzyme inhibitors (ACE-Is) not yet used in previous reports, the cough incidence were as follows: (1) Cilazapril--22.86% (16/70), (2) Enalapril--21.95% (18/82), (3) Perindopril--10.96% (6/73), and (4) Imidapril--13.16% (10/76) (P=0.041). Control of hypertension was significantly better with Enalapril during the first follow-up period.. Statistically significant differences in the incidence of cough among the studied ACE-Is were noted. Control of hypertension was observed to be better in those with a higher incidence of cough; however, the mean change of both systolic and diastolic blood pressure levels were not significantly different.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cilazapril; Cough; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Imidazolidines; Incidence; Male; Middle Aged; Perindopril; Philippines; Treatment Outcome

Twenty-four-hour ambulatory blood pressure monitoring (ABPM) provides the most accurate efficacy assessment of an antihypertensive agent throughout a 24-hour dosing interval. The objective of this prospective, randomised, double-blind, parallel-group, multicentre study was to compare the antihypertensive efficacy of imidapril versus candesartan cilexetil using ABPM.. After screening and a single-blind, placebo run-in phase, ambulatory adult patients with mild to moderate hypertension (defined as a mean office sitting diastolic BP [DBP] and systolic BP [SBP], respectively, of 90-109 mm Hg and 140-179 mm Hg, and a mean ABPM DBP and SBP, respectively, of >or=80 mm Hg and >or=125 mm Hg) were randomised to once-daily treatment with imidapril or candesartan cilexetil for 12 weeks. ABPM was performed at baseline and at the end of the 12-week treatment period in 112 patients (imidapril group, n=55; candesartan cilexetil group, n=57). To achieve the target BP of

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Humans; Hypertension; Imidazolidines; Middle Aged; Prospective Studies; Tetrazoles

Left ventricular hypertrophy is an independent risk factor for cardiovascular disease. We evaluated the effect of long-term and strict antihypertensive therapy with and without the angiotensin-converting enzyme inhibitor (ACEI) imidapril on left ventricular hypertrophy using a novel indicator of chronic burden on the left ventricle, the area under the blood pressure curve x the duration of high blood pressure (AUSBP and AUDBP), in patients with essential hypertension. The patients were divided into 2 groups: an ACEI group, in which imidapril was used in addition to antihypertensive drugs such as Ca channel blockers, beta-blockers, diuretics or angiotensin II antagonist; and a non-ACEI group, in which Ca channel blockers and diuretics were used. Systolic and diastolic blood pressures (SBP and DBP) were both maintained at below 140 and 90 mmHg, respectively, for 2 years. There was no significant difference in the left ventricular mass (LVM) assessed by echocardiography at baseline and that at 2 years of follow-up in the non-ACEI group. However, the LVM in the ACEI group was significantly decreased at 2 years of follow-up as compared to that at the baseline visit. There was no difference in the mean AUSBP and AUDBP between the ACEI and non-ACEI groups. Changes in the LVM were not correlated with the AUSBP or AUDBP in both the ACEI and non-ACEI groups. These findings suggest that the decrease in the LVM in the ACEI group was mediated through mechanisms other than the blood pressure lowering-effect and that AUSBP and AUDBP may be novel indicators of the long-term burden on the left ventricle.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Imidazolidines; Male; Middle Aged; Prospective Studies; Time Factors

Our objective was to investigate the association between the -344C/T or A6547G polymorphism of the aldosterone synthase gene and the blood pressure response to angiotensin-converting enzyme inhibitors in a hypertensive cohort.. After a 2-week single-blind placebo run-in period, either benazepril or imidapril was administered for 6 weeks to 509 patients with mild to moderate essential hypertension. Polymerase chain reaction combined with restriction enzyme digestion was used to detect the 2 polymorphisms. The achieved changes in systolic and diastolic blood pressure were analyzed for their association with genotypes at the aldosterone synthase gene loci.. Regarding the -344C/T polymorphism, we observed the CC genotype in 53 patients (10.4%), the CT genotype in 204 (40.1%), and the TT genotype in 252 (49.5%). After 6 weeks of treatment, the reductions in diastolic blood pressure were significantly greater in patients carrying the TT or CT genotype compared with those carrying the CC genotype (9.1+/-7.0 mm Hg or 8.9+/-7.0 mm Hg versus 5.1+/-7.3 mm Hg, respectively; P=.001, ANOVA). Regarding the A6547G polymorphism, we observed the AA genotype in 19 patients (3.7%), the AG genotype in 184 (36.2%), and the GG genotype in 306 (60.1%). There were no significant differences in the blood pressure reductions after treatment among the 3 genotype groups, and there was no interaction between it and the -344C/T polymorphism. Stepwise multiple regression analysis showed that the significant predictors of diastolic blood pressure reduction at 6 weeks were baseline diastolic blood pressure (P<.001), -344C/T genotype (P=.007), and sex (P=.033).. The -344C/T variant, but not the A6547G variant, of the aldosterone synthase gene may be a determinant of the blood pressure response to angiotensin-converting enzyme inhibitors in hypertensive patients.

Topics: Administration, Oral; Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Asian People; Benzazepines; Blood Pressure; China; Cytochrome P-450 CYP11B2; Female; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Polymorphism, Genetic; Severity of Illness Index; Single-Blind Method

We investigated whether long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor imidapril or the calcium channel antagonist nifedipine increases systemic nitric oxide (NO) production in patients with essential hypertension. Twenty-nine patients with essential hypertension were randomly divided into two groups, and they were treated with either imidapril or nifedipine once daily p.o. for 4 weeks. Long-term treatment with imidapril significantly decreased blood pressure and increased plasma NOx concentration. Long-term treatment with nifedipine also caused a comparable extent of significant decrease in blood pressure, but failed to alter plasma NOx levels. The imidapril treatment significantly inhibited serum ACE activity and increased plasma bradykinin concentration. Furthermore, the extent of inhibition of serum ACE activity and the extent of increase in plasma bradykinin concentration in response to the imidapril treatment were both significantly correlated with the extent of increase in plasma NOx concentration. In contrast, no such changes were noted after the nifedipine treatment. These results provide the first evidence that long-term treatment with imidapril enhances plasma NOx concentration in patients with essential hypertension. This effect does not seem to be due to the decrease in blood pressure. The increase in bradykinin concentration may be involved in the enhancing effect of the ACE inhibitor on NOx production in vivo.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bradykinin; Female; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Nifedipine; Nitric Oxide; Time Factors

The aim of this study was to evaluate the annhypertensive efficacy and tolerability of the angiotensin-converting enzyme inhibitor imidapril and the angiotensin II type 1 receptor antagonist candesartan in mild to moderate essential hypertension.. The trial was conducted at 8 centers across Portugal and Spain (the Iberian Multicenter Imidapril Study on Hypertension [IMISH] Study Group). Patients aged between 30 and 70 years with essential hypertension were eligible. Following a 2- to 4-week, single-blind, placebo run-in period, patients were randomly assigned to receive imidapril at doses of up to 20 mg/d, or candesartan at doses up to 16 mg/d, once daily in a double-blind, parallel-group design with a 12-week active-treatment period. To achieve the target systolic/diastolic blood pressure (SBP/DBP) of <140/<90 mm Hg, imidapril was titrated from 5 to 20 mg/d and candesartan was titrated from 4 to 16 mg/d. The main end point was the change from baseline in sitting blood pressure (BP) at trough. Secondary end points were response rate, evaluation of SBP and DBP throughout the study, and change of SBP and DBP in subgroup of patients with moderate hypertension, as well as incidence and severity of adverse events related to treatment reported throughout the study.. The intent-to-treat analysis consisted of 122 patients (imidapril group, 60 patients; 32 men, 28 women; mean [SD] age, 54.7 [9.2] years; white race, 59 [99.2%], Hispanic race, 1 [0.8%]; mean [SD] weight, 80.1 [12.8] kg; candesartan group, 62 patients; 36 men, 26 women; mean [SD] age, 53.9 [9.9] years; white race, 62 [100%]; mean [SD] weight, 77.6 [14.1] kg). In the imidapril group, the mean (SD) SBP and DBP were, respectively, 155.7 (10.2) and 96.7 (4.7) mm Hg at baseline and 139.4 (11.9) and 86.9 (7.6) mm Hg at the end of the 12-week treatment period (visit 5); SBP had decreased significantly from baseline, by 10.5% (mean [SD] Delta, -16.3 [12.3] mm Hg [95% CI, -19.5 to -13.1; P < 0.001]) and DBP had decreased significantly, by 10.1% (mean [SD] A, -9.8 [7.8] mm Hg [95% CI, -11.8 to -7.8; P < 0.001]). In the candesartan group, the mean (SD) SBP and DBP values were, respectively, 158.4 [11.2] and 98.3 [4.1] mm Hg at baseline and 139.8 [12.5] and 87.6 7.5] mm Hg at 12 weeks, corresponding to decreases of 11.7% in SBP (mean [SD] A, -18.6 [12.8] mm Hg [95% CI, -21.9 to -15.4; P < 0.001]) and 10.9% in DBP (mean [SD] A, -10.7 [7.3] mm Hg [95% CI, -12.5 to -8.8; P < 0.001]). Response rates were 78.3% (47/60) with imidapril and 69.4% (43/62) with candesartan, and BP normalization (<140/<90 mm Hg) was achieved in 55.0% (33/60) of patients with imidapril and 45.2% (28/62) of patients with candesartan. The incidences of adverse events were similar between groups. Most (73.9%) adverse events were mild in intensity. A serious adverse event (severe anxiety) was reported in the candesartan group and led to study discontinuation. No cases of dry cough or hypotension were reported.. The results of this study suggest that imidapril once daily at doses up to 20 mg and candesartan once daily at doses up to 16 mg were effective in this population of mildly to moderately hypertensive patients. Both treatments were well tolerated.

Topics: Adult; Aged; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Double-Blind Method; Drug Administration Schedule; Female; Heart Rate; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Portugal; Severity of Illness Index; Spain; Tetrazoles

This study examined the association between T1198C polymorphism of the angiotensinogen (AGT) gene and the blood pressure response to ACE inhibitors in a Chinese hypertensive cohort. After a 2-week single-blind placebo run-in period, benazepril (10-20 mg/day) or imidapril (5-10 mg/day) was administered for 6 weeks to 509 patients with mild-to-moderate essential hypertension. Polymerase chain reaction combined with restriction enzyme digestion was used to detect the polymorphism, and the patients were classified as having the TT, TC, or CC genotype. The achieved changes in systolic and diastolic blood pressure (SBP and DBP) were analyzed to determine their association with genotypes at the AGT gene locus. In the total 509 patients, the TT genotype was observed in 44 patients (8.7%), the TC genotype in 214 patients (42.0%), and the CC genotype in 251 patients (49.3%). The SBP reductions in patients with the TT genotype, TC genotype, and CC genotype were -15.3+/-12.7 mmHg, -14.0+/-12.7 mmHg, and -14.4+/-12.4 mmHg, respectively (p=0.809). The DBP reductions in patients with the TT genotype, TC genotype, and CC genotype were -8.5+/-8.1 mmHg, -8.3+/-7.5 mmHg, and -8.9+/-6.6 mmHg, respectively (p=0.638). There were no significant differences in the changes in SBP or DBP after treatment among the three genotype groups. In conclusion, these results suggest that the AGT genotype does not predict the blood pressure-lowering response to antihypertensive treatment with ACE inhibitors in Chinese hypertensive patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Antihypertensive Agents; Benzazepines; Blood Pressure; China; Double-Blind Method; Female; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Polymorphism, Genetic

The aim of this study was to investigate the relationship between polymorphism of the anglotensin-converting enzyme (ACE) gene and the blood pressure response to ACE inhibition in a hypertensive cohort. Imidapril (5-10 mg/day) or benazepril (10-20 mg/day) was administered for 6 weeks to 517 essential hypertensives. ACE gene polymorphism was examined by the polymerase chain reaction (PCR) method and the patients were classified as having the 190-bp deletion homozygous (DD) genotype, the 490-bp insertion homozygous (II) genotype, or the 490-bp insertion, 190-bp deletion heterozygous (ID) genotype. The achieved change in systolic and diastolic blood pressure (SBP and DBP) was analyzed for association with genotypes at the ACE gene locus. The DD genotype was observed in 132 patients (25.5%), the ID genotype in 255 patients (49.3%), and the II genotype in 130 patients (25.2%). The SBP reductions in the patients with the DD genotype, II genotype, and ID genotype were -14.5 +/- 12.7 mmHg, -14.3 +/- 13.1 mmHg and -14.0 +/- 12.2 mmHg, respectively (p = 0.94). The DBP reductions in the patients with the DD genotype, II genotype, and ID genotype were -8.7 +/- 7.4 mmHg, -8.7 +/- 7.7 mmHg and -8.5 +/- 6.7 mmHg, respectively (p = 0.96). There was no significant association between the ACE gene polymorphisms and the response to ACE inhibition. These results suggest that ACE genotype does not predict the blood pressure-lowering response to antihypertensive treatment with ACE inhibition.

Topics: Aged; Alleles; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Data Interpretation, Statistical; DNA; DNA Primers; Double-Blind Method; Female; Gene Frequency; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Sex Characteristics

Although the role of angiotensin-converting enzyme (ACE) inhibitors for the treatment of hypertension has been well established, no data has been generated regarding the influence of ACE inhibitors for health-related quality-of-life (QOL) dimensions for Chinese patients.. A double-blind, active-control, randomized clinical trial was used to compare the effects of two ACE inhibitors, imidapril and captopril, on quality-of-life dimensions in one outpatient clinic in one tertiary clinical-care facility. After a 2-3 week washout period with placebo, 59 patients with mild-to-moderate hypertension were randomly assigned to receive imidapril (5 to 10 mg per day) or captopril (25 to 50 mg twice per day) for 12 weeks. Patients completed the Short-form 36 (SF 36) health survey questionnaire, which evaluates 8 QOL dimensions, just before treatment, during the 8th week, and at the end of treatment (12th week). ANOVA for repeated measures was used to analyze the QOL-score changes over time and compare treatments, and to assess the interaction of treatment duration and group on these scores.. No significant differences were demonstrated for changes in blood-pressure, frequency of adverse effects and withdrawal of patients from the study comparing the two drugs. Significant improvement, however, was demonstrated for mental-component summary scores after 12 weeks of treatment for both drugs (P = 0.029). No significant differences were established for individual QOL dimensions comparing the two drugs. A significantly higher baseline systolic blood pressure was found in the participants who did not complete the questionnaire than in those who did.. Similar and significant improvements were determined for the mental-component QOL summary scores for the two ACE inhibitors, imidapril and captopril, and no significant differences were demonstrated comparing treatments.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Asian People; Blood Pressure; Captopril; Double-Blind Method; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Quality of Life; Surveys and Questionnaires; Taiwan; Treatment Outcome

The purpose of this study was to determine whether there are differences in the restoration of endothelial function by angiotensin-converting enzyme inhibition based on the severity of hypertension. Forearm blood flow (FBF) was measured in 69 patients with essential hypertension (mild, n = 23; moderate, n = 29; and severe, n = 17 randomly assigned to treatment with either imidapril or amlodipine for 24 weeks in a double-blind fashion during reactive hyperemia and after sublingual administration of nitroglycerin. Imidapril augmented the FBF response to reactive hyperemia after 24 weeks of treatment in the mild and moderate hypertensive groups, but not in the severe hypertensive group. The augmentation of the FBF response to reactive hyperemia induced by imidapril was significantly greater in the moderate hypertensive group than in the mild hypertensive group. Amlodipine did not alter the FBF response to reactive hyperemia. The increase in FBF after the sublingually administered nitroglycerin was similar in all groups. The infusion of NG-monomethyl-l-arginine, a nitric oxide synthase inhibitor, abolished the enhancement of reactive hyperemia in the mild and moderate hypertensive groups treated with imidapril. These findings suggest that the effects of imidapril on endothelial function are affected by the severity of hypertension and that angiotensin-converting enzyme inhibitor-induced augmentation of reactive hyperemia may be due to increased nitric oxide production.

Topics: Adult; Amlodipine; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hyperemia; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Peptidyl-Dipeptidase A; Regional Blood Flow; Severity of Illness Index; Vascular Resistance

In this 12-week, double-blind, parallel-group, comparative trial, 57 adult patients with mild-to-moderate hypertension were randomly allocated to receive imidapril or captopril, initially at a dose of 5 mg once a day and 25 mg twice daily, respectively. After 4 weeks of therapy, the dose of each drug was increased twice if diastolic blood pressure (DBP) remained > or =90 mm Hg. Both treatments effectively lowered DBP in a comparable manner. Mean changes from baseline in DBP at 12 weeks were -9.9 mm Hg for imidapril and -8.8 mm Hg for captopril (p = 0.488). Responder rates in patients receiving active treatment for at least 6 weeks were 53.9% for imidapril and 48% for captopril (p = 0.676). Both treatments were well tolerated. Adverse drug reactions were observed in 20.7% (6/29) of the imidapril group and 46.4% (13/28) of the captopril group (p < 0.05). A cough was the most frequent side effect, reported in 13.8% of the imidapril group and 35.7% of the captopril group. The results indicate that imidapril is as effective as captopril in the treatment of hypertension. Imidapril produces less adverse effects compared with captopril.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Captopril; Cough; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Taiwan; Treatment Outcome

The purpose of the study was to identify differences in the patterns of efficacy and duration of effects of imidapril administered at different times of the day (morning versus evening) in dipper and nondipper hypertensive patients. Twenty patients with untreated hypertension were classified into two groups: dippers (n = 9) and nondippers (n = 11). Imidapril (10 mg) was given at 07:00 or 18:00 for 4 weeks in a crossover fashion. Blood pressure (BP) and heart rate (HR) were monitored before and after morning and evening treatment every 30 min for 48h by ambulatory BP monitoring (ABPM). In dipper hypertension, the mean 48h BP was reduced with both doses. The decrease in the diurnal BP was stronger when the drug was administered in the evening than morning, but without significant difference. In nondipper hypertension, the systolic BP decreased at night with both doses, but the extent of the nocturnal reduction in systolic BP was greater after morning therapy. There were no significant differences in the decrease in BP during the day or night between the morning and evening administrations. When imidapril was administered in the morning, its serum concentration reached a maximum at 16:00, and when the drug was administered in the evening, it reached a maximum at 6:00. In dipper hypertension, the time taken for the blood concentration of imidapril to reach a maximum changed depending on its time of administration, and the time when the maximum antihypertensive effect of the drug appeared was different. In nondipper hypertension, decreases in the BP were confirmed at night regardless of the time of administration; this might be caused by angiotensin converting enzyme (ACE) inhibitors effectively blocking the BP from increasing by activating the parasympathetic nervous system. Therefore, when assessing the effectiveness of antihypertensive agents, factors such as the various patterns of BP before therapy and administration time must be considered.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Circadian Rhythm; Epinephrine; Female; Heart Rate; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Norepinephrine; Peptidyl-Dipeptidase A; Renin

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Deglutition Disorders; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Losartan; Male; Pneumonia, Aspiration; Stroke; Substance P

Angiotensin-converting enzyme (ACE) inhibitors are known to be the most effective antihypertensive drugs for reducing left ventricular mass in hypertensives when compared to other classes of drugs. In the present study, we evaluated the effects of imidapril, an ACE inhibitor, on serum procollagen type III amino-terminal peptide (PIIIP) levels as well as the left ventricular mass index (LVMI). The subjects consisted of 15 patients (12 men and 3 women) in the outpatient clinic of our hospital who were diagnosed as essential hypertensives and who had not been treated with any antihypertensive medication prior to the study. Left ventricular hypertrophy was observed in all of the patients, ie., LVMI >110 g/m2 in men and >106 g/m2 in women. Blood pressure, LVMI, and serum PIIIP levels were measured before and after treatment with imidapril for 6 months. The starting dose of imidapril was 5 mg, and this was increased to 10 mg. Finally, 1 mg of trichlormethiazide was added to obtain adequate control of blood pressure. Blood pressure significantly decreased in 12 patients, and the mean LVMI decreased significantly from 153.1 +/- 9.0 to 135.4 +/- 6.3 (p< 0.01) after treatment. The changes in LVMI and PIIIP levels with treatment had significant correlation (r=0.639, p< 0.05). The present study showed that imidapril reduces the left ventricular mass in hypertensives after 6 months of treatment, and that this may at least in part be due to a decrease in the collagen content of the hypertrophied heart, suggesting that serum PIIIP levels are a useful marker of the regression of left ventricular hypertrophy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Echocardiography; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Imidazoles; Imidazolidines; Male; Middle Aged; Peptide Fragments; Procollagen; Trichlormethiazide

To compare the incidence of cough between two angiotensin converting enzyme (ACE) inhibitors, imidapril and enalapril, comparative crossover study was performed in 489 patients (228 men and 261 females) with essential or renal parenchymal hypertension. Patients were randomly assigned to one of two treatment groups, a group receiving imidapril for 12 wk (Period I) followed by enalapril for 12 wk (Period II), and a group in which the order of drugs was reversed. The occurrence of cough during treatment was monitored by questionnaire in all cases. There were no differences in background characteristics between the two groups. The incidence of cough during Period I was 15.2% (32/210) in the group initially treated with imidapril (Group IE) and 38.6% (85/220) in the group initially treated with enalapril (Group EI), the difference being statistically significant (p < 0.001). During Period I, decrease in blood pressure was observed in 63.9% (115/180) of Group IE and 64.6% (115/178) of Group EI patients. In approximately half of the patients in Group EI who developed cough during Period I and in whom the treatment was subsequently switched to imidapril, cough subsequently disappeared. It was concluded that the incidence of cough was significantly less under imidapril than under enalapril treatment, while there was no difference in the antihypertensive effects of the two ACE inhibitors.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Cough; Cross-Over Studies; Enalapril; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Treatment Outcome

1. The role of angiotensin (Ang)II in and the effects of angiotensin-converting enzyme (ACE) inhibitors on the regulation of sympathetic neural activity were examined in humans. 2. We measured baseline values of muscle sympathetic nerve activity (MSNA) and its reflex inhibition in 28 patients with essential hypertension with elevated plasma renin activity (PRA; > 1.0 ng/mL per h = 0.28 ng/L per s) before and after either acute or chronic oral administration of an ACE inhibitor or placebo and in 20 normotensive subjects before and after infusion of either AngII (5 ng/kg per min = 4.8 pmol/kg per min) or vehicle (5% dextrose). Muscle sympathetic nerve activity was recorded from the tibial nerve and its reflex inhibition was evaluated during pressor responses to bolus injection of phenylephrine (2 micrograms/kg, i.v.). 3. Blood pressure was significantly decreased (P < 0.01) after the acute oral administration of captopril (25 mg), accompanied by a slight increase in MSNA in patients with essential hypertension compared with control patients who received placebo administration. Reflex changes in MSNA were significantly augmented after oral administration of captopril (-4.1 +/- 0.5 vs -6.2 +/- 0.6%/mmHg, respectively; P < 0.01), with a significant reduction of plasma AngII, while they were not affected by placebo administration. 4. In contrast, acute AngII infusion was accompanied by decreases in both PRA and MSNA in normotensive subjects. Reflex changes in MSNA were significantly reduced after AngII infusion (-11.0 +/- 0.8 vs -7.4 +/- 1.0%/mmHg, respectively; P < 0.01) but not after vehicle alone. 5. Chronic ACE inhibition by 12 week oral imidapril administration (5-10 mg/day) significantly (P < 0.05) decreased baseline values of MSNA, which were accompanied by a significant (P < 0.05) increase in the reflex inhibition of MSNA, while plasma concentrations of noradrenaline were unaffected. 6. These results indicate that AngII blunts reflex inhibition of sympathetic neural activity and that inhibition of the renin-angiotensin system by an ACE inhibitor augments reflex regulation of sympathetic neural activity and reduces baseline values in patients with essential hypertension.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Baroreflex; Captopril; Cardiovascular Physiological Phenomena; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Renin; Sympathetic Nervous System

To investigate the pharmacokinetic profile of the ACE-inhibitor imidapril in 10 hypertensive patients after a first single dose (10 mg) and after 28 days therapy with imidapril 10 mg once daily.. Cmax, tmax, t1/2 and AUC of imidapril and imidaprilat were obtained. ACE-activity and arterial blood pressure during imidapril were corrected by a preceding placebo-investigation.. The AUC of imidapril was 140 (43 s.d.) ng ml(-1) h after the first dose and 123 (34 s.d.) ng ml(-1) h at steady state. AUC of the active moiety imidaprilat averaged 211 (101 s.d.) ng ml(-1) h after the first dose and 240 (55 s.d.) ng ml(-1) h at the steady state investigation. Maximal ACE-inhibition was 75% after the single dose as well as at steady state. ACE inhibition before drug intake at day 28 (i.e. trough) was 50%. The (placebo-corrected) maximal drop in diastolic blood pressure after imidapril was 22 mm Hg after the first dose and 25 mmHg at steady state. Exploratory analysis of imidaprilat plasma concentration vs effect profiles suggests a hyperbolic concentration effect relationship where data of the single dose contribute to the ascending part of an Emax-curve, whereas the plateau around Emax is maintained at steady state.. In this group of hypertensive patients, the pharmacokinetic profile and the drop in ACE-activity as well as in blood pressure seen after a single dose of imidapril and at steady state were similar. The initial response to a test dose might therefore predict the response during chronic dosing.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Area Under Curve; Female; Half-Life; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Placebos

This study was conducted to examine whether imidaprilat, an active diacid of the angiotensin-converting enzyme (ACE) inhibitor imidapril, preferentially inhibits angiotensin I degradation rather than bradykinin degradation, and whether imidapril is less active than other ACE inhibitors in inducing cough in patients with hypertension. The effect of imidaprilat on the inhibition of pressor response to angiotensin I and augmentation of depressor response to bradykinin was compared with that of enalaprilat and captopril in anesthetized rats. To determine the incidence of cough associated with imidapril, patients with a history of ACE inhibitor-induced dry cough were enrolled in a randomized, open-labeled, crossover trial with two 6-week periods to be treated with imidapril or amlodipine, a calcium-channel blocker. The recurrence of cough was assessed during both treatments. In the animal study, there were no significant differences in the ratio of inhibition of pressor response to angiotensin I and the augmentation of depressor response to bradykinin among the ACE inhibitors. In the cough-challenge trial, a total of 60 patients with hypertension were enrolled in the study. Cough and cough related symptoms recurred in 98.3% of the patients (59/ 60) during imidapril therapy. In contrast, only two patients reported cough during treatment with amlodipine. These results indicate that imidapril has no selectivity in inhibiting angiotensin I- and bradykinin-degradation in rats, and that clinically it is not different from other ACE inhibitors in inducing cough in patients with hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cough; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Rats; Rats, Wistar

Endothelial function has been shown to be impaired in patients with essential hypertension. The purpose of the present study was to determine whether antihypertensive drug therapy improves impaired endothelium-dependent renal vasorelaxation in essential hypertensive patients without atherosclerosis. We evaluated the effects of intravenous infusion of L-arginine (500 mg/kg given over 30 minutes) on systemic and renal hemodynamics in 27 patients with mild to moderate essential hypertension who were randomly assigned to treatment with either the angiotensin-converting enzyme inhibitor imidapril or the calcium antagonist amlodipine for 12 weeks in a double-blind fashion. After the 12 weeks, the decrease in blood pressure was similar in the imidapril (n=14) and amlodipine (n=13) groups. The increase in renal plasma flow was also similar in both groups. L-Arginine-induced renovascular relaxation was increased by imidapril (renal plasma flow, 9.6+/-5.1% to 14.4+/-7.4%; renal vascular resistance, -10.4+/-8.1% to -16.7+/-9.2%, P<0.05, respectively) but not by amlodipine. Urinary excretion of nitrite/nitrate in response to L-arginine was significantly increased by imidapril (90+/-29% to 134+/-63%, P<0.05) but remained unchanged by amlodipine. These findings suggest that angiotensin-converting enzyme inhibition improves the impaired endothelium-dependent renovascular relaxation in patients with essential hypertension due to the increase in nitric oxide production and that the reduction in blood pressure with a calcium antagonist does not play a major role in the potentiation of L-arginine/nitric oxide-mediated effects.

Topics: Adult; Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arginine; Calcium Channel Blockers; Data Interpretation, Statistical; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Infusions, Intravenous; Kidney; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Renal Circulation; Time Factors; Vascular Resistance

To assess the value of using imidapril hydrochloride (ACE/TA-6366), a long-acting angiotensin converting enzyme (ACE) inhibitor developed in Japan, to treat patients with essential hypertension.. A double-blind, comparative, phase III study was carried out using enalapril maleate as a control, with a 4-week observation period and a 12-week treatment period. Both drugs were started at a dose of 5 mg once a day, increasing to 10 mg in patients whose antihypertensive response was insufficient after 4 weeks. The study included 231 outpatients aged 30-74 years; of these, 108 in the imidapril group and 115 in the enalapril group were assessed. There were no differences in background factors between groups.. An adequate antihypertensive effect was observed in 71.3% (77/108) in the imidapril group in in 66.1% (76/115) in the enalapril group, with no significant difference between groups. The pulse rate was unchanged in both groups. The drug had no adverse effects in 86.1% (93/108) of the imidapril group and 79.1% (91/115) of the enalapril group, with no significant difference between groups. Adverse drug effects were observed din 5.6% (6/108) of the imidapril group and 12.2% (14/115) of the enalapril group. Cough was the most frequent side effect, reported in 0.9% (1/108) of the imidapril group and 7.0% (8/115) of the enalapril group. Other side effects were reported in 4.6% (5/108) of the imidapril group and 5.2% (6/115) of the enalapril group. Abnormal laboratory values were observed in 3.7% (4/108) of the imidapril group and 0.9% (1/115) of the enalapril group.. Imidapril showed excellent clinical efficacy and safety compared to enalapril. The low incidence of cough is of particular interest.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged

1. We describe an approach involving a smaller, shorter study, leading onto a longer, larger study in which the antihypertensive effects of ascending doses of imidapril, a new ACE inhibitor, were investigated. Both studies were planned prospectively, assuming a clinically useful fall in BP to be 8 mm Hg (s.d. = 9). The studies included patients with mild to moderate essential hypertension (baseline sitting diastolic blood pressure (SDBP) 95-115 mm Hg). After a placebo run-in of 2-3 weeks patients received either placebo or imidapril 2.5, 5, 10 or 20 mg in the 2 week study (n = 91) or imidapril 5, 10, 20 or 40 mg in the 4 week study (n = 162). 2. The overall mean baseline SDBP was 103.4 mm Hg (s.d. 0.62) in the initial study and 101.5 mm Hg (s.d. 0.41) in the 4 week study. 3. Compared with placebo, imidapril 10, 20 and 40 mg significantly reduced SDBP. There was no significant difference between these doses, suggesting that 10 mg achieved maximal ACE inhibition in most patients. The 2.5 mg dose showed no significant effect. The 5 mg dose gave an intermediate effect. In both studies the overall incidence of adverse events was similar in the imidapril and placebo groups, and was not worrying.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Prospective Studies

The effect of temperature and relative humidity (RH) on the stability of imidapril hydrochloride (IMD) in solid state was investigated. The main aim of this study was to determine the most appropriate conditions of storage and manufacture of IMD so that the efficiency of the technological process could be improved and its costs could be minimized. A reversed-phase high-performance liquid chromatography was validated and applied for the determination of IMD degradation samples under the following operating conditions: stationary phase, LiChrospher 100 RP-18 (size 5 μm) 250 × 4 mm I.D., and mobile phase, acetonitrile-methanol-phosphate buffer, pH 2.0, 0.035 mol L(-1) (60:10:30 v/v/v). The effect of temperature on IMD degradation rate was analyzed under increased RH ≈ 76.4% (within temperature range of 70-90°C) and decreased RH ≈ 0% (within temperature range of 90-110°C). The influence of RH was investigated under 90°C within RH range of 25.0-76.4%. IMD degradation accords with autocatalytic reaction model, and RH has no influence on its mechanism yet it increases its rate. The reaction also accelerates under high temperatures and in the presence of IMD degradation product. Pure IMD is more stable than other structurally related angiotensin-converting enzyme inhibitors, such as enalapril maleate, but it still should be stored in tightly closed containers and protected from moisture and high temperatures.

Topics: Antihypertensive Agents; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Humans; Hypertension; Imidazolidines; Particle Size; Reproducibility of Results; Temperature

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Endothelium, Vascular; Fibrinolysis; Humans; Hypertension; Imidazolidines; Insulin Resistance; Plasminogen Activator Inhibitor 1; Tetrazoles; Tissue Plasminogen Activator; Treatment Outcome

Imidapril is an angiotensin converting enzyme (ACE) inhibitor without a sulfhydril group which has been shown from previous study to have low incidence of ACE inhibitor induced cough.. To compare the incidence of cough between two ACE inhibitors, imidapril and enalapril.. A comparative cross over study was performed in 119 patients with hypertension or left ventricular dysfunction. Patients were assigned to one of the two treatment groups, either a group receiving imidapril or enalapril for 4 weeks (Period I) and then these same groups were crossed over to receive either enalapril or imidapril for 4 weeks (Period II). The occurrence of cough during treatment was monitored by interviewing the patients.. The incidence of cough was 44 % while on imidapril treatment and 66% while on enalapril treatment (p = 0.0014). The antihypertensive effects of two drugs were not different.. The incidence of cough was significantly less under imidapril than under enalapril treatment, while there was no difference in the antihypertensive effects between the two ACE inhibitors.

Topics: Administration, Oral; Aged; Angiotensin-Converting Enzyme Inhibitors; Cough; Cross-Over Studies; Enalapril; Female; Humans; Hypertension; Imidazolidines; Incidence; Male; Middle Aged; Treatment Outcome; Ventricular Dysfunction, Left

The renin-angiotensin system regulates the vascular fibrinolytic balance. In the human forearm vasculature, angiotensin-converting enzyme (ACE) inhibitors (ACE-Is) increase the release of t-PA through endogenous bradykinin. We tested the hypothesis that ACE inhibition and sex modulate the endogenous coronary release of tissue plasminogen activator (t-PA) in hypertensive patients. Seventy-three patients underwent diagnostic coronary angiography and had normal coronary angiograms. Thirty-three patients (21 men and 12 women) were treated with imidapril (5 mg/day) for 4 weeks (ACE-I group), and 40 (23 men and 17 women) were not treated with ACE-I (non-ACE-I group). All of the women were postmenopausal. Coronary blood flow in the left anterior descending artery was evaluated by measuring Doppler flow velocity. Net coronary t-PA release was determined as (coronary sinus-aorta gradient of t-PA)x(coronary blood flow)x[(100-hematocrit)/100]. Age, arterial pressure, heart rate, lipid levels, coronary flow, and the plasma level of t-PA at either aorta or coronary sinus were comparable among the 4 groups. In women, net t-PA release in the ACE-I group was significantly higher than that in the other groups (P<0.05; man non-ACE-I group: 1.4+/-2.6 ng/mL; woman non-ACE-I group: 1.4+/-3.1 ng/mL; man ACE-I group: -1.8+/-2.8 ng/mL; woman ACE-I group: 14.8+/-3.6 ng/mL). Correction for smoking status gave similar results. There was a significant negative correlation between serum ACE activity and coronary t-PA release in women (r=-0.38; P<0.05) but not in men. ACE inhibition increases coronary release of t-PA in women but not in men.

Topics: Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Coronary Angiography; Coronary Vessels; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Sex Factors; Tissue Plasminogen Activator

Renin-angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), are recommended by the American Diabetes Association for blood pressure control and prevention or management of cardiovascular disease in patients with diabetes mellitus. However, some investigators have suggested that ARBs may increase the risk of myocardial infarction in hypertensive patients. Activation of the RAS is associated with an increased risk of ischaemic events. Angiotensin II stimulates the production of plasminogen activator inhibitor type-1 (PAI-1), a powerful predictor of cardiovascular disease. ACE inhibitors are reported to reduce PAI-1 levels and activity, while ARBs do not reduce or may even elevate levels of this atherogenic marker. The objective of this study was to determine whether the ACE inhibitor imidapril reduces PAI-1 levels in hypertensive patients already being treated with an ARB.. This was a prospective cohort study carried out in primary care with a follow-up period of 6 months. Estimating the alpha error (p-value) at 0.05, the power of the test as 80%, and the difference in PAI-1 levels as 10 + or - 15 ng/mL, the required sample size was calculated to be 40. Participants were hypertensive patients taking ARBs for more than 8 weeks, and having dyslipidaemia, obesity or abnormal glucose metabolism. Imidapril 5-10 mg/day was prescribed for 6 months to reduce blood pressure to <130/80 mmHg. The main outcome measure, PAI-1 level, was measured before and 6 months after the addition of imidapril to ARBs in 21 subjects (13 men, eight women), all with abnormal glucose metabolism, nine with dyslipidaemia, and six who were obese. Bodyweight, body mass index, blood pressure, homeostasis model assessment of insulin resistance, glycosylated haemoglobin, creatinine, potassium, high sensitivity C-reactive protein (hs-CRP), and high molecular weight adiponectin levels were measured as secondary outcomes.. PAI-1 level was not significantly changed overall. Hs-CRP level was also not significantly changed; however, the high molecular weight adiponectin level was significantly increased (p = 0.044), especially in men (p = 0.026). There were no significant changes in the other outcomes measured.. The current study showed that imidapril added to ARBs did not decrease PAI-1 levels in hypertensive patients with abnormal glucose metabolism; however, this combination therapy significantly increased high molecular weight adiponectin levels in men.

Topics: Adiponectin; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; C-Reactive Protein; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; Glucose; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Primary Health Care; Prospective Studies; Treatment Outcome

Angiotensin receptor blockers (ARB) have been emerging as drugs to treat atherosclerosis. The effectiveness of the ARB losartan at reducing atherosclerosis was compared with that of ACE inhibitors in hypertensive patients. A total of 50 patients with hypertension were divided into 3 groups: a control group receiving neither an ARB nor an ACE inhibitor (n = 14), a losartan group (n = 22) receiving 50 mg/day of losartan, and an ACE inhibitor group (n = 14) receiving either 5 mg/day of enalapril or 5 mg/day of imidapril. Atherosclerosis was evaluated based on the intima-media thickness (IMT) of the common carotid artery measured by B-mode ultrasound at baseline and after approximately 12 months of treatment. After the treatment, IMT significantly decreased with losartan (from 0.87 +/- 0.14 to 0.79 +/- 0.16 mm, P < 0.05) and with ACE inhibitor (from 0.81 +/- 0.14 to 0.74 +/- 0.11 mm, P < 0.05). The reduction was comparable between the two groups, -0.078 +/- 0.136 with losartan and -0.073 +/- 0.109 mm with ACE inhibitor, and the rate of the reduction was similar between the two drugs; -0.098 +/- 0.142 mm/year with losartan and (-0.076 +/- 0.118 mm/year) with ACE inhibitor. On the contrary, IMT did not change in the control group (from 0.90 +/- 0.20 to 0.95 +/- 0.26 mm) during the treatment period. Concomitant medication and coronary risk factors such as hyperlipidemia, diabetes mellitus, and smoking did not differ significantly among the groups. The antiatherosclerotic effect of losartan on the carotid artery was comparable to that of ACE-inhibitors, and less adverse effects, such as coughing that occurs with ACE inhibitors, were observed. Losartan appears to be a better alternative to ACE inhibitors for treating atherosclerosis in Japanese hypertensive patients.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atherosclerosis; Carotid Artery, Common; Enalapril; Humans; Hypertension; Imidazolidines; Losartan; Middle Aged; Tunica Intima; Tunica Media; Ultrasonography

We investigated the effect of the timing of imidapril administration in patients with morning hypertension (home blood pressure [HBP] in the morning [morning HBP] > or =135/85 mmHg). Eighty-seven patients (mean age, 61 years; 48% women) with morning hypertension each measured HBP in the early morning, before going to bed for the final five days of the observation, and during treatment. Imidapril (2.5 or 5.0 mg) was administered once every morning (n = 57) or at bedtime (n = 30) for four weeks (monotherapy: n = 30, 34%; combined with other antihypertensive drugs: n = 57, 66%). The morning (M) versus evening (E) effect (M/E ratio) and the evening versus morning effect (E/M ratio) were calculated to assess the duration of imidapril action. Morning HBP was significantly reduced (all p < 0.05) except when 2.5 mg of imidapril was administered once at bedtime. The individual M/E ratios expressed as means +/- standard deviation for systolic HBP were 0.9 +/- 0.7 and 0.7 +/- 0.7 for the morning administration of 2.5 and 5.0 mg of imidapril, respectively. The corresponding E/M ratios for bedtime administration were 0.3 +/- 0.5 and 1.0 +/- 0.7, respectively. One daily dose of imidapril taken either in the morning or at bedtime lowered morning HBP, indicating that imidapril is useful for controlling morning hypertension.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Determination; Circadian Rhythm; Drug Administration Schedule; Female; Heart Rate; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Self Care; Time Factors

Many clinical trials have demonstrated that angiotensin converting enzyme inhibitors have protective effects on organ damage, suggesting the importance of inhibition of the renin-angiotensin system. In this study, we investigated the effects of a non-depressor dose of imidapril on organ damage induced by diabetes and hypertension. Diabetes was induced by an intravenous injection of streptozotocin (STZ, 40 mg/kg) in 15-week-old male spontaneously hypertensive rats (SHR). Imidapril (2 mg/kg/day) or vehicle was given orally for 28 days, and then the heart weight, left ventricle mass (LVM), urinary albumin excretion (UAE) and endothelial function were examined, as well as the urinary NOx level and local hepatocyte growth factor (HGF) expression. There were no significant differences between the treated groups in systolic blood pressure and plasma parameters. On the other hand, UAE was significantly suppressed in the imidapril-treated group (450+/-44 mg/day) compared to the vehicle-treated group (963+/-182 mg/day) (p<0.01). Moreover, endothelial function assessed by dilative reaction to acetylcholine as well as cardiac hypertrophy assessed by both heart/body weight ratio and LVM were significantly improved in the imidapril-treated group (p<0.05 and p<0.01, respectively). The urinary NOx concentration and local HGF expression in vessel walls were also significantly increased in the imidapril-treated group (p<0.01). A non-depressor dose of imidapril showed protective effects against organ damage in diabetic SHR, which may be partially due to the increase of HGF and NO.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Diabetes Complications; Diabetes Mellitus, Experimental; Endothelium, Vascular; Heart Ventricles; Hepatocyte Growth Factor; Hypertension; Imidazolidines; Male; Nitric Oxide; Rats; Rats, Inbred SHR; Renin-Angiotensin System

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Clinical Trials as Topic; Humans; Hypertension; Imidazolidines; Treatment Outcome

We investigated the effect of adding spironolactone to treatment with an angiotensin-converting enzyme (ACE) inhibitor, imidapril, in Dahl salt-sensitive (DS) hypertensive heart failure rats with preserved systolic function. Male DS rats were fed laboratory chow containing 8% NaCl from 7 weeks of age. Rats were divided into four groups and treated for 9 weeks with vehicle alone (water; n = 23), the ACE inhibitor imidapril (1 mg kg(-1) day(-1); n = 16), spironolactone (2 mg kg(-1) day(-1); n = 15), or a combination of imidapril and spironolactone at the doses above (n = 16). The left ventricular weight to body weight (BW) ratio was significantly lower in the imidapril group (3.28 +/- 0.30 mg g(-1)) and the combination group (3.34 +/- 0.38 mg g(-1)) than in the vehicle group (3.71 +/- 0.46 mg g(-1)). Adding spironolactone to imidapril inhibited an increase in the ratio of lung weight to BW (4.38 +/- 0.50 mg g(-1)) related to high salt intake, while monotherapy (imidapril group, 4.61 +/- 0.90 mg g(-1); spironolactone group, 5.40 +/- 2.50) did not significantly change the ratio from that seen with vehicle treatment (6.32 +/- 3.62 mg g(-1)). All active treatments (imidapril, 0.66% +/- 0.67%; spironolactone, 0.51% +/- 0.55%; both together, 0.31% +/- 0.26%) inhibited a salt-intake related increase in the percentage area representing fibrous tissue compared with vehicle treatment alone (1.81% +/- 1.51%). These findings suggest that adding spironolactone to an ACE inhibitor is more effective in improving pulmonary congestion and edema in hypertensive heart failure with preserved systolic function than an ACE inhibitor alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Output, Low; Drug Therapy, Combination; Hypertension; Imidazolidines; Male; Mineralocorticoid Receptor Antagonists; Pulmonary Edema; Rats; Rats, Inbred Dahl; Spironolactone

Imidapril is an angiotensin-converting enzyme inhibitor that is widely used in treating hypertension, although the responses vary among individuals. We investigated whether a single nucleotide polymorphism at position -816 of the carboxylesterase 1 (CES1) gene, which activates imidapril in the liver, is involved in the responsiveness to imidapril medication. A total of 105 Japanese hypertensives with systolic/diastolic blood pressures (SBP/DBP) of 140/90 mmHg or higher were prescribed 5-10 mg/day of imidapril. At baseline, blood pressure levels were not different between patients with and those without the -816C allele (AA vs. AC+ CC groups). After 8 weeks of treatment, we classified the responders and non-responders based on the decline in their blood pressures, and found that the responder rate was significantly higher in the AC+CC group than in the AA group (p=0.0331). Also, the reduction in SBP was significantly greater in the AC+CC group than in the AA group (24.7+/-11.8 vs. 17.6+/-16.8 mmHg, p=0.0184). Furthermore, an in vitro reporter assay revealed that the -816C construct had significantly higher promoter activity (p<0.0001). These findings suggest that the A(-816)C polymorphism affects the transcriptional activity, and that this may account for the responsiveness to imidapril.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Carboxylesterase; Female; Genotype; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Polymorphism, Single Nucleotide; Promoter Regions, Genetic

Studies were performed to test the hypothesis that the angiotensin-converting enzyme (ACE)/epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases (ERK) pathway, nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase/lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) pathway, and Rho-kinase pathway contribute to the pathogenesis of aldosterone/salt-induced hypertensive rats. Wistar rats were given 1% NaCl to drink and treated with one of the following combinations for 6 weeks: vehicle; aldosterone (0.75 microg/h); aldosterone plus a mineralocorticoid receptor antagonist, spironolactone (20 mg/kg/day); aldosterone plus an ACE inhibitor, imidapril (1 mg/kg/day); aldosterone plus an NAD(P)H oxidase inhibitor, apocynin (0.5 mmol/l); and aldosterone plus an Rho-kinase inhibitor, Y-27632 (3 mg/kg/day). Upregulated expression of ACE and EGFR and p44/p42ERK phosphorylation were suppressed by spironolactone or imidapril. Upregulated NAD(P)H oxidase subunits and LOX-1 expression were inhibited by spironolactone or apocynin. Increased expression of RhoA and Rho-kinase and myosin light chain phosphorylation were decreased by spironolactone or Y-27632. Moreover, these drugs effectively inhibited the vascular lesion formation, as measured by the medial thickness and level of perivascular fibrosis, and suppressed the expression of transforming growth factor-beta1, type I and III collagen, and monocyte chemoattractant protein-1 mRNA. Spironolactone may be useful as a cardioprotective agent to prevent cardiovascular remodeling via the ACE/EGFR/ERK, NAD(P)H oxidase/LOX-1, and Rho-kinase pathways.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Chemokine CCL2; Coronary Vessels; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Fibrillar Collagens; Gene Expression; Heart Ventricles; Hypertension; Imidazolidines; Intracellular Signaling Peptides and Proteins; Male; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Peptidyl-Dipeptidase A; Phosphorylation; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; rho-Associated Kinases; rhoA GTP-Binding Protein; Scavenger Receptors, Class E; Signal Transduction; Sodium Chloride; Spironolactone; Transforming Growth Factor beta; Transforming Growth Factor beta1

To compare diverse effects of angiotensin II type 1 receptor antagonists (irbesartan) and angiotensin converting enzyme inhibitors (imidapril) on left ventricular remodeling in spontaneously hypertensive rats (SHR). Thirty male SHR were randomly divided into three groups: SHR-IR (treated with irbesartan, 50 mg/kg), SHR-IM (imidapril, 3 mg/kg), SHR-C (placebo). Ten male Wistar Kyoto rats (WKY) treated with placebo acted as the control. All treatments were administered once daily from 14 to 27 weeks of age. Imidapril and irbesartan have the similar inhibitor effects on blood pressure and left ventricular mass indexes in SHR. Despite both drugs suppressed ERK-1 protein expression, decreased cardiomyocytes apoptosis index, blocked collagen type I deposition, reduced TGF-beta(1) gene expression in SHR, imidapril elicits a stronger inhibitory effect. Irbesartan had little effect on MKP-1 protein expression, but imidapril decreased it significantly. As a result, the ERK-1/MKP-1 ratio in SHR-IR was significantly greater than that in SHR-IM (P < 0.05). These results suggest that the balance between MKP-1 and ERKs in myocardial tissue is important for cardiac cell proliferation and growth. They also indicate that the similar efficacy of antihypertensive treatment in reducing blood pressure does not predict the similar capacity to control the individual facet of left ventricular remodeling. Irbesartan is more effective in regressing the homeostasis between ERK-1 and MKP-1, however imidapril is superior in suppressing apoptosis and collagen synthesis in cardiac tissue.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Apoptosis; Biphenyl Compounds; Blood Pressure; Cell Cycle Proteins; Collagen Type I; Dual Specificity Phosphatase 1; Gene Expression; Heart Ventricles; Hypertension; Imidazoles; Imidazolidines; Immediate-Early Proteins; Irbesartan; Male; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Phosphoprotein Phosphatases; Protein Phosphatase 1; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Tetrazoles; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

In a survey including 2224 patients with essential hypertension we investigated efficacy and tolerability of the new ACE-inhibitor Imidapril. Mean blood pressure at baseline was 172 +/- 19/98 +/- 10 mmHg. Treatment with Imidapril 5-20 mg once daily caused a decrease in BP by 21 +/- 17/11 +/- 10 mmHg (p < 0.01/0.01). Systolic BP was reduced by > 15 mmHg in 71% diastolic BP by > 10 mmHg in 64% of patients. 29% of patients achieved the treatment goal of a blood pressure < or = 140/90 within an average of 26 days. Imidapril decreased pulse-pressure (one of the most important risk markers in hypertension) by 18% (74 +/- 17 to 61 +/- 11 mmHg, p < 0.01). ACE-inhibitor related adverse effects (cough, vertigo, headache, pruritus, tachycardia, orthostatic dysregulation or nausea) were observed in 38 patients (< 2%). Efficacy of treatment was graded by the physician in charge of the patient care by means of a questionnaire. Gradings were excellent or good in 96% of patients, moderate in 3% and poor in < 1%. In summary, the effects of Imidapril on blood pressure were comparable to those of other ACE-inhibitors. However, the frequency of adverse effects was low and similar to that of angiotensin-II-antagonists.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diastole; Humans; Hypertension; Imidazoles; Imidazolidines; Pulse; Reproducibility of Results; Surveys and Questionnaires; Systole

The purpose of this study was to evaluate the effects of the angiotensin-converting enzyme (ACE) inhibitor imidapril and the calcium antagonist amlodipine on endothelial function before and after 2, 4, 8, 12, 24 and 48 weeks of treatment.. There are limited data on whether and how long endothelial function is improved after initiation of ACE inhibitor treatment and how the grade of endothelial function further progresses after improvement of endothelial dysfunction in patients with essential hypertension.. The forearm blood flow (FBF) was measured in 25 patients with essential hypertension and in 25 normotensive subjects by using strain-gauge plethysmography during reactive hyperemia (RH) (280 mm Hg for 5 min) and after sublingual administration of nitroglycerin (NTG, 0.3 mg).. The FBF of patients with essential hypertension during RH was significantly less than that of normotensive subjects. The increase in FBF after sublingual NTG was similar in both groups. Both imidapril (n = 13) and amlodipine (n = 12) significantly reduced systolic blood pressure and diastolic after eight weeks of treatment from the pretreatment values. Forearm vascular resistance was significantly decreased after two weeks of treatment. Imidapril significantly augmented RH after 12 weeks of treatment from the pretreatment values (31.6 +/- 5.7 to 38.2 +/- 6.0 m/min per 100 ml tissue, p < 0.05), whereas amlodipine did not alter RH for each treatment period. The ability of imidapril to improve RH was maintained throughout the 48-week treatment period. There was no significant difference in RH at 12, 24 and 48 weeks. The increase in FBF after sublingual administration of NTG was similar in all treatment periods for the two groups. The infusion of NG-monomethyl-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished the enhancement of RH in hypertensive patients treated with imidapril.. These findings suggest that the ACE inhibitor imidapril augments RH after 12 weeks of treatment in patients with essential hypertension and that this ACE inhibitor-induced augmentation of RH may be due to an increase in NO.

Topics: Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Endothelium, Vascular; Female; Forearm; Humans; Hyperemia; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; omega-N-Methylarginine; Regional Blood Flow; Vascular Resistance; Vasodilation

Chronically administered N(omega)nitro-L-arginine methyl ester (L-NAME) produces vascular structural changes and fibrosis of the left ventricle (LV). However, very few studies have evaluated whether the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors on these myocardial remodelings are associated with local gene expression of nitric oxide synthase (NOS) and ACE mRNA in the LV. Effects of long term treatment with imidapril, an ACE inhibitor, on gene expression of endothelial-cell NOS (eNOS) and ACE mRNA in the LV and its relation to myocardial remodeling in L-NAME-induced hypertensive rats were evaluated. Fifteen male Sprague-Dawley rats were given L-NAME (60 mg/ kg/day) in drinking water for 6 weeks to induce hypertension, and then treated with imidapril (L-NAME-I, n = 8, 1 mg/kg/day, subdepressor dose), or a vehicle (L-NAME-V, n = 7) for 4 weeks. Age-matched rats (C, n = 7) served as a control group. Blood pressure in L-NAME-V and L-NAME-I was similar and significantly higher than that in C. The level of eNOS mRNA in the LV was significantly decreased in L-NAME-V compared with C, and was significantly increased in L-NAME-I compared with C and L-NAME-V. The ACE mRNA and type I collagen mRNA expression levels were significantly increased in L-NAME-V compared with C, and significantly suppressed in L-NAME-I compared with L-NAME-V. L-NAME-V demonstrated a significant increase in wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis. These changes in the microvasculature were improved significantly by imidapril. Myocardial remodeling in L-NAME-induced hypertensive rats was significantly ameliorated by a subdepressor dose of imidapril, which may be due to an increase in local eNOS mRNA expression and a decrease in angiotensin II in the LV.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen; Disease Models, Animal; DNA Primers; Gene Expression; Heart Ventricles; Hypertension; Imidazoles; Imidazolidines; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ventricular Remodeling

There is increasing evidence of important cardiovascular effects of aldosterone via classical mineralocorticoid receptors in the heart. Aldosterone plus excess salt administration has been shown to produce both cardiac hypertrophy and cardiac fibrosis in rats. Various clinical studies have reported that aldosterone plays an important role in cardiac hypertrophy; however, the factors that control plasma aldosterone concentrations during angiotensin-converting enzyme (ACE) inhibitor treatment have still not been established. In the present study, we examined the relationship between plasma aldosterone concentrations and the degree of ACE inhibition in 25 essential hypertensive patients treated with an ACE inhibitor. Blood pressure decreased with treatment and plasma ACE activity, estimated in vitro (by a colorimetric method) and in vivo (by plasma angiotensin II/angiotensin I ratio) assay, was suppressed compared with that of hypertensive patients treated with medication other than ACE inhibitors. No relationship was found between the level of ACE inhibition and plasma aldosterone concentrations, which rose in parallel with the duration of ACE inhibitor treatment. The present study demonstrates that continuous ACE inhibitor therapy produces significant suppression of plasma ACE activity in essential hypertensive patients, but that no relationship exists between plasma aldosterone concentrations and levels of ACE inhibition. Plasma aldosterone concentrations tend to increase with the duration of ACE inhibitor treatment, although this increase did not reflect a reduced inhibition of ACE activity.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Biomarkers; Blood Pressure; Echocardiography; Electrolytes; Enalapril; Female; Heart Rate; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Peptidyl-Dipeptidase A; Radioimmunoassay; Renin

Inhibitors of angiotensin converting enzyme (ACE) have been developed recently for therapeutic purposes in hypertension and ischemic cardiovascular diseases. Ogiku et al. reported that one such inhibitor, imidapril, significantly prolonged survival in stroke-prone spontaneously hypertensive rats (SHRSP). The present study was designed to investigate the effect of imidapril on cerebral blood vessels in SHRSP to clarify role of the ACE inhibitor in mechanisms of cerebral thrombosis and stroke. Imidapril was administered orally at 1.0 and 5.0 mg/kg/day for 3 weeks from the age of 7 weeks, and was shown to prevent the usual increase in blood pressure seen in these animals. It also delayed He-Ne laser-induced cerebral thrombosis and increased significantly the plasma concentration of nitric oxide metabolites (NO2/NO3). To confirm the association between nitric oxide (NO) and these effects of imidapril, an inhibitor of nitric oxide synthase, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) was dissolved in drinking water and administered to the animals for 3 weeks. Four of six rats died from stroke when L-NAME was given alone. When imidapril (5.0 mg/kg/day) was administered with L-NAME, however, the animals showed no signs or symptoms of stroke. In these instances, therefore, the concurrent administration of L-NAME with imidapril reversed significantly the effects of imidapril. Intravenous injection of imidaprilat (100 microg/kg), an active metabolite of imidapril, also decreased blood pressure significantly and increased the plasma levels of NO2/NO3 after 5 min. Moreover, imidaprilat enlarged arteriolar diameters and caused an increase in red cell velocity and mean blood flow in pial arterioles after 15 min. The results strongly suggested that imidapril protects cerebral vessels in SHRSP by elevating the release of NO, thereby improving the cerebral circulation and reducing the tendency to thrombosis and stroke.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arterioles; Cerebral Arteries; Drug Evaluation, Preclinical; Female; Genetic Predisposition to Disease; Hemorheology; Hypertension; Imidazoles; Imidazolidines; Intracranial Thrombosis; Lasers; Male; Microcirculation; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Inbred SHR

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

A 53-year-old male was found to have hypertension caused by the significant secretion of renin from an atrophic left kidney. He had undergone extracorporeal shock-wave lithotripsy (ESWL) for left renal lithiasis 11 years previously. A renal dynamic study with 99mTc-diethylenetriaminepentaacetic acid (DTPA) indicated that the rate of renal excretion and uptake was decreased in the left kidney and normal in the right kidney. Renal angiography demonstrated a normal right renal artery and a small but nonstenotic left renal artery. The ratio of PRA in the left renal vein to that in the right renal vein was 1.7. Blood pressure could be lowered to the range of 140-150/80-90 mmHg with imidapril, an ACE inhibitor. ESWL may cause hypertension via the well-known Page kidney effect. In this case, the kidney, atrophic probably due to ESWL, released a significant amount of renin.

Topics: Angiography, Digital Subtraction; Angiotensin-Converting Enzyme Inhibitors; Aortography; Blood Pressure; Humans; Hypertension; Imidazoles; Imidazolidines; Kidney Calculi; Lithotripsy; Male; Middle Aged; Renal Artery; Renal Veins; Renin; Technetium Tc 99m Pentetate

To examine whether chronic oral treatment with an angiotensin-converting enzyme inhibitor imidapril and an angiotensin II type 1 receptor antagonist TCV-116 would alter the response to angiotensin II in the rostral ventrolateral medulla.. Twelve-week-old spontaneously hypertensive rats (SHR) were treated with imidapril (20 mg/kg per day, n = 7), TCV-116 (5 mg/kg per day, n = 8) or vehicle (n = 8) for 4 weeks. Wistar- Kyoto rats (WKY) (n = 8) served as normotensive controls. At 16 weeks of age, angiotensin II (100 pmol) was microinjected into the rostral ventrolateral medulla of anaesthetized rats.. Blood pressure decreased significantly in the rats treated with either imidapril or TCV-116. Pressor responses to angiotensin II microinjected into the rostral ventrolateral medulla were comparable in the untreated SHR, the imidapril-treated SHR and WKY (12 +/- 2, 15 +/- 4 and 10 +/- 1 mmHg, respectively), but were abolished in SHR treated with TCV-116 (0 +/- 2 mmHg, P< 0.01). Angiotensin-converting enzyme activity in the brain stem was significantly lower in SHR treated with imidapril (0.70 +/- 0.06 nmol/mg per h), but significantly higher in SHR treated with TCV-116 (1.62 +/- 0.04 nmol/mg per h) than in the untreated SHR (1.37 +/- 0.05 nmol/mg per h).. Chronic oral treatment with imidapril and TCV-116 may have divergent influences on the renin-angiotensin system within the brain stem. TCV-116, but not imidapril, abolishes the pressor effect of angiotensin II in the rostral ventrolateral medulla.

Topics: Administration, Oral; Angiotensin II; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Hypertension; Imidazoles; Imidazolidines; Male; Medulla Oblongata; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Tetrazoles; Vasoconstrictor Agents

A 85-year-old woman with diabetes mellitus and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by hyperkalemia. The T wave during right ventricular pacing was tall and tent-shaped while the concentration of serum potassium was high, and its amplitude during pacing was decreased after correction of the serum potassium level. Simultaneously with the correction, normal sinus rhythm was restored. The cause of hyperkalemia was considered to be several doses of loxoprofen, a nonsteroidal anti-inflammatory drug (NSAID), prescribed for her lumbago by an orthopedic specialist, in addition to the long-term intake of imidapril, an angiotensin-converting enzyme inhibitor (ACEI), prescribed for her hypertension by a cardiologist. This case warns physicians that the combination of NSAID and ACEI can produce serious side effects in aged patients who frequently suffer from hypertension, diabetes mellitus, ischemic heart disease, and degenerative joint disease.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Bradycardia; Drug Therapy, Combination; Electrocardiography; Female; Humans; Hyperkalemia; Hypertension; Imidazoles; Imidazolidines; Low Back Pain; Phenylpropionates; Syncope

To elucidate the relationship between renin-angiotensin system and nitric oxide in hypertensive heart failure, we evaluated the effects of long-term treatment with imidapril, angiotensin-converting enzyme inhibitor, on endothelial-cell nitric oxide synthase (eNOS) and inducible NOS (iNOS) expression in the left ventricle (LV) and its relation to myocardial remodelling in failing heart of Dahl salt-sensitive hypertensive rats (DS) 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 fatal left ventricular failure with chamber dilatation at 18 weeks (DSCHF). Imidapril (DSCHF-I, n = 7, 1 mg/kg/day, subdepressor dose) or vehicle (DSCHF-V, n = 7) were given from DSLVH to DSCHF stage for 7 weeks, and age-matched (18 weeks) Dahl salt-resistant rats fed the same diet were served as control group (DR-C, n = 7).. Markedly increased left ventricular end-diastolic diameter and reduced fractional shortening in DSCHF-V was significantly ameliorated in DSCHF-I using transthoracic echocardiography. The level of eNOS mRNA and protein in the LV was significantly suppressed in DSCHF-V compared with DR-C, and significantly increased in DSCHF-I compared with DR-C and DSCHF-V. The iNOS mRNA and protein and the fibrosis factor expression of type I collagen mRNA were significantly increased in DSCHF-V compared with DR-C, and significantly decreased in DSCHF-I compared with DSCHF-V. DSCHF-V demonstrated a significant increase in wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis. These changes in the microvasculature were improved significantly by imidapril.. Subdepressor dose of imidapril may ameliorate the endothelial damage not only by inhibiting production of angiotensin II but also by promoting eNOS and inhibiting iNOS mRNA and protein expression in the LV, and this increased eNOS mRNA and protein level may have a role in the improvement of congestive heart failure and myocardial remodelling.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Collagen; Glyceraldehyde-3-Phosphate Dehydrogenases; Hypertension; Imidazoles; Imidazolidines; Male; Myocardium; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Rats, Inbred Dahl; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ventricular Remodeling

To examine chronic changes in mitogen-activated protein (MAP) kinases in cardiac hypertrophy, we determined the activities of two subfamilies of MAP kinases, including extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs), in the heart of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) aged 5, 8, 14, and 24 weeks. MAP kinases were determined by using in-gel kinase assay. In both the left and right ventricles of WKY, the activities of ERKs (p44ERK and p42ERK) and JNKs (p46JNK and p55JNK) decreased significantly with age, indicating that aging remarkably downregulated cardiac MAP kinase activities. In SHRSP, left ventricular ERK and JNK activities were already significantly higher at the mild hypertensive phase than they were in the same age of WKY, and they remained higher until development of left ventricular hypertrophy. On the contrary, the right ventricle of SHRSP, which did not exhibit cardiac hypertrophy, had no significant increase in ERK or JNK activities compared with WKY, except for the slight increase in p55JNK in 24-week-old SHRSP. Antihypertensive treatment of SHRSP with imidapril, an angiotensin-converting enzyme inhibitor, decreased the left ventricular JNK activities (P<.01) but did not affect ERK activities, suggesting the contribution of hypertension or the renin-angiotensin system to the increase in JNKs. Our observations provide the first evidence that both ERK and JNK activities are higher in the left ventricle of SHRSP than WKY. However, further study is needed to elucidate the mechanism and the significance of the increased cardiac MAP kinases in SHRSP.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cardiomegaly; Cerebrovascular Disorders; Heart; Hypertension; Imidazoles; Imidazolidines; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases; Myocardium; Protein Kinases; Rats; Rats, Inbred Strains; Rats, Inbred WKY

The present study was performed to compare cardioprotective effects of an angiotensin-converting-enzyme inhibitor, imidapril, and of a Ca2+ channel antagonist, amlodipine, against the cardiac hypertrophy in male spontaneously hypertensive rats (SHRs) at the established stage of hypertension. Fifteen-week-old SHRs were given imidapril (2 and 5 mg/kg/day) or amlodipine (10 mg/kg/day) by gavage for 8 weeks. Three hours after the 1st treatment, imidapril moderately reduced blood pressure without changing heart rate, while amlodipine caused a marked reduction in blood pressure accompanied by transient tachycardia. At the end of the treatments, ventricular weight in the imidapril-treated groups was markedly lower, but that in the amlodipine-treated group was only slightly lower than that in the vehicle-treated group. Myocardial collagen content in the imidapril-treated group tended to be decreased, and significant reduction was observed in the low-dose group. In another experiment, the isolated heart of the imidapril-treated animals demonstrated better cardiac compliance than that in the vehicle-treated animals. In contrast, amlodipine failed to improve cardiac function. The present results suggest that imidapril possesses advantageous effects to prevent cardiac hypertrophy and deteriorated cardiac function in SHRs of established stage of hypertension as compared with amlodipine.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Calcium Channel Blockers; Cardiovascular Agents; Collagen; Heart Function Tests; Heart Rate; Hypertension; Imidazoles; Imidazolidines; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY

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

We investigated the ability of the ETA receptor antagonist T-0115 and the angiotensin-converting enzyme (ACE) inhibitor imidapril hydrochloride to prevent hypertensive complications induced in rats by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/l, or L-NAME plus imidapril 10 mg/l in the drinking water. In rats treated with L-NAME 500 mg/l plus T-0115, T-0115 was given in the food at a dose of 0.2 mg/g food or 0.6 mg/g food. We then collected 24-h urine samples at 2, 4, and 6 wk, obtained blood samples at 6 wk, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90+/-0.65 vs. 0.05+/-0.02 mg/d/100 g in control), and the area of the left ventricular wall (83.3+/-3.0 vs. 69.8+/-1.8 mm2 in control). The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of T-0115 0.6 mg/g food with L-NAME ameliorated the tail-cuff pressure and the albuminuria (0.56+/-0.23 mg/d/100 g), although to a lesser extent than the changes seen with imidapril 10 mg/l. T-0115 0.6 mg/g food prevented left ventricular hypertrophy as effectively as imidapril 10 mg/l (70.8+/-1.8 with T-0115 vs. 68.3+/-2.7 mm2 with imidapril). Chronic inhibition of NO synthesis produced left ventricular hypertrophy and nephrosclerosis. Our results demonstrate that inhibition of the renin-angiotensin system morely effectively prevents nephrosclerosis than does the blockade of ETA receptors in a model of hypertension induced by chronic NO blockade. However, inhibition of the ET-1 pathway appeared to be as effective as ACE inhibitors in preventing left ventricular hypertrophy in this model.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Drug Combinations; Endothelin Receptor Antagonists; Enzyme Inhibitors; Hypertension; Hypertrophy, Left Ventricular; Imidazoles; Imidazolidines; Male; Nephrosclerosis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Receptor, Endothelin A; Time Factors

Changes in valvular function and blood pressure level during long-term pharmacological anti-hypertensive therapy were investigated in patients with mild to moderate essential hypertension. Sixty-seven patients with hypertension (mean [+/-SD] 60 +/- 10 years) were followed up for 5.4 +/- 1.6 years with antihypertensive medication. During the follow-up period, valvular dysfunction was assessed by color Doppler echocardiography. Increased mitral valve regurgitation > or = grade II and/or aortic valve regurgitation > or = grade II were aggravated in 17 patients, whereas the other 50 patients did not reveal any significant changes in valvular functions. Systolic blood pressure and end-systolic wall stress at the end of the follow-up period were higher in the aggravated group (156 +/- 30 mmHg and 79 +/- 23 dyne/cm2) than in the unchanged group (143 +/- 17 mmHg and 63 +/- 18 dyne/cm2). Dimensions of the left atrium and left ventricle at both systole and diastole were enlarged in the aggravated group (37 +/- 4 to 40 +/- 4, 31 +/- 4 to 33 +/- 4 and 48 +/- 3 to 51 +/- 3 mm, respectively), but not in the unchanged group. Nine patients in the aggravated group received additional treatment with imidapril hydrochloride over 6 months in an attempt to further reduce blood pressure levels, resulting in significant improvements in systolic blood pressure (151 +/- 12 to 129 +/- 7 mmHg), diastolic blood pressure (91 +/- 4 to 79 +/- 8 mmHg), left atrial dimension (41 +/- 3 to 39 +/- 3 mm) and left ventricular end-diastolic dimension (49 +/- 4 to 48 +/- 3 mm). Adequate pharmacological intervention can ameliorate valvular dysfunction, left ventricular enlargement and increased ventricular wall stress.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Aortic Valve Insufficiency; Echocardiography, Doppler, Color; Female; Follow-Up Studies; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Middle Aged; Mitral Valve Insufficiency

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

The pharmacokinetics and pharmacodynamics (PK/PD) of a sustained-release biodegradable pellet containing imidapril, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated in comparison with those of an osmotic pump in male spontaneously hypertensive rats (SHRs). A pellet was prepared from copolymer of DL-lactic acid and glycolic acid by the melt-pressing technique. Imidapril was released in vitro from the pellet at an approximately zero-order rate and the release profile was similar to that of the osmotic pump. Imidapril was administered subcutaneously via a pellet or an osmotic pump implanted under the skin in the back of SHRs. Plasma concentrations of imidaprilat as an active metabolite of imidapril, plasma ACE activity and systolic blood pressure (SBP) were determined periodically. The plasma concentration of imidaprilat during the administration of a pellet was maintained for 4 weeks, and the plasma concentration profile was close to that of the osmotic pump. Both groups of pellet and osmotic pump significantly inhibited plasma ACE activity and reduced SBP for 4 weeks, and these action profiles were similar in both groups. In addition, in vivo release profile of the pellet was close to the in vitro release profile, and the in vivo release profiles of the pellet and the osmotic pump were similar to each other. From these results, it was found that the PK/PD of a biodegradable pellet were close to those of the osmotic pump, and it was shown that the pellet may be a useful system to maintain the plasma concentration of imidaprilat for a long time.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biodegradation, Environmental; Blood Pressure; Delayed-Action Preparations; Drug Implants; Hypertension; Imidazoles; Imidazolidines; Infusion Pumps, Implantable; Male; Osmotic Pressure; Rats; Rats, Inbred SHR

We evaluated the effects of angiotensin-converting enzyme (ACE) inhibition on metabolic changes in myocardial organelles, myocardial hypertrophy, and interstitial fibrosis in the early stage of hypertension. An ACE inhibitor, imidapril (2.5 mg/kg per day), a calcium-channel blocker, diltiazem (30 mg/kg per day), or vehicle was given to spontaneously hypertensive rats (SHRs) from 10 to 18 weeks of age. Single myocytes were isolated enzymatically from the left ventricles of these SHRs and normotensive Wistar-Kyoto (WKY) controls at 18 weeks of age. In single ventricular myocytes, enzyme activities in the sarcoplasmic reticulum (SR) and the sarcolemma (SL) and the mitochondrial respiratory control ratio (RCR) were determined. In 18-week-old SHRs receiving vehicle, myocardial hypertrophy and interstitial fibrosis developed, and SR Ca2+ AT-Pase activity and the mitochondrial RCR were significantly lower and SL Na+, K(+)-ATPase activity was significantly higher than in age-matched WKYs. However, compared with diltiazem, imidapril was better able to prevent the development of myocardial hypertrophy and interstitial fibrosis, to improve SR Ca(2+)-ATPase activity and the mitochondrial RCR, and to increase SL Na+, K(+)-ATPase activity. These results suggest that ACE inhibition can prevent the development of morphologic changes associated with hypertension-induced left ventricular remodeling, such as myocardial hypertrophy and interstitial fibrosis, and can counteract ongoing dysfunction of organelle metabolism early in the development of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Calcium-Transporting ATPases; Cardiomegaly; Diltiazem; Hypertension; Imidazoles; Imidazolidines; Male; Mitochondria, Heart; Myocardium; Organelles; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium-Potassium-Exchanging ATPase

To examine whether endothelial dysfunction in hypertension is reversible or not, we studied the effects of imidapril, an angiotensin-converting enzyme inhibitor, on nitric oxide release in stroke-prone spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. After a 4-week treatment with imidapril (1 or 10 mg/d SC) or vehicle, acetylcholine-induced vasodilation and nitric oxide release in the isolated kidneys were determined. Nitric oxide release was measured by a chemiluminescense assay. Imidapril lowered blood pressure in stroke-prone SHR in a dose-dependent manner. Untreated stroke-prone SHR exhibited significantly attenuated responses to acetylcholine (10(-8) mol/L) of both renal perfusion pressure (stroke-prone SHE 42 +/- 4% versus Wistar-Kyoto rats [WKY] 58 +/- 4% [mean +/- SE], P < .01) and nitric oxide release (stroke-prone SHR +7.6 +/- 2.1 versus WKY +29.7 +/- 9.7 fmol/min per gram of kidney wt, P < .01). Imidapril at 10 mg/d significantly increased acetylcholine-induced renal vasodilation and nitric oxide release in stroke-prone SHR (renal perfusion pressure, 56 +/- 3%; nitric oxide release, +27.1 +/- 6.4 fmol/min per gram of kidney wt; both P < .01 versus stroke-prone SHR treated with vehicle). On the other hand, imidapril neither decreased blood pressure nor changed nitric oxide release induced by acetylcholine in DOCA-salt hypertensive rats. Staining for endothelial nitric oxide synthase and brain nitric oxide synthase was clearly detected in the kidneys of both stroke-prone SHR and WKY, whereas staining intensity was weaker in DOCA-salt hypertensive rats. Inducible nitric oxide synthase immunoreactivity was barely noticeable in any type of rat. Thus, imidapril restored endothelial damage by pressure-dependent mechanisms. Most of the nitric oxide detected in the perfusate seemed to be derived from constitutive nitric oxide synthase.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Hypertension; Imidazoles; Imidazolidines; Infusion Pumps, Implantable; Kidney; Nitric Oxide; 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

The antihypertensive mechanism of imidapril was investigated in relation to its inhibition of ACE activities in the serum, thoracic-abdominal aorta, lung, kidney, heart and brain from adult spontaneously hypertensive rats (SHRs). In comparison with normotensive rats (NTRs), the ACE activities in the aorta, heart, brain and lung were higher, while those in the serum and kidney were considerably lower. Imidapril (2 mg/kg) showed remarkable inhibitions within 6 hr in all tissues, except for the brain, after a single oral administration. Consecutive administration of imidapril (2 mg/kg/day) for 30 days produced inhibitions in all tissues. The inhibitions in the serum, aorta and lung were greater, and the duration of inhibition in the aorta, brain and lung were longer. Blood pressure declined gradually until 6 hr, and the reductions were significant at 24 hr after the single and chronic administrations. Imidapril (0.5 mg/kg, ineffective on normal blood pressure) inhibited ACE activities in NTRs similarly. Enalapril at the same dose exhibited less ACE inhibition and antihypertension. These results suggest that the ACE inhibition in the serum, lung and aorta by imidapril correlate with the antihypertension in SHRs; especially, the lung and vascular ACE inhibitions play an important role in the duration of antihypertension in SHRs.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Brain; Hypertension; Imidazoles; Imidazolidines; In Vitro Techniques; Lung; Male; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Wistar

To investigate the involvement of the sympathoinhibitory effect of imidapril and enalapril in their antihypertensive effect at a clinically reasonable dose, we studied whether some responses induced by the stimulation of the sympathetic nervous system (SNS) were affected by intravenous administration of imidaprilat and enalaprilat in curarized pithed spontaneously hypertensive rats. Imidaprilat and enalaprilat (both at 100 micrograms/kg, i.v.), which are active metabolites of imidapril and enalapril, respectively, suppressed the pressor responses to electrical stimulation (ES) of the spinal cord (T1-L7) and exogenous noradrenaline (NA). The pressor responses to NA were significantly suppressed after either alpha 1- or alpha 2-adrenoceptors were blocked. Furthermore, imidaprilat (100 micrograms/kg, i.v.) suppressed these reduced responses. When the reduced basal blood pressure was restored by vasopressin infusion, imidaprilat and enalaprilat (both at 100 micrograms/kg, i.v.) did not suppress the responses to ES and exogenous alpha-adrenoceptor agonists. They affected neither basal plasma concentrations of NA and adrenaline nor ES-induced increase of these catecholamines. These results suggest that the suppressive effects of imidaprilat and enalaprilat on the pressor responses to ES and alpha-adrenoceptors agonists are apparently observed in pithed SHR because of a reduction of vascular tone and that imidapril and enalapril do not lower the blood pressure through suppressing SNS.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Chromatography, High Pressure Liquid; Decerebrate State; Electric Stimulation; Enalapril; Enalaprilat; Epinephrine; Hypertension; Imidazoles; Imidazolidines; Male; Norepinephrine; Rats; Rats, Inbred SHR; Spinal Cord; Sympathetic Nervous System; Vasopressins

Many of the disorders in urinary, biochemical, and hematological parameters induced by salt-loading in stroke-prone spontaneously hypertensive rats (SHRSP) were significantly ameliorated by chronic treatment with angiotensin converting enzyme inhibitors, imidapril (1 and 2 mg/kg) and enalapril (2 mg/kg). Through the improvement of these parameters, the treatment reduced the incidence of stroke but did not suppress the development of hypertension. These results suggest that the prophylaxis of stroke in SHRSP is probably due to systemic improvement as judged from the parameters of renal functions.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Cell Count; Blood Pressure; Cerebrovascular Disorders; Disease Susceptibility; Electrolytes; Enalapril; Hypertension; Imidazoles; Imidazolidines; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium, Dietary

The long-term oral administration of TA-6366 (5 mg/kg/day) from 4-weeks old impeded the genetic hypertension development with only a slight decrease in heart rate in spontaneously hypertensive rats (SHRs). However, the lower dose (1 mg/kg/day) of TA-6366 did not affect the development, but it lowered blood pressure after the development was almost accomplished. Concomitantly, relative heart weights in both the groups were markedly decreased to almost the same degree. The reduction of ACE activity in the aorta, brain and lung of both groups was found at 24 hr after the final administration, particularly at the 5 mg/kg/day dose; and that of the aorta was kept at almost the same low level even on the 9th day after withdrawal. After withdrawal of TA-6366 (5 mg/kg/day), the significant decrease in blood pressure was sustained at least for 10 weeks. The beneficial effect of TA-6366 on the hypertension development in SHRs seems to be related to its strong and long-lasting ACE inhibition, especially in the vasculature.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Heart; Hypertension; Imidazoles; Imidazolidines; Longitudinal Studies; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Renin; Water-Electrolyte Balance

TA-6366 and its active metabolite 6366A inhibited swine renal angiotensin converting enzyme (ACE) activity with IC50s of 9900 and 2.6 nM, respectively. TA-6366 (0.05-0.5 mg/kg, p.o.) inhibited the angiotensin I (AT-I)-induced pressor response in rats. 6366A augmented bradykinin (BK)-induced contraction of guinea pig ileum more potently than captopril. However, when the augmentation on BK-induced hypotension in rats was used as an indicator, TA-6366 was less active than captopril. TA-6366 increased plasma renin activity and plasma AT-I concentration. Oral administration of TA-6366 lowered the blood pressure in two-kidney one-clip renal hypertensive rats at 0.5 to 2 mg/kg and in spontaneously hypertensive rats (SHRs) at 2 to 10 mg/kg. The antihypertensive effect of TA-6366 was approximately 5 times more potent than that of captopril and almost as potent as that of enalapril. In SHRs, the antihypertensive action of TA-6366 was intensified in potency when administered repeatedly. The duration of action was longer than those of captopril and enalapril. However, TA-6366 had no substantial effect on the blood pressure in DOCA/saline hypertensive rats. These results indicate that TA-6366 is a potent and long lasting antihypertensive agent and that its antihypertensive action is attributable to the inhibition of ACE.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Desoxycorticosterone; Heart Rate; Hypertension; Hypertension, Renovascular; Imidazoles; Imidazolidines; Kidney Cortex; Male; Muscle Contraction; Muscle, Smooth; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Renin; Swine