delapril and Hypertension

Angiotensin-converting enzyme inhibitors (ACEIs) are the first-line therapy for the treatment of hypertension. However, not all ACEIs are equal. Delapril is a nonsulfhydryl ACEI with unique properties. Delapril has a high lipophilicity and weak bradykinin potentiating action. As a result, delapril has a more potent inhibition capacity of vascular wall angiotensin-converting enzyme activity and a lower incidence of cough than enalapril or captopril. With regard to efficacy, delapril has a long-lasting antihypertensive effect with a trough/peak ratio that is in the upper range of different ACEIs and a positively high smoothness index. Thus, delapril effectively and smoothly reduces blood pressure over 24 h. Moreover, the benefits of delapril are not limited to hypertensive patients, but also in those with microalbuminuria, left ventricular hypertrophy, myocardial infarction or heart failure; delapril appears to be effective and well tolerated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Humans; Hypertension; Indans

The majority of patients with hypertension, and in particular high-risk patients or those with diabetes mellitus or renal dysfunction, are likely to require combination therapy with at least two antihypertensive agents (from different classes) to achieve their blood pressure (BP) target. The delapril/manidipine fixed-dose combination consists of two antihypertensive agents with different, yet complementary, mechanisms of action. Delapril/manidipine has demonstrated short- and long-term antihypertensive efficacy in a number of clinical studies in patients with hypertension with an inadequate response to monotherapy. Comparative studies have demonstrated that delapril/manidipine is as effective as enalapril/hydrochlorothiazide (HCTZ) in patients with hypertension with an inadequate response to monotherapy, and as effective as irbesartan/HCTZ, losartan/HCTZ, olmesartan medoxomil/HCTZ, ramipril/HCTZ and valsartan/HCTZ in reducing BP in patients with hypertension and diabetes, or in obese patients with hypertension. Therapy with delapril/manidipine also appears to exert beneficial effects that extend beyond a reduction in BP, including nephroprotective activity and an improvement in fibrinolytic balance, supporting its value as a treatment option in these patient populations at high or very high cardiovascular risk because of the presence of organ damage, diabetes or renal disease.

Topics: Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Clinical Trials as Topic; Diabetes Complications; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Indans; Irbesartan; Losartan; Nitrobenzenes; Obesity; Olmesartan Medoxomil; Piperazines; Ramipril; Tetrazoles; Valine; Valsartan

In patients with hypertension and diabetes, atherothrombosis is a leading cause of morbidity and mortality, and there is now compelling evidence demonstrating that lowering elevated blood pressure (BP) is one of the most beneficial aims of therapy in this high-risk population. Indeed, major international guidelines have set a target BP goal of 130/80 mmHg in high-risk patients and recommend combination treatment with two or more drug classes to help achieve this objective. Manidipine plus delapril is a fixed-dose combination of a third-generation dihydropyridine calcium antagonist and an angiotensin-converting enzyme inhibitor, which is effective in mild-to-moderately hypertensive patients with an inadequate response to monotherapy. It is also effective in the long-term (50 weeks) management of essential hypertension. Comparative studies have demonstrated that manidipine plus delapril is as effective as enalapril plus hydrochlorothiazide (HCTZ) in patients with hypertension that is unresponsive to monotherapy, and as effective as ramipril plus HCTZ, valsartan plus HCTZ, irbesartan plus HCTZ and olmesartan plus HCTZ in patients with essential hypertension and Type 2 diabetes. In addition, manidipine plus delapril exhibited renoprotective effects in normotensive Type 2 diabetic patients, and improved fibrinolytic function (significantly more than irbesartan plus HCTZ) in hypertensive patients with Type 2 diabetes. Manidipine 10 mg plus delapril 30 mg once daily was generally well tolerated, with no unexpected adverse effects and evidence of a low incidence of ankle edema. Thus, manidipine plus delapril is a fixed-dose combination treatment that significantly reduces elevated BP with once-daily administration. It is well tolerated and has ancillary properties, such as nephroprotective activity and improvement of fibrinolytic balance, which may help reduce cardiovascular morbidity and mortality, particularly in high-risk patients, such as those with Type 2 diabetes mellitus.

Topics: Blood Pressure Determination; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Male; Nitrobenzenes; Piperazines; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Survival Analysis

Although many data indicate that the management of hypertension has improved over the last two decades, there is still a large proportion of hypertensive individuals who do not receive adequate management of their blood pressure (BP). Combination therapy with two or more antihypertensive agents from different drug classes is increasingly being recognised as the most effective means of achieving target BP values by pharmacological means, particularly in the large number of patients in whom monotherapy proves to be ineffective. Use of an angiotensin-converting enzyme (ACE) inhibitor combined with a diuretic is a well established antihypertensive combination that is very effective because of the different, yet synergistic, mechanisms of actions of agents from these two drug classes. Delapril is a potent antihypertensive ACE inhibitor, and indapamide is a thiazide-like diuretic with additional antihypertensive properties. The combination of delapril and indapamide provides renoprotective effects, and indapamide is also cardioprotective. Use of these two drugs together is therefore a rational selection for combination therapy, and one that has consistently demonstrated lowering of BP to target values with a level of efficacy that is at least as good as other combinations of ACE inhibitors and diuretics. This combination has also been found to provide favourable effects on haemodynamic parameters, including left ventricular mass index and ejection fraction. Furthermore, combining an ACE inhibitor and a thiazide-type diuretic has been associated with a decreased risk of stroke and is recommended for patients with cerebrovascular disease, a setting in which the combination of delapril and indapamide has therapeutic potential. Because of the additive mechanisms of delapril and indapamide, the dose required for an effective antihypertensive effect is relatively low, and the combination is well tolerated at such doses. In particular, metabolic effects normally associated with diuretics are rare at the therapeutic dose of indapamide used in combination with delapril, making the combination suitable for patients with metabolic disorders in whom diuretic therapy would otherwise not be recommended. Delapril 30 mg and indapamide 2.5mg have been combined in a fixed combination, offering the convenience of a one-tablet-per-day antihypertensive drug regimen for most patients, which, along with good tolerability, helps to address the issue of noncompliance.

Topics: Animals; Antihypertensive Agents; Drug Combinations; Humans; Hypertension; Indans; Indapamide

High blood pressure (BP) is the major cardiovascular risk factor and the main cause of death around the world. Control of blood pressure reduces the high mortality associated with hypertension and the most recent guidelines recommend reducing arterial BP values below 140/90 mmHg for all hypertensive patients (130/80 in diabetics) as a necessary step to reduce global cardiovascular risk, which is the fundamental objective of the treatment. To achieve these target BP goals frequently requires combination therapy with two or more antihypertensive agents. Although the combination of a diuretic and an angiotensin converting enzyme inhibitor (ACEI) is the most commonly used in the clinical practice, the combination of an ACEI and a calcium channel blocker may have an additive antihypertensive effect, a favorable effect on the metabolic profile, and an increased target organ damage protection. The new oral fixed combination manidipine 10 mg/delapril 30 mg has a greater antihypertensive effect than both components of the combination separately, and in non-responders to monotherapy with manidipine or delapril the average reduction of systolic and diastolic BP is 16/10 mmHg. The combination is well tolerated and the observed adverse effects are of the same nature as those observed in patients treated with the components as monotherapy. However, combination therapy reduces the incidence of ankle edema in patients treated with manidipine.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Indans; Nitrobenzenes; Piperazines

This present study assessed the antihypertensive efficacy of the fixed combination of manidipine and delapril by ambulatory blood pressure monitoring in patients with hypertension inadequately controlled by monotherapy with either component. After a 2-week placebo period, 55 mild to moderate hypertensive patients were randomized to manidipine 20 mg o.d. or delapril 30 mg b.i.d. for 4 weeks. After this period, 30 patients, aged 30-76 years (18 males and 12 females) whose diastolic blood pressure was not adequately controlled (> or = 90 mmHg) by monotherapy were treated with the fixed combination of manidipine 10 mg plus delapril 30 mg o.d. for 8 weeks. A 24-h ambulatory blood pressure monitoring recording was performed at the end of the placebo washout, of the monotherapy and of the combination therapy. Blood pressure control over the 24 h was quantified by the trough-to-peak ratio and the smoothness index. As compared to placebo, the fixed combination of manidipine and delapril produced a statistically significant (p<0.01) decrease in sitting clinic (18 +/- 9/14 +/- 5 mmHg) and 24-h blood pressure (12 +/- 7/10 +/- 5 mmHg) without affecting heart rate. This reduction was greater than that observed with single components. At the end of the 8-week combination treatment period, the rate of normalilized patients was 73%. Treatment with the fixed combination was associated with a positively high smoothness index (1.2 +/- 0.7/13.8 +/- 0.8) and with a relatively good trough-to-peak ratio (0.46/0.60). The combination of manidipine and delapril produced significant and smooth reductions in blood pressure values, which persisted over the 24-h dosing interval. These results support the use of fixed manidipine-delapril combination in the treatment of mild to moderate hypertensive patients inadequately controlled by monotherapy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines; Random Allocation; Time Factors

Delapril, a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, which has an indanylglycine moiety differing from the proline moiety of captopril or enalapril, is an esterified prodrug that is converted in vivo to its active metabolites. Delapril effectively inhibits rabbit lung ACE activity and lowers blood pressure in spontaneously hypertensive rats. Delapril has several characteristics that differ from captopril and enalapril, including high lipophilicity and weak bradykinin potentiating action. Delapril is a more potent inhibitor of vascular wall ACE activity than enalapril or captopril. It also shows a weaker potentiating action on the citric acid-induced cough in the guinea pig model compared with captopril and enalapril. In 12 out of 150 patients with essential hypertension who complained of cough during treatment with enalapril, changing to delapril resulted in resolution of the cough in 6 out of 12 of these patients: the percentage of patients in the total population with cough decreased from 8% to 4%.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cough; Guinea Pigs; Humans; Hypertension; Indans; Rats; Rats, Inbred SHR

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Body Mass Index; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Kidney Function Tests; Male; Middle Aged; Nitrobenzenes; Piperazines; Prognosis; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome

Patients with diabetes complicated by hypertension and microalbuminuria have elevated cardiovascular risk, and controlling blood pressure in these patients is an urgent clinical priority. The present study aimed to examine the effects of a fixed-dose combination of antihypertensives on blood pressure and microalbuminuria.. Patients with type 2 diabetes, mild-to-moderate hypertension (diastolic blood pressure 85-105 mmHg, systolic blood pressure <160 mmHg, and 24-hour mean systolic blood pressure >130 mmHg), and microalbuminuria were randomized to 1 year of doubleblind treatment with fixed-dose manidipine/delapril (n=54) or losartan/hydrochlorothiazide (HCTZ) (n=56).. Blood pressure was significantly reduced at 1 year in both groups (-22.2/-14.6 mmHg and -19.5/-14.3 mmHg, for systolic and diastolic blood pressure respectively, P<0.001 for each), with no significant between-group difference. Reductions in microalbuminuria occurred in both groups, with mean changes at 1 year of -3.9 mg/mmol creatinine (95% CI -5.3, -2.5) for manidipine/delapril (P<0.001 vs. baseline) and -2.7 mg/mmol creatinine (95% CI -4.0, -1.3) for losartan/HCTZ (P<0.001 vs. baseline and P=0.199 between groups). Glycemia over the 1-year study was largely unaffected; the blood glucose concentration was reduced from baseline with manidipine/delapril, although not statistically significant (mean change -0.2 mmol/L, P=0.064). Both treatments were well tolerated, with discontinuation for adverse events for one (1.9%) patient in the manidipine/delapril group and two (3.6%) in the losartan/HCTZ group.. A fixed-dose manidipine/delapril combination represents a useful addition to the treatment options available to control hypertension complicated by diabetes and microalbuminuria.

Topics: Aged; Aged, 80 and over; Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Combinations; Female; Humans; Hydrochlorothiazide; Hypertension; Indans; Losartan; Male; Middle Aged; Nitrobenzenes; Piperazines

To compare the effect of delapril/manidipine vs olmesartan/hydrochlorothiazide (HCTZ) combination on insulin sensitivity and plasma fibrinogen in obese hypertensive patients.. After a 4-week placebo period, 88 obese, hypertensive (DBP >95 and <110 mmHg) outpatients were randomized to delapril 30 mg/manidipine 10 mg combination or to olmesartan 20 mg/HCTZ 12.5 mg combination for 24 weeks according to a prospective, randomized, open-label, blinded endpoint, parallel group design. At the end of the placebo period and treatment period, clinical BP, fasting plasma glucose (FPG), plasma insulin, insulin sensitivity (by euglycemic hyperinsulinemic clamp) and plasma fibrinogen were evaluated. Insulin sensitivity was expressed as the amount of glucose infused during the last 30 minutes (glucose infusion rate, GIR) in mg/Kg/min. The total glucose requirement (TGR) to maintain a steady-state blood glucose level in response to a defined increase in plasma insulin concentration was also evaluated.. Both combinations significantly reduced SBP/DBP values (-22.3/16.4 mmHg and -22.6/17.2 mmHg, respectively, all p <0.001 vs placebo). GIR was significantly increased only by delapril/manidipine (+3.01 mg/min/Kg, p=0.038 vs placebo), the difference between treatments being significant (p <0.05). TGR was significantly increased by delapril/manidipine (+9.7 g, p=0.034), while it was unaffected by olmesartan/HCTZ. Plasma insulin as well as fibrinogen were significantly reduced by delapril/manidipine (-17.8 pmol/l, p=0.047 and -67.5 mg/dl, p=0.021, respectively), but not by olmesartan/HCTZ, the difference between the two treatments being statistically significant (p <0.05).. In obese hypertensive patients the delapril/manidipine combination but not the olmesartan/HCTZ combination significantly decreased insulin resistance and plasma fibrinogen levels, despite the similar BP lowering efficacy.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Female; Fibrinogen; Glucose Clamp Technique; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Indans; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Obesity; Piperazines; Tetrazoles

Hypertension markedly increases the already high risk for cardiovascular complications in patients with diabetes mellitus. Less than one in eight patients with hypertension and type 2 diabetes have adequately controlled blood pressure. As a result, antihypertensive combinations are now widely used in management of hypertension associated with diabetes.. This double-blind study investigated efficacy of a new fixed dose combination of a calcium antagonist, manidipine 10 mg, and an angiotensin-converting enzyme inhibitor, delapril 30 mg, compared with a combination of an angiotensin receptor blocker, losartan 50 mg, and a diuretic, hydrochlorothiazide 12.5 mg. Patients with hypertension (blood pressure > or = 130/80 mmHg) with controlled type 2 diabetes (HbA1c < or = 7.5%) were randomized to manidipine/delapril (n = 153) or losartan/hydrochlorothiazide (n = 161), administered once daily for 12 weeks. Patients underwent ambulatory blood pressure monitor evaluation at baseline and end of treatment.. Mean decreases in 24-h systolic blood pressure were seen with both manidipine/delapril (-9.3 mmHg) and losartan/hydrochlorothiazide (-10.7 mmHg) combinations. The mean (95% confidence interval) treatment difference was -1.4 (-4.5/1.8) mmHg, demonstrating noninferiority of the manidipine/delapril combination. Reduction in 24-h diastolic blood pressure (-4.6 versus -4.5 mmHg) and daytime (systolic blood pressure -10.5 versus -11.1 mmHg) and night-time (systolic blood pressure -7.1 versus -9.3 mmHg) blood pressure were also not significantly different between treatments. Compliance and adverse events were comparable for both groups.. The study demonstrated that the combination of manidipine and delapril is as effective as losartan and hydrochlorothiazide in treatment of hypertension in type 2 diabetes.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Indans; Losartan; Male; Middle Aged; Nitrobenzenes; Piperazines; Treatment Outcome

The purpose of this study was to compare the combination treatments of manidipine/delapril and olmesartan/hydrochlorothiazide (HCTZ) in elderly diabetic hypertensives. After a 4-week placebo period, 158 hypertensive patients with type 2 diabetes (age range: 66 to 74 years) were randomized to receive combination treatment of 10 mg manidipine plus 30 mg delapril or 20 mg olmesartan plus 12.5 mg HCTZ for 48 weeks in a prospective, parallel arm trial. After 12 weeks, manidipine or HCTZ was doubled in nonresponders (systolic blood pressure [SBP] > or =130 mmHg and/or diastolic blood pressure [DBP] > or =80 mmHg). Patients were checked at the end of the placebo period and every 12 weeks thereafter. At each visit, lying, sitting and standing BP as well as fasting glycemia, glycosylated hemoglobin (HbA1c), electrolytes, uric acid, total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG) were evaluated. Both combinations reduced sitting SBP (-27.7 and -28.3 mmHg, respectively; both p<0.001) and DBP (-15.1 and -14.8 mmHg, respectively; both p<0.01) with no difference between the two treatments. Standing DBP was more markedly reduced by olmesartan/HCTZ (-19.5 mmHg; p<0.001) than by manidipine/delapril (-14.7 mmHg; p<0.05 vs. olmesartan/HCTZ). No changes in metabolic parameters were observed with manidipine/delapril, whereas an increase in HbA1c (+0.7%; p<0.05), uric acid (+0.4 mg/dL; p<0.05) and TG (+41.3 mg/dL; p<0.05), and a decrease in serum potassium (-0.3 mmol/L; p<0.05) and HDL-C (-3.4 mg/dL; p<0.05) were found in the olmesartan/HCTZ group. In conclusion, both combinations were similarly effective in reducing BP in elderly hypertensive diabetic patients. However, manidipine/delapril offered some advantages in terms of the less-pronounced BP orthostatic changes and absence of metabolic adverse effects.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Diuretics; Drug Combinations; Endpoint Determination; Female; Humans; Hydrochlorothiazide; Hypertension; Hypotension, Orthostatic; Imidazoles; Indans; Male; Nitrobenzenes; Piperazines; Posture; Prospective Studies; Tetrazoles

Use of the combination of an angiotensin-converting enzyme inhibitor (ACEI) and a calcium channel blocker (CCB) is considered a rational approach in patients whose hypertension is not controlled by monotherapy, providing better blood pressure (BP) control than the individual components with a lower incidence of adverse effects. In particular, such combinations have been found to reduce the incidence of ankle edema, the most common adverse effect of dihydropyridine annhypertensives.. The present study was undertaken to evaluate the effect on the development of ankle edema of adding the ACEI delapril to the CCB manidipine in patients with mild to moderate essential hypertension.. Patients between the ages of 30 and 70 years who had mild to moderate hypertension (diastolic BP [DBP] >90 and <110 mm Hg) were included in the study. After a 4-week placebo run-in period, eligible patients were randomized to receive 6 weeks each of manidipine 10 mg/d, delapril 30 mg/d, and both in a crossover fashion. There was a 2-week washout period between treatments. Ankle edema was assessed based on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP). Sitting BP, AFV, and PSTP were measured at the end of the placebo run-in period and the end of each active-treatment period.. The study enrolled 40 patients with previously untreated hypertension (21 women, 19 men). Both manidipine and delapril monotherapy were associated with significant reductions from baseline in systolic BP (SBP) (mean [SD], -17.3 [4] and -14.8 [4] mm Hg, respectively; both, P<0.01) and DBP (-14.6 [3] and -12.9 [3] mm Hg; both, P<0.01). Compared with monotherapy, the combination of manidipine and delapril was associated with greater reductions from baseline in SBP (-21.8 [5] mm Hg; P<0.001) and DBP (-18.6 [4] mm Hg; P<0.001). Manidipme monotherapy was associated with significant increases from baseline in both AFV (7.9%; P<0.001) and PSTP (36.6%; P<0.01). Compared with manidipine alone, the combination of manidipine and delapril was associated with less pronounced increases in AFV (3.3%; P<0.05) and PSTP (10.4%; P<0.05). Ankle edema was clinically evident in 3 patients after receipt of manidipine monotherapy and in 1 patient after receipt of combination treatment.. In these patients with mild to moderate essential hypertension, the addition of delapril to manidipine partially counteracted the manidipine-induced microcirculatory changes responsible for ankle edema.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Ankle; Antihypertensive Agents; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Drug Therapy, Combination; Edema; Female; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines; Treatment Outcome

This present study assessed the antihypertensive efficacy of the fixed combination of manidipine and delapril by ambulatory blood pressure monitoring in patients with hypertension inadequately controlled by monotherapy with either component. After a 2-week placebo period, 55 mild to moderate hypertensive patients were randomized to manidipine 20 mg o.d. or delapril 30 mg b.i.d. for 4 weeks. After this period, 30 patients, aged 30-76 years (18 males and 12 females) whose diastolic blood pressure was not adequately controlled (> or = 90 mmHg) by monotherapy were treated with the fixed combination of manidipine 10 mg plus delapril 30 mg o.d. for 8 weeks. A 24-h ambulatory blood pressure monitoring recording was performed at the end of the placebo washout, of the monotherapy and of the combination therapy. Blood pressure control over the 24 h was quantified by the trough-to-peak ratio and the smoothness index. As compared to placebo, the fixed combination of manidipine and delapril produced a statistically significant (p<0.01) decrease in sitting clinic (18 +/- 9/14 +/- 5 mmHg) and 24-h blood pressure (12 +/- 7/10 +/- 5 mmHg) without affecting heart rate. This reduction was greater than that observed with single components. At the end of the 8-week combination treatment period, the rate of normalilized patients was 73%. Treatment with the fixed combination was associated with a positively high smoothness index (1.2 +/- 0.7/13.8 +/- 0.8) and with a relatively good trough-to-peak ratio (0.46/0.60). The combination of manidipine and delapril produced significant and smooth reductions in blood pressure values, which persisted over the 24-h dosing interval. These results support the use of fixed manidipine-delapril combination in the treatment of mild to moderate hypertensive patients inadequately controlled by monotherapy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines; Random Allocation; Time Factors

The aim of this double-blind, double-dummy, parallel group study was to compare the effects of delapril-manidipine combination vs a irbesartan-hydrochlorothiazide combination on plasma tissue plasminogen activator (t-PA) and plasmogen activator inhibitor type I (PAI-l) activities in hypertensive patients with type II diabetes mellitus. After a 4-week run-in placebo period, 80 patients (37 male and 43 female), aged 41-65 years, were randomly allocated to an 8-week treatment with delapril 30 mg once daily or irbesartan 150 mg once daily. Thereafter, manidipine l0 mg once daily was added to delapril treatment and hydrochlorothiazide 12.5 mg to irbesartan treatment for a further 8 weeks. Blood pressure (BP), plasma t-PA and PAI-l activities were evaluated at the end of the run-in period, after 4-week monotherapy treatments, and at the end of the combination treatment periods. Both combination treatments, delapril-manidipine and irbesartan-hydrochlorothiazide, produced a greater reduction in systolic BP/diastolic BP (SBP/DBP) values (-27.6/21.8 mmHg and -26.4/20.2 mmHg, respectively) than the respective monotherapies (-15.2/11.7 mmHg with delapril and -16.3/11.3 mmHg with irbesartan). Delapril monotherapy significantly decreased plasma PAI-l activity (-10.4 IU/mI; P<0.05). The addition of manidipine produced a significant increase in t-PA activity (+0.27 IU/mI); P<0.05). Irbesartan monotherapy did not significantly affect the fibrinolytic balance, whereas the addition of hydrochlorothiazide worsened it, producing a significant increase in PAI-l activity (+9.5 IU/ml; P<0.05). In hypertensive patients with type II diabetes mellitus, the combination delapril-manidipine may determine a greater improvement of the fibrinolytic function than the respective monotherapy, while the association irbesartan-hydrochlorothiazide may worsen it.

Topics: Adult; Aged; Antihypertensive Agents; Biphenyl Compounds; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Female; Fibrinolysis; Humans; Hydrochlorothiazide; Hypertension; Indans; Irbesartan; Male; Middle Aged; Nitrobenzenes; Piperazines; Plasminogen Activator Inhibitor 1; Tetrazoles; Tissue Plasminogen Activator; Treatment Outcome

The use of combination therapy is required to achieve blood pressure targets in 40% to 75% of patients with hypertension. There have been few studies comparing the efficacy and tolerability of the new fixed combination of the angiotensin-converting enzyme (ACE) inhibitor delapril 30 mg and the calcium channel antagonist manidipine 10 mg with those of a standard combination of another ACE inhibitor and a diuretic.. The aim of this study was to compare the antihypertensive efficacy and tolerability of delapril 30 mg given alone or with manidipine 10 mg with those of enalapril 20 mg given alone or with hydrochlorothiazide (HCTZ) 12.5 mg in patients with mild to moderate essential hypertension.. This was a multicenter, active-controlled, parallel-group trial. After an initial 2-week placebo run-in period, patients aged 18 to 75 years with diastolic blood pressure (DBP) > or =90 and < or =109 mm Hg were randomized in a 2:1 ratio to receive delapril or enalapril for 8 weeks. After the initial 8 weeks, nonresponders (DBP > or =85 mm Hg) received an additional 8 weeks of treatment with a fixed combination of delapril + manidipine or enalapril + HCTZ; patients whose DBP was normalized continued their initial monotherapy through the end of the study. The primary efficacy variable was the change in sitting DBP at the end of treatment. Secondary efficacy variables were the percentage of patients whose DBP was normalized (DBP Z:85 mm Hg) and the percentage of responders (> or =10-mm Hg reduction in DBP or DBP <85 mm Hg).. One hundred sixty patients (84 men, 76 women) were randomized to receive delapril (n = 106) or enalapril (n = 54). After 16 weeks of treatment, the mean (SD) reduction in DBP was similar with the 2 treatments (delapril, -14 [8] mm Hg; enalapril, -15 [8] mm Hg). In the delapril and enalapril groups, DBP was normalized in a respective 55 (51.9%) and 29 (53.7%) patients, and 77 (72.6%) and 38 (70.4%) were responders; there was no significant difference between groups. Tolerability was also similar in both groups--10 (9.4%) patients in the delapril group and 5 (9.3%) in the enalapril group experienced adverse events that were judged related to treatment.. The results of this study suggest that delapril alone or combined with manidipine is well tolerated and as effective as enalapril alone or combined with HCTZ in lowering blood pressure in patients with mild to moderate essential hypertension.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines; Single-Blind Method; Time Factors; Treatment Outcome

The aim of the study was to evaluate efficacy and tolerability of two different fixed combinations of an angiotensin-converting enzyme inhibitor and a diuretic: delapril+indapamide (D+I) and captopril+hydrochlorothiazide (C+H) administered for 6 months to patients with mild to moderate essential hypertension. In all, 96 centres participated in this randomised, parallel groups, controlled study. A total of 829 patients with uncomplicated mild to moderate hypertension were randomised, and 790 were eligible for the analysis of efficacy (intention to treat). Patients of both sexes, aged 18-75 years, newly diagnosed or untreated during the last month were included in the study if their diastolic blood pressure (DBP) was > or =95 and < or =114 mmHg. The starting doses of the drugs were delapril 30 mg+indapamide 1.25 mg tablets o.d. or captopril 50 mg+hydrolchlorothiazide 15 mg tablets o.d. After a 1-month treatment period, nonresponders (DBP >90 mmHg, or decrease in DBP <10 mmHg) had the daily dose increased to either delapril 30 mg+indapamide 2.5 mg or captopril 50 mg+hydrochlorothiazide 25 mg tablets for a further 5 months. The primary assessment of antihypertensive efficacy was the percentage of patients who responded after a 6-month drug treatment. The responder rates were 72.6% with D+I and 62.9% with C+H (P=0.004 between treatments) after 60 days of treatment, and 92.6% in the D+I and 85.2% in the C+H (P<0.001 between treatments) at the end of the treatment period. The final value of systolic blood pressure was 134.5+/-13.1 mmHg with D+I and 138.3+/-14.0 mmHg with C+H (P<0.001 between treatments). At the final visit, DBP was 84.57+/-7.0 mmHg in the D+I group and 85.57+/-8.0 mmHg in the control group (P=0.017 between treatments). In all, 11 patients in the D+I group and 19 patients in the C+H group were withdrawn from the study because of adverse events. In all, 30 patients (7.6%) with D+I and 32 patients (8.1%) with C+H experienced adverse events. In conclusion, D+I was more effective than C+H in terms of overall reduction in blood pressure and response rate. Greater efficacy was obtained without any increase in adverse effects, since both treatments were equally well tolerated.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Drug Combinations; Female; Humans; Hydrochlorothiazide; Hypertension; Indans; Indapamide; Male; Middle Aged; Severity of Illness Index

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Double-Blind Method; Female; Humans; Hypertension; Indans; Losartan; Male; Middle Aged; Plasminogen Activator Inhibitor 1

To assess the homogeneity of the antihypertensive effect of delapril over 24 h.. After 2 weeks of placebo 50 mild to moderate essential hypertensives (age 54+/-5 years) were subjected to 8 weeks of treatment with delapril 30 mg once daily. At the end of each period, blood pressure (BP) was assessed by conventional sphygmomanometry (clinic or CBP) and ambulatory (A) BP monitoring. Twenty-four-hour means, trough-to-peak ratio (T/P) and smoothness index (SI, the ratio between the average of the 24-h BP changes after T and its standard deviation) were calculated for systolic (S) and diastolic (D) BP.. CBP and ABP were significantly reduced by treatment. Pulse pressure (PP, the SBP-DBP difference) was also significantly (p < 0.01) reduced by delapril (5.7+/-6.2 and 3.3+/-3.8 mmHg, CPP and APP). The median T/P was higher (0.51 and 0.62, SBP and DBP) in the 43 responders at trough than in the whole group (0.44 and 0.51). The SI was similarly high in the whole group (1.3+/-0.6 and 1.4+/-0.6, SBP and DBP) and in the responders (1.4+/-0.5 and 1.5+/-0.6).. Delapril effectively and smoothly reduces BP over 24 h, this effect being evident also on PP, a parameter with a relevant prognostic value.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Female; Humans; Hypertension; Indans; Male; Middle Aged

Thirty-nine hypertensive patients with type 2 diabetes mellitus were followed under long-term treatment (mean, 20.7 months) with manidipine hydrochloride, a Ca antagonist, or delapril hydrochloride, an ACE inhibitor, at nine institutions. Both the treatments showed similar antihypertensive effects, although slight but significantly larger decreases were observed in systolic and mean blood pressures at months 12 and 24 in the patients treated with manidipine (P < 0.02). The urinary albumin excretion index (AEI) tended to increase throughout the study in both treatment groups, but no significant difference in AEI was observed between the two treatment groups at any time point. Overt albuminuria developed in four patients on manidipine but did not appear in any of the patients on delapril. The risk of progression to overt albuminuria was significantly different between manidipine and delapril groups (P = 0.011). No increase in serum creatinine (Cr) was observed with delapril. The average excretion indexes of tubular markers such as beta2-microglobulin, alpha1-microglobulin, and NAG tended to be higher in the patients on manidipine than in those on delapril. Taken in sum, these findings suggest that the ACE inhibitor delapril is more beneficial than the Ca antagonist manidipine in the treatment of diabetic renal diseases via mechanisms other than the blood pressure regulation, partly through their different effects on tubular function. In conclusion, delapril was significantly more effective than manidipine in inhibiting progression to overt albuminuria in hypertensive type 2 diabetes mellitus patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines

Patients aged 60 years and older with essential hypertension were treated with an angiotensin-converting enzyme inhibitor (ACE-I), delapril (Adecut) or a long-acting calcium (Ca)-antagonist, manidipine (Calslot) for 3 years. The incidences of cardiovascular events as well as drug-related side effects were compared between the two groups to investigate whether both classes of antihypertensive drugs are beneficial in elderly hypertensive patients. There were no significant differences in characteristics of patients between the two intervention groups, except for slightly lower blood pressure (P = .08) in the Ca-antagonist group at the initiation of the study. There were no significant differences in total death between the two groups. Cardiovascular events (both fatal and nonfatal) were noted in 34 of 699 patients (22.5/1000 patient-years) in the ACE-I group and 50 of 1049 patients (19.7/1000 patient-years) in the Ca-antagonist group, with no significant difference found between the two groups. The correlation between cardiovascular incidence and the blood pressure attained during treatment showed a J-shaped phenomenon and suggests that an excessive reduction less than 120 mm Hg in systolic blood pressure (SBP) is unnecessary and may be harmful in certain cases. Side effects were more frequent in the ACE-I group than in the Ca-antagonist group (P = .01). Cough was the major adverse event, occurring in 5.0% of patients in the ACE-I group. In conclusion, the study indicates that both ACE-I (delapril) and Ca-antagonist (manidipine) were equally beneficial for reducing cardiovascular morbidity and mortality in elderly hypertensive patients. However, tolerability of ACE-I was lower due to the adverse event of coughing.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Delayed-Action Preparations; Dihydropyridines; Female; Humans; Hypertension; Incidence; Indans; Japan; Male; Nitrobenzenes; Piperazines; Prospective Studies; Safety; Stroke; Survival Rate

We investigated the relationship between cardiovascular autonomic nervous system function and carotid arterial distensibility during treatment with an angiotensin converting enzyme inhibitor (derapril) or a calcium channel blocker (manidipine) for hypertension. In 37 patients with hypertension, autonomic function was assessed by heart rate variability and baroreceptor sensitivity using phenylephrine injection. Left ventricular mass index and carotid arterial distensibility were assessed by ultrasound examinations. Before the medication, both baroreceptor sensitivity and heart rate variability correlated with carotid arterial distensibility, but not with left ventricular mass index by multiple regression analysis. Subsequently, patients were randomly allocated into two groups, derapril (n = 18) and manidipine (n = 19) for 20 weeks. At the end of the study, the change in baroreceptor sensitivity correlated with change in carotid arterial distensibility (r = 0.41, P < .05), but not with change in left ventricular mass index. Although derapril and manidipine decreased blood pressure and left ventricular mass index to the same extent, the former improved heart rate variability, baroreceptor sensitivity (5.0 +/- 1.9 --> 5.6 +/- 2.0 msec/mm Hg), and carotid arterial distensibility (2.1 +/- 0.8 --> 2.5 +/- 1.0 %kPa), but the latter did not improve them at all. Thus, impairment of the autonomic balance was related to the impairment of carotid arterial distensibility in hypertension; derapril, but not manidipine, significantly improved these abnormalities.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Autonomic Nervous System; Baroreflex; Calcium Channel Blockers; Carotid Arteries; Dihydropyridines; Female; Heart; Heart Rate; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines

The long-term effect of delapril hydrochloride, a non-sulfhydryl angiotensin converting enzyme inhibitor, on serum concentrations of procollagen type III amino-terminal peptide (PIIIP) and left ventricular mass (LVM) and function were investigated in 15 hypertensive patients. Patients were treated with delapril hydrochloride 30 mg/day po for 12 months. Blood samples and an echocardiogram were obtained before treatment and after 6 and 12 months of treatment. Blood pressure, PIIIP, and LVM significantly decreased associated with an increase in left ventricular fractional shortening and mean systolic and diastolic posterior wall velocity at 6 and 12 months of treatment. Positive correlations between PIIIP and LVM (r=0.49, p<0.005) and negative correlations between PIIIP and left ventricular fractional shortening (r=-0.31, p<0.05) were found. Delapril hydrochloride reduced PIIIP and LVM and improved cardiac function in hypertensive patients.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Female; Heart Ventricles; Hemodynamics; Humans; Hypertension; Indans; Male; Organ Size; Peptide Fragments; Procollagen; Time Factors; Ventricular Function, Left

We present a single-blinded, placebo-controlled trial of the effects on blood pressure and left ventricular mass and of the safety of a combined antihypertensive treatment with delapril, a new nonsulfhydryl angiotensin-converting enzyme inhibitor, and indapamide, a sulfonamide diuretic. We studied 28 elderly patients aged 65-85 years (mean age, 69 +/- 1) with sitting systolic/diastolic blood pressure of 160-200/95-115 mm Hg (at the end of the placebo period). After a 2-week placebo run-in, patients took 30 mg delapril in combination with 1.25 mg indapamide once daily for 24 weeks. Twenty-four-hour ambulatory blood pressure was monitored and M- and B-mode echocardiography were performed before and after 24 weeks of treatment. Blood pressure decreased from 156 +/- 1.5/101 +/- 1 mm Hg before treatment to 133 +/- 1/73 +/- 1 mm Hg after treatment. The total blood pressure burden also decreased; the percentage of measurements with a systolic blood pressure > or = 140 mm Hg and a diastolic blood pressure > or = 90 mm Hg decreased from 48.7% +/- 5%/31.5% +/- 4.3% to 23.5% +/- 4%/20.5% +/- 2.9% (p < 0.0005 and p < 0.05). The area under the curve of the 24-hour blood pressure decreased from 250 +/- 41/103 +/- 21 mm Hg to 97 +/- 21/37 +/- 8.5 mm Hg (p < 0.001 and p < 0.005). The left ventricular mass index (LVMI) in the 15 patients with pretreatment left ventricular hypertrophy was reduced after therapy from 167.5 +/- 8.5 g/m 2 to 152.2 +/- 7.6 g/m 2 (p < 0.05). A positive correlation was observed between percent changes of the area under the curve of the 24-hour diastolic blood pressure and percent changes of LVMI (r = 0.6; p < 0. 05) in the 15 patients with left ventricular hypertrophy. Only 2 patients reported side effects: 1 developed skin rash and 1 developed headache. The safety of the treatment was confirmed by laboratory tests. In elderly hypertensive patients, the combination of delapril and indapamide at low doses reduced blood pressure and had favorable effects on LVMI with few side effects.

Topics: Age Factors; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Drug Therapy, Combination; Echocardiography; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Indans; Indapamide; Infant, Newborn; Male; Single-Blind Method

This study was designed to investigate the effects of angiotensin II (AII) receptor antagonist and angiotensin converting enzyme (ACE) inhibitor on insulin resistance, and the mechanism by which ACE inhibitor improves insulin-dependent glucose uptake (insulin sensitivity) in an insulin-resistant hypertensive rat model (fructose-fed rats, FFR) and in essential hypertensives (EHT). Male Sprague-Dawley rats were fed on fructose-rich or standard chow for 4 weeks and treated either with 10 mg/kg/day of delapril (n = 8), 1 mg/kg/day of TCV-116 (AII receptor antagonist; n = 13), or vehicle (n = 9) for the latter 2 weeks. Steady-state plasma glucose (SSPG) was measured with the subjects in the conscious state; simultaneously, we infused insulin (2.5 mU/kg/min) and glucose (8 mg/kg/min) to determine insulin sensitivity in each group. Thirteen EHT were hospitalized and the 2-h euglycemic hyperinsulinemic glucose clamp (GC) method was performed in a fasting condition before and after 2 weeks' administration of TCV-116 (8 mg/day) in 7 EHT and of delapril (120 mg/day) in 6 EHT. Insulin sensitivity was evaluated as M-value calculated from the infusion rate of glucose. Mean blood pressure (MBP) was higher in FFR (137.7 +/- 73.8 mm Hg, P < .05) compared to controls (120.8 +/- 2.7 mm Hg), and was lower in both the delapril (108.1 +/- 6.3 mm Hg, P < .05) and TCV-116 (112.8 +/- 4.3 mm Hg, P < .05) groups than in FFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Glucose; Blood Pressure; Diet; Fructose; Glucose Clamp Technique; Humans; Hypertension; Indans; Insulin Resistance; Male; Middle Aged; Rats; Rats, Sprague-Dawley; Tetrazoles

Effects of manidipine, a new calcium antagonist, and delapril, an angiotensin converting enzyme inhibitor, on glucose and lipid metabolism were investigated in mild to moderate hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM). The patients were treated with either manidipine 10 mg/day (n = 12, mean age 63 +/- 2 years) or delapril 30 mg/day (n = 8, 62 +/- 3 years) for 12 weeks. Glucose and insulin (IRI) responses to 75 g oral glucose load, glycosylated hemoglobin A1c (Hb A1c), serum levels of total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, triglyceride and apolipoproteins, and 24 h urinary excretion of C-peptide were measured before and at the end of treatment. Both manidipine and delapril showed adequate hypotensive effects. Neither manidipine nor delapril affected blood glucose and IRI responses to glucose load. Manidipine showed no effect on lipids whereas delapril increased HDL cholesterol (47 +/- 5 mg/dL to 61 +/- 7, p < 0.05), although total cholesterol and triglyceride were not altered. The ratio of TC-HDL cholesterol/HDL cholesterol was decreased by delapril (3.44 +/- 0.30 to 2.61 +/- 0.45, p < 0.05). There were no significant changes in apolipoproteins. Both manidipine and delapril have adequate antihypertensive actions without unfavorable effects on glucose and lipid metabolism in hypertensive patients with NIDDM. Delapril seems to have a beneficial effect on lipid metabolism.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Indans; Lipids; Male; Middle Aged; Nitrobenzenes; Piperazines

The angiotensin converting enzyme (ACE) inhibitors delapril and enalapril were compared in a double-blind, randomized, parallel study. The population included 142 patients with essential hypertension who were treated with delapril and 140 treated with enalapril. At the end of a 2 week initial placebo period, the diastolic blood pressure of these patients ranged from 95 to 115 mm Hg in the sitting position. After this placebo period, randomization took place. Patients in the delapril group received 15 mg of the drug twice daily. Treatment with enalapril was started with a daily dose of 10 mg. If the diastolic blood pressure did not fall to less than or equal to 90 mm Hg or at least by 15 mm Hg after 2 weeks of treatment, the doses of the ACE inhibitors were doubled. After another 2 weeks, 25 mg hydrochlorothiazide daily was added if the target level of diastolic blood pressure was not reached. Both drugs caused a similar decrease of systolic and diastolic blood pressure. The antihypertensive effect of both ACE inhibitors was increased by the addition of the diuretic. The frequency and severity of side effects were similar in the two groups of patients. It is concluded from this study that delapril and enalapril do not differ in antihypertensive efficacy nor in safety.

Topics: Adolescent; Adult; Aged; Blood Pressure; Double-Blind Method; Enalapril; Humans; Hypertension; Indans; Middle Aged

Delapril, a new angiotensin converting enzyme (ACE) inhibitor discovered in the laboratory of Takeda Chemical Industries, Ltd., is the result of drug design based on the structure-activity relationships of ACE inhibitors. Delapril is an antihypertensive agent with a relatively long duration of action and no SH moiety in its structure. Following administration, it is converted into two active metabolites. Delapril effectively lowered blood pressure in 73% of 1,008 patients with hypertension during clinical trials in Japan. Efficacy rates were 73% for essential hypertension, 85% for renal hypertension, and 80% for renovascular hypertension. Excellent hypotensive response was observed in all age groups, from young to elderly patients. Side effects during administration of delapril, based on subjective evidence, were reported in 80 out of the 1,008 cases (7.9%). The main symptoms included orthostatic dizziness (1.7%), dizziness (1.3%), and nausea (1.1%). Dry cough, which has attracted attention in recent years as a side effect of ACE inhibitors, was reported at a low incidence of 1.1%. In a double-blind, controlled study in patients with mild to moderate essential hypertension in which captopril served as a positive control, delapril showed superior hypotensive effect and greater safety. Data derived from the Japan Study Group on Delapril indicate that this ACE inhibitor has excellent hypotensive effects and a high level of safety. It is suitable as a first-line drug in both monotherapy and combined therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Female; Heart Rate; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Indans; Japan; Male; Middle Aged

To compare the effects of three different angiotensin converting enzyme (ACE) inhibitors on the cough reflex, capsaicin and citric acid challenge tests were done in normal subjects and hypertensive patients before and after administration of delapril, captopril, or enalapril. Two groups of 7 normal subjects (single dose study: 15 mg delapril v 18.75 mg captopril or 2.5 mg enalapril) and a group of 6 mildly hypertensive patients (1 week study: cross-over administration of 30 mg/day delapril, 37.5 mg/day captopril, or 5 mg/day enalapril) were studied. Another group of 6 patients with essential hypertension was treated with three ACE inhibitors for 4 weeks in a randomized order, with a 2 week washout period between active therapies. Aerosols of 1 mumol/L and 3 mumol/L capsaicin and 0.68% citric acid in 0.9% NaCl were generated by an ultrasonic nebulizer, and the frequency of cough was counted during inhalation. Delapril treatment resulted in substantially fewer patients with a significant increase (greater than or equal to 4 coughs during treatment than during the control period) in the frequency of cough than did captopril treatment. In the 1 and 4 week studies, enalapril and captopril had substantially more occurrences of significantly increased capsaicin-induced cough than did delapril. These results indicate that delapril has the least cough stimulatory effect among these ACE inhibitors, which may be clinically beneficial.

Topics: Administration, Inhalation; Adult; Angiotensin-Converting Enzyme Inhibitors; Capsaicin; Captopril; Citrates; Citric Acid; Cough; Enalapril; Humans; Hypertension; Indans; Male; Middle Aged; Reference Values; Reflex

The controlled study was carried out on 15 patients with essential hypertension not sufficiently controlled after one month of monotherapy with an ACE-inhibitor. To the above therapy was therefore associated a low dosage diuretic (indapamide 2.5 mg/day). The observation period was of 12 weeks. The delapril-indapamide combination was found to be very effective in reducing blood pressure values; no significant metabolic adverse effects were observed.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Diuretics; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Indapamide; Indenes; Male

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Indans; Male; Nitrobenzenes; Piperazines

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Combinations; Humans; Hypertension; Indans; Nitrobenzenes; Piperazines; Treatment Outcome

Delapril/manidipine 30 mg/10 mg is a new oral, once-daily, fixed combination of an ACE inhibitor and a dihydropyridine calcium-channel antagonist for the treatment of essential hypertension. In a dose-finding study in 400 patients with mild to moderate hypertension, delapril/manidipine 30mg/10mg once daily produced the greatest reduction in blood pressure (BP) of the combinations tested. Delapril/manidipine 30mg/10mg once daily for 6 weeks reduced systolic BP (SBP)/diastolic BP (DBP) by 15/13mm Hg. In nonresponders to monotherapy with delapril (n = 155) or manidipine (n = 152), delapril/manidipine 30mg/10mg once daily for 12 weeks reduced mean SBP/DBP by 16/11mm Hg and 16/10mm Hg, respectively. Delapril/manidipine 30mg/10mg once daily for 12 weeks in patients with mild to moderate hypertension (n = 131) demonstrated significantly greater antihypertensive efficacy than monotherapy with manidipine 10mg once daily (n = 134) or delapril 15mg twice daily (n = 136). Mean SBP/DBP reductions from baseline were 19/14, 15/11 and 14/10mm Hg, respectively. After 50 weeks of therapy with delapril/manidipine 30mg/10mg once daily, mean SBP/DBP was reduced by 22/14mm Hg in patients with mild to moderate hypertension (n = 309). Delapril/manidipine 30mg/10mg once daily was generally well tolerated. The incidence and nature of adverse events were similar to those observed in recipients of monotherapy with the individual agents. Combination therapy was associated with less ankle oedema than manidipine monotherapy.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Combinations; Humans; Hypertension; Indans; Nitrobenzenes; Piperazines; Treatment Outcome

Combined treatment with the angiotensin-converting enzyme (ACE) inhibitor delapril and the diuretic indapamide prevented vascular damage in vital organs of salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp). Whether the changes occurring after long-term hypertension could also be modulated in large arteries was investigated. Two-month-old SHRsp were salt loaded and treated with the drug regimen until they reached 50% mortality or around midlife. In a first experiment, delapril (12 mg/kg) and indapamide (1 mg/kg) were administered daily separately or in combination. In the second dose-finding experiment, delapril (6, 3, 1.5 mg/kg) and indapamide (0.5, 0.25, 0.125 mg/kg) in decreasing dose combinations were analyzed. Ultrastructural, histomorphometric, and biochemical studies were performed on the thoracic aorta. When compared with delapril (12 mg/kg) or indapamide (1 mg/kg) administered individually for 5 months, the combination 12 + 1 mg/kg was able to prevent the increase in extracellular matrix deposition observed in other treatment groups, as assessed by histomorphometry or 4-OH-proline biochemical determination. In the second experiment, a half-dose (delapril 6 mg/kg + indapamide 0.5 mg/kg) combination was similarly effective in counteracting fibrosis, but the other doses progressively failed. In the first experiment, the combination had a stabilizing effect on hypertension and stimulated diuresis. In the second experiment, arterial blood pressure values and sodium balance were not consistently affected by the treatments that antagonized fibrosis (i.e., delapril 6 mg/kg + indapamide 0.5 mg/kg and, less efficiently, delapril 3 mg/kg + indapamide 0.25 mg/kg). These results suggest that indapamide interacts with ACE inhibitors to limit aortic fibrosis independent of any well-established mechanism.

Topics: Animals; Aorta, Thoracic; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Fibrosis; Hypertension; Indans; Indapamide; Male; Rats; Rats, Inbred SHR; Stroke

Hypertensive nephrosclerosis is a leading cause of end-stage renal disease; therefore, strategies to prevent the development of renal disease require close study. Here it is demonstrated that transient treatment of prepubescent rats with angiotensin inhibitors attenuated their susceptibility to the development of hypertensive nephrosclerosis after maturation. Stroke-prone spontaneously hypertensive Izumo strain rats were divided into four groups, treated with vehicle, the angiotensin-converting enzyme inhibitor (ACEI) delapril (40 mg/kg per d), the angiotensin receptor antagonist (AT1R-Ant) candesartan cilexetil (1 mg/kg per d), or the vasodilator hydralazine (25 mg/kg per d) from weaning to puberty (3 to 10 wk of age), and then monitored without treatment for 6 mo. BP in the ACEI- and AT1R-Ant-treated groups remained significantly decreased, compared with the untreated and hydralazine-treated groups. Moreover, marked proteinuria and nephrosclerosis developed in the untreated and hydralazine-treated groups at 30 wk but were suppressed in the ACEI- and AT1R-Ant-treated groups. Of interest, plasma renin activity, plasma angiotensin II concentrations, and renal renin mRNA levels were reduced by >50% in the ACEI- and AT1R-Ant-treated rats, suggesting that the treatments may have attenuated the development of nephrosclerosis by overcoming the susceptibility of stroke-prone spontaneously hypertensive rats to overactivation of the renin-angiotensin system.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cardiomegaly; Gene Expression; Genetic Predisposition to Disease; Hydralazine; Hypertension; Indans; Kidney; Male; Nephrosclerosis; Proteinuria; Rats; Rats, Inbred SHR; Renin; Stroke; Tetrazoles; Time Factors; Vasodilator Agents

In previous articles, we have shown that the combination of the angiotensin-converting enzyme (ACE) inhibitor delapril (12 mg/kg/day) and the diuretic indapamide (1 mg/kg/ day) was able to prolong the life span significantly in salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp). Because this finding was partly dependent on the antagonism of salt-loading effects by pharmacologic induction of diuresis, which prevented any increase in blood pressure values, we decided to evaluate whether lower doses of the combination could be equally protective without changing the progression of hypertension. Thus, we studied several treatments with progressively lower doses of delapril (6, 3, or 1.5 mg/kg/day) combined with indapamide (0.5, 0.25, or 0.125 mg/kg/day) or hydrochlorothiazide (2.5, 1.25, or 0.625 mg/kg/day) in salt-loaded SHRsp. Salt-loaded untreated animals were considered to be the control group. In agreement with previous experiments, control rats reached 50% mortality approximately 7 weeks after the beginning of salt loading. The combination of delapril and hydrochlorothiazide at the two lowest doses was not able to delay animal death significantly, whereas treatment with delapril and indapamide at the lowest dose was effective (50% survival rate, 15 weeks). The groups treated with the highest dose of delapril and hydrochlorothiazide or with the intermediate or highest dose of delapril and indapamide did not reach 50% mortality by the end of the experiment, at 44 weeks of treatment (i.e., when animals reached age 1 year). Only the highest delapril and indapamide doses were able to increase diuresis, but for a relatively short period. None of the treatments was able to lower or control blood pressure levels adequately. Therefore, blood pressure levels by themselves were not predictive of rat mortality. In contrast, the maximal value of proteinuria in the weeks preceding death was inversely correlated with the survival time. In conclusion, this study shows that low doses of an ACE inhibitor in combination with a diuretic can be effectively protective in a model of severe hypertension, independent of any change in blood pressure levels.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electrolytes; Hydrochlorothiazide; Hypertension; Indans; Indapamide; Male; Proteinuria; Rats; Rats, Inbred SHR

Production of angiotensin II (Ang II) in spontaneously hypertensive rats (SHR)-derived vascular smooth muscle cells (VSMC) has now been investigated. A nonpeptide antagonist (CV-11974) of Ang II type 1 receptors inhibited basal DNA synthesis in VSMC from SHR, but it had no effect on cells from Wistar-Kyoto (WKY) rats. Ang II-like immunoreactivity, determined by radioimmunoassay after HPLC, was readily detected in conditioned medium and extracts of SHR-derived VSMC, whereas it was virtually undetectable in VSMC from WKY rats. Isoproterenol increased the amount of Ang II-like immunoreactivity in conditioned medium and extracts of SHR-derived VSMC, whereas the angiotensin-converting enzyme inhibitor delapril significantly reduced the amount of Ang II-like immunoreactivity in conditioned medium and extracts of these cells. Reverse transcription-polymerase chain reaction analysis revealed that the abundance of mRNAs encoding angiotensinogen, cathepsin D, and angiotensin-converting enzyme was greater in VSMC from SHR than in cells from WKY rats. The abundance of cathepsin D protein by Western blotting was greater in VSMC from SHR than in cells from WKY rats. Ang I-generating and acid protease activities were detected in VSMC from SHR, but not in cells from WKY rats. These results suggest that SHR-derived VSMC generate Ang II with increases in angiotensinogen, cathepsin D, and angiotensin-converting enzyme, which contribute to the basal growth. Production of Ang II by homogeneous cultures of VSMC is considered as a new mechanism of hypertensive vascular disease.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aspartic Acid Endopeptidases; Benzimidazoles; Biphenyl Compounds; Cathepsin D; Cathepsin E; Cell Division; Cells, Cultured; Culture Media, Conditioned; Hyperplasia; Hypertension; Hypertrophy; Indans; Kallikreins; Male; Muscle, Smooth, Vascular; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Tissue Kallikreins

The effects of long-term oral administration of delapril (CAS 83435-67-0), indapamide (CAS 26807-65-8) and their combination on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp) for 31 weeks of treatment (8th-39th week of age) and up to 8 weeks thereafter. Body weight and saline consumption were investigated at regular intervals and cerebrovascular lesions, renal and heart weight were assessed after sacrifice. Untreated SHRsp served as controls. About 50% of control animals died within 6 weeks of saline administration and in 56% of surviving animals cerebral lesions were present at sacrifice, while no death and no cerebral lesions were observed in animals drinking saline, to which delapril, indapamide and their combination had been added, up to the end of treatment. This protective effect was maintained even in the withdrawal period. All treatments induced a highly significant (p < 0.001) reduction of heart weight/body weight and kidney weight/body weight ratios.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Cerebrovascular Disorders; Diuretics; Drug Interactions; Hemodynamics; Hypertension; Indans; Indapamide; Longevity; Male; Organ Size; Rats; Rats, Inbred SHR; Sodium, Dietary

The open trial was designed to evaluate the effects of long-term antihypertensive treatment with the calcium-channel blocker, manidipine and the angiotensin converting enzyme (ACE) inhibitor, delapril on insulin sensitivity in Japanese non-insulin dependent diabetes mellitus (NIDDM) patients with essential hypertension. We measured the insulin sensitivity index (SI) and the glucose-effectiveness (SG) by the use of Bergman's minimal model method in 18 hypertensive NIDDM patients before and after administration of manidipine (group A) or delapril (group B) for 3 months. Manidipine treatment for 3 months significantly improved SI in group A from 3.35 +/- 0.61 (x 10(-4) min-1 microU-1 ml-1) to 4.70 +/- 1.34 (P < 0.05). Delapril treatment for 3 months also significantly improved SI in group B from 3.56 +/- 1.04 to 5.00 +/- 0.87 (P < 0.05). Manidipine significantly improved SG in group A from 1.60 +/- 0.64 (x 10(-2) min) to 2.19 +/- 0.38 (P < 0.05). Delapril treatment also significantly improved SG in the group B from 1.41 +/- 0.56 to 1.91 +/- 0.35 (P < 0.05). Manidipine and delapril did not affect urinary C-peptide excretion for 24 h in the hypertensive NIDDM patients. Treatment with manidipine or delapril significantly reduced systolic and diastolic blood pressures in the hypertensive NIDDM patients. There were no differences between plasma glucose, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions, heart rate and body weight after 3 months on manidipine or delapril. This study confirmed the improving effects on SI and SG by long-term treatment with manidipine or delapril in the hypertensive NIDDM patients.

Topics: Antihypertensive Agents; Blood Glucose; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Glycated Hemoglobin; Humans; Hypertension; Indans; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Piperazines

This study was performed to investigate the beneficial effects of prolonged treatment with an angiotensin converting enzyme (ACE) inhibitor, delapril, on the appearance of symptoms of hypertensive cardiovascular disease in stroke-prone spontaneously hypertensive rats (SHRSP). Cardiovascular disease symptoms: stroke, kidney dysfunction and cardiac hypertrophy, were evaluated by monitoring the incidence of stroke signs, urinary excretion of protein and the heart weight, respectively. The SHRSP that were kept under salt-loaded conditions (1% NaCl drinking solution) from six weeks of age developed severe hypertension, showed an increased incidence of stroke signs and increased urinary excretion of protein. Long-term treatment with delapril (10mg/kg/day, p.o. for four weeks) decreased the blood pressure and completely inhibited the incidence of stroke signs and the increase in urinary excretion of protein. In SHRSP that were kept under normal conditions (without 1% NaCl drinking solution), long term treatment with delapril at the same dose decreased the heart weight and, after five weeks of treatment, left ventricular weight was decreased significantly and the wall/lumen ratio of small coronary arterioles and the thickness of the left ventricular wall were decreased slightly. These results indicate that delapril can prevent the development of symptoms of hypertensive cardiovascular diseases: stroke, kidney dysfunction and cardiac hypertrophy, with antihypertensive activity in SHRSP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomegaly; Cerebrovascular Disorders; Drug Evaluation, Preclinical; Hypertension; Indans; Male; Proteinuria; Rats; Rats, Inbred SHR

The aims were (1) to investigate the effect of hypertention on left ventricular dilatation and haemodynamic alterations following acute myocardial infarction in spontaneously hypertensive rats (SHR) and normotensive rats (WKY); (2) to compare haemodynamic indices between the two groups; (3) to assess whether the angiotensin II type 1 receptor antagonist (AIIA), TCV-116, prevented left ventricular dilatation after myocardial infarction; and (4) to compare the effect of AIIA with that of the angiotensin converting enzyme (ACE) inhibitor, delapril.. Myocardial infarction was produced in SHR and WKY by coronary artery ligation. Haemodynamic measurements were obtained three weeks later in rats that had been treated from the next day after the operation for three weeks with TCV-116 (1 mg.kg-1.d-1) or delapril (1 g.litre-1 in drinking water), and in untreated controls.. After myocardial infarction, left ventricular weight, and left ventricular weight were greater in SHR than in normotensive rats. Right ventricular weight, left ventricular end diastolic pressure, and LVEDVI correlated positively with infarct size in both SHR and WKY and these slopes were steeper in SHR than in WKY (P < 0.05). TCV-116 and delapril each significantly attenuated the increases in left ventricular end diastolic pressure, left ventricular weight, right ventricular weight, and LVEDVI following myocardial infarction in both in WKY and SHR, and shifted pressure-volume curve significantly to the left.. Hypertension accelerates left ventricular dilatation and haemodynamic alterations following myocardial infarction in rats. These effects are attenuated by an angiotensin II type 1 receptor antagonist as well as by an ACE inhibitor.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Cardiomyopathy, Dilated; Hemodynamics; Hypertension; Indans; Male; Myocardial Infarction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles

This study evaluated insulin secretion and insulin sensitivity in 17 non-obese hypertensive patients (aged 45.6 +/- 2.2 years, body mass index 24.0 +/- 0.5 kg/m2, mean +/- S.E.M.) with (n = 8) and without glucose intolerance (n = 9) and compared the results with those of 16 age-matched non-obese normotensive subjects with (n = 7) and without glucose intolerance (n = 9). The hypertensive patients without glucose intolerance showed a significantly lower insulin-mediated glucose disposal and a compensating increase in second-phase insulin secretion compared with normotensives without glucose intolerance. In hypertensives with glucose intolerance, insulin-mediated glucose disposal was significantly lower and second-phase insulin secretion was comparable to that in normotensives without glucose intolerance. After 3 months of angiotensin-converting enzyme (ACE) inhibition with oral administration of delapril, blood pressure was significantly reduced in the hypertensives with glucose intolerance (n = 9). The insulin-mediated glucose disposal significantly (P < 0.01) recovered from 6.0 +/- 0.81 to 8.0 +/- 0.71 mg/kg per min. The second-phase insulin secretion tended to be lower (but not significantly) but insulin clearance increased from 15.4 +/- 0.85 to 19.1 +/- 1.42 ml/min (P < 0.05). These data show that in hypertensive patients without glucose intolerance insulin resistance might compensatorily augment second-phase insulin secretion and lead to hyperinsulinemia. In hypertensives with glucose intolerance, insulin resistance might induce postprandial hyperglycemia, which leads to hyperinsulinemia because of second phase insulin secretion at a level similar to that of normotensives.

Topics: Administration, Oral; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Body Mass Index; Female; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypertension; Indans; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged

We have recently found that vascular natriuretic peptide (NP)-A receptor mRNA is upregulated in genetically hypertensive (SHR-SP/Izm) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In the present study, we examined the effects of antihypertensive treatments on aortic NP-A receptor mRNA expression in these hypertensive rats using ribonuclease protection assay. Oral administration of an angiotensin converting enzyme inhibitor, derapril, but not a calcium channel blocker, manidipine, produced a significant decrease of the NP-A receptor mRNA level after 4 weeks, while both antihypertensive agents showed similar hypotensive effects. Plasma renin was high in SHR-SP/Izm and low in DOCA-salt rats. These results suggest that the vascular renin-angiotensin system rather than the blood pressure has an important role in the regulation of the vascular NP-A receptor.

Topics: Animals; Aorta; Blood Pressure; Dihydropyridines; Down-Regulation; Hypertension; Indans; Male; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; RNA, Messenger

To investigate the effects of long term treatment with delapril hydrochloride (an angiotensin-converting enzyme inhibitor) on myocardial contractility and ventricular myosin isoenzymes in spontaneously hypertensive rats (SHR).. Delapril hydrochloride (10 mg/kg/day by mouth) was administered to 22- to 24-week-old male SHR for eight to 10 weeks. The isometric contractions of isolated left ventricular papillary muscles were observed while being perfused with Tyrode's solution (32 degrees C, pH 7.4, bubbled with 95% oxygen: 5% carbon dioxide, stimulation frequency 0.2 Hz). The left ventricular myosin isoenzymes were separated using pyrophosphate-gel electrophoresis.. The mean systolic blood pressure of the delapril-treated group was significantly lower than that of the untreated control group. The mean ventricular weight was also lower in the delapril-treated than control group (mean +/- SD, untreated: 211 +/- 11 mmHg, n = 6; delapril-treated: 183 +/- 14 mmHg, n = 8, P < 0.01). The mean isometric developed tension (T) and +/-dT/dtmax of isolated left ventricular papillary muscles from the delapril-treated and untreated SHR did not differ significantly. The left ventricular myosin isoenzyme pattern obtained by pyrophosphate-gel electrophoresis, however, showed a significant shift towards VM-1 after long term delapril treatment.. Long term treatment of SHR with delapril hydrochloride reduced blood pressure, which was associated with regression of cardiac hypertrophy, and changed the ventricular myosin isoenzyme pattern without significantly affecting myocardial contractility.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Hypertension; Indans; Isoenzymes; Male; Myocardial Contraction; Myocardium; Myosins; Rats; Rats, Inbred SHR

This study aimed to assess the left ventricular diastolic function of borderline hypertensive patients (BHT) and to determine the effect of long-term blood pressure control by an angiotensin converting enzyme inhibitor on the left ventricular filling profile. Pulsed Doppler echocardiograms were obtained from 18 BHT (14 men, 4 women; mean age: 55 years) and 20 age-sex matched normotensive controls. Studies were done at rest and immediately after exercise on a supine ergometer bicycle. Of the 18 patients, 11 were treated with delapril (30 mg/day) and followed up with longitudinal studies for 24 weeks. At baseline, BHT had a normal left ventricular structure. They showed a decreased peak velocity of early filling (E) (43 +/- 7 v 56 +/- 13 cm/sec, P < .01) and E/A ratio (0.83 +/- 0.2 v 1.08 +/- 0.3, P < .01), whereas peak velocity of late filling (A) and deceleration time (Dec T) were similar in the two groups. Exercise-enhanced filling indices were observed in both groups. Following blood pressure control, no change was observed in the left ventricular morphology. In contrast, progressive improvement of resting and after exercise peak velocity of early filling and E/A ratio were achieved. This indicates that long-term angiotensin converting enzyme inhibition ameliorates cardiac function in borderline hypertension.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; Diastole; Echocardiography, Doppler; Female; Humans; Hypertension; Indans; Longitudinal Studies; Male; Middle Aged; Ventricular Function, Left

The pathophysiological role of angiotensin II in the development of renal sclerosis was investigated in 5/6-nephrectomized, 12-week-old male spontaneously hypertensive rats. After 1 week of a control period, nephrectomized rats received one of the following treatments for 4 weeks: the selective nonpeptide angiotensin II type 1 receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme inhibitor delapril (30 mg/kg per day), hydralazine (15 mg/kg per day), or vehicle. Urinary protein and albumin excretions and systolic blood pressure were determined every week. Rats with reduced renal mass treated with vehicle had a poor survival rate (30%). Although TCV-116, delapril, and hydralazine treatment significantly improved the survival rate for 4 weeks, hydralazine failed to improve proteinuria and albuminuria as well as the decline in renal function compared with delapril or TCV-116. Histological examination revealed that both TCV-116 and delapril protected glomeruli from sclerosis, whereas hydralazine did not improve histological findings (5%, 7%, and 30% of glomeruli were affected, respectively). These results indicate that angiotensin II plays a dominant role through its type 1 receptor in the pathogenesis of renal deterioration by hypertension.

Topics: Albuminuria; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chromatography, High Pressure Liquid; Hydralazine; Hypertension; Indans; Kidney; Male; Proteinuria; Rats; Rats, Inbred SHR; Survival Analysis; Tetrazoles

Regulation of the gene expression of type-1 angiotensin II receptor (AT1) by treatment with manidipine, a calcium channel blocker, or delapril, an angiotensin converting enzyme inhibitor, for one week was assessed in the adrenal gland, heart, kidney, and brain from spontaneously hypertensive rats (SHR). Tissue AT1 receptor messenger RNA (mRNA) content was measured by reverse transcriptase-polymerase chain reaction. Treatment with manidipine (3 mg/kg/day) or delapril (30 mg/kg/day) lowered systolic blood pressure (SBP) significantly (p < 0.01) (delta SBP; -73 mmHg or -67 mmHg, respectively). Although delapril markedly increased plasma renin activity (PRA), manidipine did not alter PRA. AT1 receptor mRNA content in the adrenal gland was significantly (p < 0.01) decreased by treatment with manidipine or delapril. In contrast, cardiac AT1 receptor mRNA content was significantly (p < 0.01) increased by treatment with either agent. There was no significant change in renal and brain AT1 receptor mRNA contents. These findings suggest that although the expression of AT1 receptor gene depends on the circulating renin-angiotensin system (RAS), it is regulated independently in a tissue-specific manner via the local RAS in each tissue of SHR.

Topics: Adrenal Glands; Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Base Sequence; Blood Pressure; Body Weight; Brain; Calcium Channel Blockers; Dihydropyridines; Gene Expression Regulation; Heart Rate; Hypertension; Indans; Kidney; Male; Molecular Sequence Data; Myocardium; Nitrobenzenes; Piperazines; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Renin; RNA, Messenger

This study was designed to investigate the effects of antihypertensive drugs on vascular hypertrophy and vascular angiotensin II in vivo in spontaneously hypertensive rats (SHR). Hydralazine (10 mg/kg/day), delapril (angiotensin converting enzyme inhibitor; 20 mg/kg/day), manidipine (calcium channel blocker; 10 mg/kg/day), and vehicle were given by gavage to four groups of SHR between 4 and 5 months of age. The aortic angiotensin II level was measured by highly sensitive radioimmunoassay coupled with high pressure liquid chromatography; aortic morphologic studies were performed. Each drug treatment effectively lowered blood pressure to the same level. However, the aortic wall thickness, medial-intimal areas, and wall to lumen ratio of abdominal aorta decreased significantly (p < 0.05, p < 0.01, p < 0.01, respectively) with delapril and manidipine but not hydralazine. Delapril significantly decreased aortic angiotensin II levels (p < 0.05), whereas manidipine treatment significantly increased them (p < 0.05). The aortic angiotensin II level was not changed by hydralazine. These results show that delapril and manidipine caused regression of hypertension-induced vascular hypertrophy in SHR. The probable mechanism of regression of aortic hypertrophy by delapril was inhibition of vascular angiotensin II formation, but the mechanism for manidipine was unclear.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Abdominal; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Hydralazine; Hypertension; Hypertrophy; Indans; Male; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Renin-Angiotensin System

To study the effect of antihypertensive therapy on the regulation of renin gene expression, the levels of tissue renin messenger RNA (mRNA) were measured after treatment with a calcium channel blocker (manidipine hydrochloride 3 mg/kg/day) or an angiotensin-converting enzyme inhibitor (delapril hydrochloride 30 mg/kg/day), administered orally for 1 week, in spontaneously hypertensive rats (SHR). Male SHR, aged 15 weeks old, were used in this study (n = 5 per group). Control rats were administered the vehicle alone. Tissue total RNA was isolated from kidney, adrenal gland, heart, and brain tissue, and tissue RNA was reverse-transcribed to complementary DNA (cDNA), which was specifically amplified by polymerase chain reaction with labeled-primers for the rat renin gene. The radioactivity of the cDNA products was measured directly. Although delapril increased plasma renin activity (PRA) about 5-fold compared with the control group, manidipine did not change PRA. The kidney renin mRNA content was increased about 6-fold by treatment with delapril. Manidipine and delapril significantly decreased the renin mRNA content in the heart (p < 0.01 and p < 0.05, respectively). The level of renin mRNA in the adrenal gland and brain tissues was not significantly changed by treatment with either drug. These results suggest that tissue renin gene expression in SHR is regulated by a tissue-specific process independent of the circulating renin-angiotensin system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Base Sequence; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Gene Expression; Gene Expression Regulation; Heart Rate; Hypertension; Indans; Kidney; Male; Molecular Sequence Data; Nitrobenzenes; Piperazines; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Renin; RNA, Messenger

The antihypertensive and metabolic responses to delapril and captopril in hypertensive patients were studied. Forty-six hypertensive patients entered the study and were divided into two groups. The delapril group included 21 essential hypertensive and five renoparenchymal hypertensive patients; while the captopril group included 11 essential hypertensive and nine renoparenchymal hypertensive patients. The patients in the delapril group took delapril 7.5 mg twice a day for 2 weeks. If the antihypertensive effect was inadequate, the dose was increased to 15mg twice a day, and then to 30mg twice a day. The period of delapril treatment was 12 weeks. The patients in the captopril group took captopril 25 mg twice a day or three times a day for 12 weeks. After delapril treatment, there were significant decreases in the systolic (from 163 +/- 17 to 141 +/- 15 mmHg) and diastolic blood pressure (from 105 +/- 13 to 91 +/- 10 mmHg). There were also significant decreases in the systolic (from 161 +/- 18 to 141 +/- 24 mmHg) and diastolic blood pressure (from 100 +/- 10 to 90 +/- 12 mmHg) after captopril treatment (p < 0.001). The pulse rates in both groups showed no significant changes after treatment. The laboratory data in both groups showed few changes after treatment. Plasma renin activity increased after delapril treatment. A cough was the side effect most commonly seen. We conclude that hypertensive patients have the same blood pressure and metabolic responses to delapril as captopril.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Female; Humans; Hypertension; Indans; Male; Middle Aged; Renin

It has been reported that elevation of blood pressure produces a reduction in pain sensitivity. This study was designed to clarify the correlation in spontaneously hypertensive rats (SHR) between fall in blood pressure and pain sensitivity. In seven-weeks-old male SHR, the angiotensin converting inhibitor delapril (10 mg/kg/day) or calcium antagonist nifedipine (3 mg/kg/day) was administered orally every day for 8 weeks. Systolic blood pressure (SBP) pretreatment was significantly higher in the SHR than in normotensive Wistar-Kyoto (WKY) rats and pain sensitivity measured with the hot plate method was significantly lower in the SHR than in the WKY rats. Administration of both drugs produced a significant suppression of elevation of SBP, and produced a significant elevation of pain sensitivity. Furthermore, at 8 weeks after drug administration, urinary norepinephrine (UNE) significantly decreased and plasma beta-endorphin (beta-end) significantly increased. A significant correlation was noted between pain sensitivity and SBP and also between pain sensitivity and UNE. Of these, pain sensitivity was the more closely correlated to degree of change in UNE than to degree of change in SBP. It appears that elevation of pain sensitivity is due to suppression of the sympathetic nervous system by antihypertensive drugs, but not to elevation of beta-end levels. These data suggest that a fall in blood pressure through administration of delapril or nifedipine reverses decrease in pain sensitivity in SHR and that decrease in sympathetic tone plays an important role in the restoration of levels of sensitivity to pain.

Topics: Animals; Blood Pressure; Hypertension; Indans; Male; Nifedipine; Pain; Pain Measurement; Rats; Rats, Inbred SHR; Sensory Thresholds; Sympathetic Nervous System

We report a patient presenting rapid deterioration of renal function due to primary cholesterol atheroembolism. The patient was 75-year-old hypertensive male and was admitted to a hospital because of rt. hemiplegia which developed 2 weeks earlier. On admission, his blood pressure was 200/100 mmHg and serum creatinine level was 2.9 mg/dl with urinalysis 1+ both for protein and hematuria. 2 weeks later, an angiotensin converting enzyme inhibitor (ACE inhibitor, delapril 15 mg/day) was given to control high blood pressure. Immediately after this medication, his renal failure rapidly progressed with a fall in blood pressure (110/60 mmHg) and oliguria (100 ml/day). Although he was transferred to our hospital and was treated with hemodialysis, he died of an attack of acute myocardial infarction in a week. At post-mortem examination, microscopic findings of the kidney disclosed numerous occlusions of medium-sized artery by cholesterol emboli. These emboli were also observed in other organs, but not so prominent as in the kidney. The coronary arteries exhibited severe sclerosis. In this presented case, acute deterioration of renal function was caused by ACE-inhibitor, although which was administered in a volume depleted condition. Therefore, further study would be necessary whether or not ACE-inhibitors predispose the patients with this disease to acute renal failure.

Topics: Acute Kidney Injury; Aged; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Cholesterol; Embolism; Humans; Hypertension; Indans; Male

Since dry cough has recently been recognized as a side effect of angiotensin converting enzyme (ACE) inhibitors employed in the treatment of hypertension or congestive heart failure, the incidence of dry cough in elderly patients receiving ACE inhibitors was investigated. There were 237 out-patients on either captopril, enalapril, or delapril, in August and November 1989. Questionnaires concerning dry cough and smoking were completed by 184 patients. Patients either less than 50 years of age, or with chronic pulmonary disease were excluded. The remaining 168 patients, 63 males, 105 females, with a mean age of 73 years were analyzed for the incidence of a dry cough in relation to age, sex, smoking, and type of drugs. The overall incidence of a dry cough was 21/168 (12.5%), 7/63 (11.1%) for males and 14/105 (13.3%) for females, and was less frequent with advancing age; in the 51-60 age group 4/11 (36.4%), in the 61-70 age group 5/39 (12.8%), in the 71-80 age group 9/75 (12.0%), in the 81-90 age group 3/40 (7.5%), in the 91- age group 0/3 (0%). Enalapril showed significantly higher incidence of dry cough than captopril (16/93, 17.2% vs 7/88, 8.0%, p less than 0.05). Delapril showed an incidence 4/11, 36.4%, however, 9 out of the 11 patients who were given delapril had had a history of a dry cough with captopril or enalapril, and in 4 out of these 9 patients the dry cough disappeared by replacement of captopril or enalapril by delapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Enalapril; Female; Heart Failure; Humans; Hypertension; Indans; Male; Smoking; Surveys and Questionnaires

1. In view of a recent interesting hypothesis that the vascular renin-angiotensin system (RAS) plays an important role in the maintenance of hypertension, we examined the effect of delapril (DP), a newly developed angiotensin converting enzyme inhibitor (ACEI), on angiotensin II (Ang II) release from isolated perfused hind legs of spontaneously hypertensive rats (SHR) in comparison with normotensive rats of Wistar-Kyoto strain (WKY). 2. Male SHR and WKY were given DP orally (10 mg/kg per day) for 2 weeks. Isolated hind legs of these rats were perfused with angiotensinogen-free Krebs-Ringer solution, and Ang II released into the perfusate was determined directly by extraction with Sep-Pak C18 cartridges connected to the perfusion system. 3. Delapril produced a sustained antihypertensive action in SHR but not in WKY. The spontaneous release of Ang II in SHR was 112.9 +/- 17.6 pg during the first 30 min of perfusion, which was somewhat greater than that in WKY (96.5 +/- 9.8 pg). An active metabolite of DP, delapril diacid (DPD), when added to the perfusion medium, suppressed the Ang II release in a dose-dependent manner in the two strains. Oral pretreatment of DP for 2 weeks suppressed the Ang II release by 60% in WKY and more pronouncedly by 73% in SHR. 4. These results suggest the presence of a functional RAS in vascular tissues which contributes to the maintenance of vascular tone of SHR, and that ACEI including DP exerts their antihypertensive effect through inhibition of vascular Ang II release in this animal model of human hypertension.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Hypertension; Indans; Muscle, Smooth, Vascular; Perfusion; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System

Inhibitors of angiotensin converting enzyme, renin, and the angiotensin II (Ang II) receptor lower the blood pressure of spontaneously hypertensive rats (SHR) used as a model of essential hypertension. Since their plasma renin levels were normal or subnormal, renin in the vascular tissue was considered to play a key role in the maintenance of the hypertension. To clarify the source and localization of renin in SHR, antirenin antibodies, the converting enzyme inhibitors delapril, enalapril, and the Ang II receptor antagonist DuP 753 were administered to intact and bilaterally nephrectomized SHR and their normotensive controls. The efficient hypotensive action of the renin antibody indicated that renin of renal origin is a dominant factor. Gradual but complete disappearance of antihypertensive action of these inhibitors of the renin-angiotensin system upon bilateral nephrectomy indicated the importance of membrane-associated renin of the renal origin and angiotensin converting enzyme in the maintenance of the spontaneous hypertension.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalapril; Hypertension; Hypotension; Imidazoles; Immunoglobulin G; Indans; Losartan; Nephrectomy; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Renin; Tetrazoles; Time Factors

In order to investigate the effect of delapril, a new angiotensin converting enzyme inhibitor, on the diurnal variation of arterial pressure in patients with essential hypertension, this study examined 24 h arterial pressure using an indirect or a direct monitoring system. When the effect of twice-a-day administration of delapril at daily doses of 30 to 90 mg was examined using the indirect monitoring system in 12 outpatients, delapril decreased systolic and diastolic arterial pressures significantly only at limited points during the day. However, each of the averaged 24 h daytime and nighttime arterial pressures showed significant reductions. The 24 h intraarterial pressure monitoring demonstrated that delapril decreased systolic and diastolic arterial pressure at most of the measurement points. The arterial pressure reductions during daytime and nighttime were not significantly different, that is, there was no excessive reduction in nighttime arterial pressure. Heart rate and its variability were virtually unaffected by the delapril treatment in either monitoring study. No adverse reactions were observed in the indirect or direct monitoring studies. Thus, it is concluded that twice-a-day administration of delapril at daily doses of 30 to 90 mg brings about a safe and stable antihypertensive effect, without affecting the diurnal variation of arterial pressure.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Determination; Circadian Rhythm; Female; Heart Rate; Humans; Hypertension; Indans; Male; Middle Aged; Monitoring, Physiologic

The effects of delapril, an angiotensin converting enzyme (ACE) inhibitor, on renal function and the renin-angiotensin and kallikrein-prostaglandin systems were investigated in 10 hypertensive patients who were treated for between 4 months and 1 year. There was a significant (P less than .05) increase in renal blood flow (RBF) without affecting glomerular filtration rate. Filtration fraction increased, while renal vascular resistance decreased. There were also significant (P less than .05) increases in urinary kallikrein and prostaglandin excretion, while thromboxane excretion decreased. There was no change in urinary aldosterone excretion. These results suggest that renal hemodynamic changes seen during long-term therapy with delapril are caused, in part, by activation of the kallikrein-prostaglandin system, as well as suppression of the renin-angiotensin system.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Dinoprostone; Humans; Hypertension; Indans; Kallikreins; Kidney; Middle Aged; Renin; Thromboxane B2; Time Factors

Accumulating evidence suggests an important role of vascular renin-angiotensin system (RAS) in the local control of arterial tone. To further gain insight into the significance of vascular RAS in hypertension, we investigated the relationship between the antihypertensive action of delapril, a newly developed converting enzyme inhibitor (CEI), and its effects on vascular angiotensin II (Ang II) release in spontaneously hypertensive rats (SHR). Male SHRs were given delapril or its active metabolite (5-hydroxydelapril diacid; 5-hydroxy-DPD) orally (10 mg/kg/day) for 2 weeks. Isolated hind legs of these rats were perfused with angiotensinogen-free Krebs-Ringer solution, and Ang II released into the perfusate was directly determined by extraction with Sep-Pak C18 cartridges connected to the perfusion system. Both delapril and 5-hydroxy-DPD produced a sustained antihypertensive action. The spontaneous release of Ang II from isolated perfused hind legs of control SHRs was about 50 to 110 pg during the first 30 min of perfusion, and it remained stable up to 3 h. Another active metabolite, delapril diacid (DPD), when added to the perfusion medium (10(-9) to 5 x 10(-5) mol/L), suppressed the Ang II release in a dose-dependent manner. The maximal percent inhibition of Ang II released evoked by DPD (5 x 10(-6) mol/L) was approximately 51%. Oral pretreatment of either delapril or 5-hydroxy-DPD for 2 weeks suppressed the Ang II release by 61% and 73% for delapril and 5-hydroxy-DPD, respectively. These results suggest the presence of a functional RAS in vascular tissues, and that delapril exerts its antihypertensive effect through inhibition of vascular Ang II release in SHRs.

Topics: Administration, Oral; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Hypertension; Indans; Male; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; Time Factors

The antihypertensive effects and pharmacokinetic properties of delapril, an angiotensin-converting enzyme (ACE) inhibitor, were investigated in hypertensive patients with normal renal function (NRF; n = 6) and in those with impaired renal function (IRF; n = 5). A 15-mg oral dose of delapril was given once on the first and last days, and twice daily on the other days. The measurement of blood pressure and sampling were done at 0, 1, 2, 4, 6, 12, and 24 hours postdose on the first and last days of treatment. Plasma and urinary concentrations of delapril and its metabolites were measured by HPLC. ACE activity was suppressed from 1 hour after the first dose to 24 hours after the last dose of delapril in both the NRF and IRF groups. During the consecutive dosing, significant BP falls were observed from 1 hour postdose of delapril to 24 hours in the NRF group and to 6 hours in the IRF group. Peak plasma concentrations of 5-hydroxydelapril diacid and areas under the plasma concentration-time curve (AUC) of both delapril diacid and 5-hydroxydelapril diacid in the IRF group were significantly higher (p less than 0.001 or 0.05) than in the NRF group. No significant increase of pharmacokinetic parameters in repeated dosing was observed in both the NRF and IRF groups. Significant positive correlations (p less than 0.001) were found between the inverse of creatinine clearance and the AUCs of the active diacid metabolites in single and consecutive doses.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Drug Administration Schedule; Female; Humans; Hypertension; Indans; Kidney Diseases; Male; Middle Aged; Peptidyl-Dipeptidase A; Pulse

The effects of a new angiotensin converting enzyme inhibitor, delapril hydrochloride, (delapril) on renal function, and the renin-angiotensin-aldosterone and kallikrein-kinin prostaglandin systems were studied in 10 hypertensive patients. After 4 to 12 months (7.6 +/- 0.9 [SE]) of treatment with 15-60 mg/day (36 +/- 6.8) of delapril (b.i.d.), mean arterial pressure was decreased from 126 +/- 3.0 to 110 +/- 4.4 mmHg (p less than 0.01). Although renal blood flow (RBF), assessed by PAH clearance and hematocrit, was increased from 437 +/- 51 to 490 +/- 49 ml/min (p less than 0.05) and renal vascular resistance was decreased (p less than 0.05), glomerular filtration rate, measured by endogenous creatinine clearance, did not change significantly. Thus, filtration fraction was reduced (p less than 0.01). Plasma renin activity was increased from 1.5 +/- 0.3 to 4.4 +/- 1.1 ng/ml/hr (p less than 0.01). Plasma aldosterone concentration tended to decrease (p less than 0.1), and urinary aldosterone excretion showed on significant change. Although urinary kallikrein and prostaglandin E2 excretions were increased (p less than 0.05), urinary thromboxane B2 excretions was reduced (p less than 0.05). In addition, the changes in RBF were significantly correlated with those in urinary PGE2 excretion (r = 0.63, p less than 0.05). These results suggest that the antihypertensive effect of delapril is multifactorial and that the improvement of RBF seen during delapril administration in the present study may be partly due to the suppression of the renin-angiotensin-aldosterone system and the activation of kallikrein-kinin-prostaglandin system.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Female; Humans; Hypertension; Indans; Kallikrein-Kinin System; Kidney; Male; Middle Aged; Prostaglandins; Renin-Angiotensin System; Time Factors

The acute effect on the renin-angiotensin system and the pharmacokinetic properties of delapril, a new angiotensin converting enzyme inhibitor and its active diacid metabolites (delapril diacid and 5-hydroxy delapril diacid) arising from delapril in vivo were investigated in 4 hypertensive patients with chronic renal failure (CRF: 4 males, average age 49.5 (37-64) years, mean Ccr 22.2 ml/min/1.73 m2) and 9 patients with essential hypertension (EH: 6 males, 3 females, average age 42.8 (28-61) years, mean Ccr 79.3 ml/min/1.73 m2). In CRF, following a single dose of delapril hydrochloride (30 mg), the biological half lives (t1/2) of delapril diacid and 5-OH-delapril diacid were 4.69, 12.88 hours, the maximum serum concentration (Cmax) and the area under the plasma concentration-time curve ([AUC]24(0)) of delapril and its diacid metabolites were 414, 797 and 435 ng/ml, and 658, 6400 and 5068 ng X h/ml, respectively. In EH, the t1/2 of delapril diacid and 5-OH-delapril diacid were 1.21, 1.40 hours and the Cmax and [AUC]24(0) of delapril and its diacid metabolites were 489, 635 and 229 ng/ml, and 572, 1859 and 948 ng X h/ml, respectively. The [AUC]24(0) in CRF were significantly increased as compared with those in EH. The cumulative urinary excretions were significantly lower in CRF than in EH. The serum angiotensin converting enzyme (ACE) was markedly inhibited in both groups up to 24 hours. The plasma concentration of angiotensin II decreased in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Humans; Hypertension; Indans; Indenes; Kidney Failure, Chronic; Kinetics; Male; Middle Aged; Renin-Angiotensin System

The pharmacokinetics and depressor effect of a nonsulfhydryl angiotensin-converting enzyme inhibitor, delapril, was assessed by administering a single dose of 30 mg to nine patients with mild to moderate essential hypertension. Orally administered delapril is a prodrug and must be deesterified to its active metabolites, delapril diacid and 5-hydroxy delapril diacid. The pharmacokinetic parameters for delapril, delapril diacid, and 5-hydroxy delapril diacid were, respectively: t 1/2 0.30, 1.21, and 1.40 hours; Cmax 489, 635, and 229 ng/ml; AUC 572, 1859, and 948 ng X hr/ml. Delapril produced significant decreases in systolic blood pressure and angiotensin-converting enzyme activity 24 hours after dosing. There were no significant changes in the endogeneous creatinine clearance after the drug. Thus delapril may represent a useful antihypertensive agent for control of blood pressure in patients with essential hypertension.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Depression, Chemical; Female; Half-Life; Humans; Hypertension; Indans; Indenes; Kinetics; Male; Middle Aged; Pulse; Renin-Angiotensin System

The antihypertensive action of N-[N-[(S)-1-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl]-N-(indan-2-yl) glycine hydrochloride (CV-3317), a nonsulfhydryl compound characterized as an angiotensin converting enzyme inhibitor in our previous work, was examined in hypertensive animal models. In 2-kidney, 1 clip hypertensive rats and dogs, CV-3317 (3 and/or 10 mg/kg, p.o.) produced a sustained antihypertensive action of about 15 to 25 mmHg. Daily oral administrations of CV-3317 (1 to 10 mg/kg/day) to spontaneously hypertensive rats (SHR) for 5 weeks produced a sustained antihypertensive action of 20 to 40 mmHg. When CV-3317 (3 mg/kg) was combined with hydrochlorothiazide (10 mg/kg), its antihypertensive action was intensified in potency and duration. CV-3317 (30 mg/kg) induced a slight hypotension (5 to 10 mmHg) in normotensive rats, but had no effect on the blood pressure of 1-kidney, 1 clip hypertensive rats and on that of a low renin type of DOCA/salt hypertensive rat. The antihypertensive activity of CV-3317 was more potent than that of captopril. In pithed SHR, the pressor response induced by an electrical stimulation of the preganglionic sympathetic nerve, but not the pressor response to norepinephrine, was attenuated by both agents (0.3 mg/kg, i.v.). Both agents may exert their antihypertensive action not only primarily by inhibiting the renin-angiotensin system, but also by inhibiting norepinephrine release from the sympathetic nerve terminals indirectly by reducing the formation of vascular angiotensin II.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Decerebrate State; Desoxycorticosterone; Hypertension; Hypertension, Renal; Indans; Indenes; Male; Rats; Rats, Inbred SHR; Rats, Inbred Strains