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Roberto Fogari - One of the best experts on this subject based on the ideXlab platform.

  • Combination Delapril/Manidipine as Antihypertensive Therapy in High-Risk Patients
    Clinical Drug Investigation, 2011
    Co-Authors: Roberto Fogari, Amedeo Mugellini, Maria Circelli, Giovanni Cremonesi
    Abstract:

    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.

  • Combination Delapril/Manidipine as Antihypertensive Therapy in High-Risk Patients
    Clinical drug investigation, 2011
    Co-Authors: Roberto Fogari, Amedeo Mugellini, Maria Circelli, Giovanni Cremonesi
    Abstract:

    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.

  • combination Delapril manidipine as antihypertensive therapy in high risk patients
    Clinical Drug Investigation, 2011
    Co-Authors: Roberto Fogari, Amedeo Mugellini, Maria Circelli, Giovanni Cremonesi
    Abstract:

    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.

  • efficacy of manidipine Delapril versus losartan hydrochlorothiazide fixed combinations in patients with hypertension and diabetes
    Journal of Hypertension, 2008
    Co-Authors: Alejandro Rocacusachs, Roland E. Schmieder, Filippos Triposkiadis, René R. Wenzel, Stéphane Laurent, Osvaldo Kohlmann, Roberto Fogari
    Abstract:

    BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION 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.

  • Effect of Delapril/manidipine vs olmesartan/ hydrochlorothiazide combination on insulin sensitivity and fibrinogen in obese hypertensive patients.
    Internal medicine (Tokyo Japan), 2008
    Co-Authors: Roberto Fogari, A Zoppi, G Derosa, P Lazzari, Paola Preti, Luca Corradi, Amedeo Mugellini
    Abstract:

    Objective To compare the effect of Delapril/manidipine vs olmesartan/hydrochlorothiazide (HCTZ) combination on insulin sensitivity and plasma fibrinogen in obese hypertensive patients. Patients and Methods After a 4-week placebo period, 88 obese, hypertensive (DBP >95 and

Toshio Ogihara - One of the best experts on this subject based on the ideXlab platform.

  • Angiotensin blockade and the progression of renal damage in the spontaneously hypertensive rat.
    Hypertension, 1993
    Co-Authors: Katsuhiko Kohara, Hiroshi Mikami, Naoki Okuda, Jitsuo Higaki, Toshio Ogihara
    Abstract:

    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.

  • peripheral vs central blockade of the renin angiotensin system in spontaneously hypertensive rats comparison of novel at1 receptor antagonist tcv 116 with angiotensin converting enzyme inhibitor Delapril
    Hypertension Research, 1993
    Co-Authors: Katsuhiko Kohara, Hiroshi Mikami, Naoki Okuda, Toshio Ogihara
    Abstract:

    In the present study, we evaluated the hemodynamic and metabolic profiles derived from oral administration of the angiotensin converting enzyme inhibitor, Delapril 50mg/kg/day, and the non-peptide angiotensin II type I (AT1) receptor antagonist, TCV-116 1mg/kg/day, for five days, to try to discriminate AT1 receptor-related responses from the depressor properties of chronic treatment with Delapril in spontaneously hypertensive rats (SHRs). Both TCV-116 and Delapril oral administrations significantly decreased blood pressure without any changes in heart rate. Delapril induced dipsogenic response and natriuresis associated with augmentation of urinary catecholamine excretion, while TCV-116 did not cause any changes in these variables. Neither Delapril nor TCV-116 changed urinary excretion of prostaglandin (PG) E2 and 6-keto PG F1α. We also examined the effects of centrally administered angiotensin converting enzyme inhibitor and AT1 receptor antagonist to determine the central role of these drugs.Either the active metabolite of Delapril, Delapril-M1 1 mg/kg/day, or the active form of TCV-116, CV-11974 0.1mg/kg/day, were administered intracerebroventricularly for five days. Both treatments significantly decreased the blood pressure, in association with augmentation of the baroreceptor reflex control of heart rate, in response to phenylephrine injection. These findings suggest that the depressor properties of orally administered Delapril are more complex than those of TCV-116, while central blockade by both angiotensin converting enzyme and AT1 receptor decreases blood pressure in part through baroreceptor sensitization. (Hypertens Res;1993 16: 239-246)

  • The role of activated vascular angiotensin II generation in vascular hypertrophy in one-kidney, one clip hypertensive rats.
    Journal of hypertension, 1993
    Co-Authors: Hiromi Rakugi, Hiroshi Mikami, Jitsuo Higaki, Ryuichi Morishita, Toshio Ogihara
    Abstract:

    OBJECTIVE To investigate the role of vascular angiotensin II (Ang II) in the vascular thickening of one-kidney, one clip (1-K, 1C) hypertensive rats, which show normal plasma renin activity. METHODS The type 1 Ang II receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme (ACE) inhibitor Delapril (20 mg/kg per day), hydralazine (20 mg/kg per day) or vehicle were administered to four groups of 1-K, 1C rats aged 6-10 weeks. Vehicle was also given to uninephrectomized rats. RESULTS The aortae of 1-K, 1C rats contained significantly higher levels of Ang II than those of uninephrectomized rats and showed hypertrophy, but not hyperplasia of their medial smooth muscle cells. Hypertrophy was estimated by immunohistochemical staining of alpha-actin. Hyperplasia was estimated by DNA content and incorporation of 5-bromo-2'-deoxyuridine. The blood pressure of the 1-K, 1C rats was not affected by either TCV-116 or Delapril, even at doses sufficient to induce depressor effects in spontaneously hypertensive rats. However, subdepressor doses of TCV-116 and Delapril both significantly reduced the alpha-actin-stained area to 78 and 73%, respectively, of that in the 1-K, 1C rats, whereas a depressor dose of hydralazine did not affect the alpha-actin-stained area. The level of Ang II in the aorta, but not in plasma, was suppressed by Delapril but not by hydralazine. CONCLUSIONS These results suggest strongly that vascular Ang II plays a major role in the development of vascular hypertrophy, independently of plasma Ang II, bradykinin and ACE-independent pathways of Ang II generation, and in the regulation of blood pressure in this normoreninaemic hypertensive model.

  • Comparative study of the effects of three angiotensin converting enzyme inhibitors on the cough reflex.
    American Journal of Hypertension, 1991
    Co-Authors: Toshio Ogihara, Hiroshi Mikami, Katsutoshi Katahira, Atsuhiro Otsuka
    Abstract:

    : 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.

  • Clinical evaluation of Delapril in Japan. Report from the Japan Study Group on Delapril.
    American journal of hypertension, 1991
    Co-Authors: Toshio Ogihara, Yoshihiro Kaneko, Masao Ishii, Masao Ikeda, Kazuo Yamada, Teruo Omae, Kikuo Arakawa, Kaoru Yoshinaga, Yuichi Kumahara, Tatsuo Kokubu
    Abstract:

    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.

Amedeo Mugellini - One of the best experts on this subject based on the ideXlab platform.

  • Combination Delapril/Manidipine as Antihypertensive Therapy in High-Risk Patients
    Clinical Drug Investigation, 2011
    Co-Authors: Roberto Fogari, Amedeo Mugellini, Maria Circelli, Giovanni Cremonesi
    Abstract:

    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.

  • Combination Delapril/Manidipine as Antihypertensive Therapy in High-Risk Patients
    Clinical drug investigation, 2011
    Co-Authors: Roberto Fogari, Amedeo Mugellini, Maria Circelli, Giovanni Cremonesi
    Abstract:

    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.

  • combination Delapril manidipine as antihypertensive therapy in high risk patients
    Clinical Drug Investigation, 2011
    Co-Authors: Roberto Fogari, Amedeo Mugellini, Maria Circelli, Giovanni Cremonesi
    Abstract:

    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.

  • Effect of Delapril/manidipine vs olmesartan/ hydrochlorothiazide combination on insulin sensitivity and fibrinogen in obese hypertensive patients.
    Internal medicine (Tokyo Japan), 2008
    Co-Authors: Roberto Fogari, A Zoppi, G Derosa, P Lazzari, Paola Preti, Luca Corradi, Amedeo Mugellini
    Abstract:

    Objective To compare the effect of Delapril/manidipine vs olmesartan/hydrochlorothiazide (HCTZ) combination on insulin sensitivity and plasma fibrinogen in obese hypertensive patients. Patients and Methods After a 4-week placebo period, 88 obese, hypertensive (DBP >95 and

  • effect of Delapril manidipine vs olmesartan hydrochlorothiazide combination on insulin sensitivity and fibrinogen in obese hypertensive patients
    Internal Medicine, 2008
    Co-Authors: Roberto Fogari, A Zoppi, L Corradi, G Derosa, P Lazzari, Paola Preti, Amedeo Mugellini
    Abstract:

    Objective To compare the effect of Delapril/manidipine vs olmesartan/hydrochlorothiazide (HCTZ) combination on insulin sensitivity and plasma fibrinogen in obese hypertensive patients. Patients and Methods 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. Results 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). Conclusion 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.

Giuseppe Biagini - One of the best experts on this subject based on the ideXlab platform.

  • Dose-dependent prevention of fibrosis in aorta of salt-loaded stroke-prone spontaneously hypertensive rats by combined Delapril and indapamide treatment.
    Journal of cardiovascular pharmacology, 2002
    Co-Authors: Miranda Baccarani Contri, Francesca Taparelli, Monica Miselli, Giada Pedrazzi, Barbara Bacchelli, Giuseppe Biagini
    Abstract:

    Summary: 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.

  • Protective effects of Delapril combined with indapamide or hydrochlorothiazide in spontaneously hypertensive stroke-prone rats: a comparative dose-response analysis.
    Journal of cardiovascular pharmacology, 2000
    Co-Authors: S. Boschi, G. Vantaggiato, C. Torri, Isabella Zini, Luigi F. Agnati, Michele Zoli, Giuseppe Biagini
    Abstract:

    Summary: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).

  • Protective effects of Delapril, indapamide and their combination on stroke occurrence and lifespan in salt-loaded stroke-prone spontaneously hypertensive rats.
    Arzneimittel-Forschung, 1998
    Co-Authors: Roberta Razzetti, Stefano Bongrani, G Oberto, Rosaria Ferrari, Giuseppe Biagini
    Abstract:

    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.

Hiroshi Mikami - One of the best experts on this subject based on the ideXlab platform.

  • Angiotensin blockade and the progression of renal damage in the spontaneously hypertensive rat.
    Hypertension, 1993
    Co-Authors: Katsuhiko Kohara, Hiroshi Mikami, Naoki Okuda, Jitsuo Higaki, Toshio Ogihara
    Abstract:

    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.

  • peripheral vs central blockade of the renin angiotensin system in spontaneously hypertensive rats comparison of novel at1 receptor antagonist tcv 116 with angiotensin converting enzyme inhibitor Delapril
    Hypertension Research, 1993
    Co-Authors: Katsuhiko Kohara, Hiroshi Mikami, Naoki Okuda, Toshio Ogihara
    Abstract:

    In the present study, we evaluated the hemodynamic and metabolic profiles derived from oral administration of the angiotensin converting enzyme inhibitor, Delapril 50mg/kg/day, and the non-peptide angiotensin II type I (AT1) receptor antagonist, TCV-116 1mg/kg/day, for five days, to try to discriminate AT1 receptor-related responses from the depressor properties of chronic treatment with Delapril in spontaneously hypertensive rats (SHRs). Both TCV-116 and Delapril oral administrations significantly decreased blood pressure without any changes in heart rate. Delapril induced dipsogenic response and natriuresis associated with augmentation of urinary catecholamine excretion, while TCV-116 did not cause any changes in these variables. Neither Delapril nor TCV-116 changed urinary excretion of prostaglandin (PG) E2 and 6-keto PG F1α. We also examined the effects of centrally administered angiotensin converting enzyme inhibitor and AT1 receptor antagonist to determine the central role of these drugs.Either the active metabolite of Delapril, Delapril-M1 1 mg/kg/day, or the active form of TCV-116, CV-11974 0.1mg/kg/day, were administered intracerebroventricularly for five days. Both treatments significantly decreased the blood pressure, in association with augmentation of the baroreceptor reflex control of heart rate, in response to phenylephrine injection. These findings suggest that the depressor properties of orally administered Delapril are more complex than those of TCV-116, while central blockade by both angiotensin converting enzyme and AT1 receptor decreases blood pressure in part through baroreceptor sensitization. (Hypertens Res;1993 16: 239-246)

  • The role of activated vascular angiotensin II generation in vascular hypertrophy in one-kidney, one clip hypertensive rats.
    Journal of hypertension, 1993
    Co-Authors: Hiromi Rakugi, Hiroshi Mikami, Jitsuo Higaki, Ryuichi Morishita, Toshio Ogihara
    Abstract:

    OBJECTIVE To investigate the role of vascular angiotensin II (Ang II) in the vascular thickening of one-kidney, one clip (1-K, 1C) hypertensive rats, which show normal plasma renin activity. METHODS The type 1 Ang II receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme (ACE) inhibitor Delapril (20 mg/kg per day), hydralazine (20 mg/kg per day) or vehicle were administered to four groups of 1-K, 1C rats aged 6-10 weeks. Vehicle was also given to uninephrectomized rats. RESULTS The aortae of 1-K, 1C rats contained significantly higher levels of Ang II than those of uninephrectomized rats and showed hypertrophy, but not hyperplasia of their medial smooth muscle cells. Hypertrophy was estimated by immunohistochemical staining of alpha-actin. Hyperplasia was estimated by DNA content and incorporation of 5-bromo-2'-deoxyuridine. The blood pressure of the 1-K, 1C rats was not affected by either TCV-116 or Delapril, even at doses sufficient to induce depressor effects in spontaneously hypertensive rats. However, subdepressor doses of TCV-116 and Delapril both significantly reduced the alpha-actin-stained area to 78 and 73%, respectively, of that in the 1-K, 1C rats, whereas a depressor dose of hydralazine did not affect the alpha-actin-stained area. The level of Ang II in the aorta, but not in plasma, was suppressed by Delapril but not by hydralazine. CONCLUSIONS These results suggest strongly that vascular Ang II plays a major role in the development of vascular hypertrophy, independently of plasma Ang II, bradykinin and ACE-independent pathways of Ang II generation, and in the regulation of blood pressure in this normoreninaemic hypertensive model.

  • Comparative study of the effects of three angiotensin converting enzyme inhibitors on the cough reflex.
    American Journal of Hypertension, 1991
    Co-Authors: Toshio Ogihara, Hiroshi Mikami, Katsutoshi Katahira, Atsuhiro Otsuka
    Abstract:

    : 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.

  • Angiotensin converting enzyme inhibitors suppress the vascular renin-angiotensin system of spontaneously hypertensive rats.
    American journal of hypertension, 1991
    Co-Authors: Koichi Higashimori, Hiroshi Mikami, Toshio Ogihara, Masahiro Nagano, Mitsuaki Nakamaru, Yoshikatsu Tabuchi, Tadashi Inagami
    Abstract:

    The effects of angiotensin converting enzyme (ACE) inhibitors on the release of angiotensin II (Ang II) from isolated mesenteric arteries of spontaneously hypertensive rats (SHRs) were examined. Delapril, enalapril, and captopril suppressed Ang II release in a dose-dependent manner. After oral treatment with Delapril (10 mg/kg/day), enalapril (10 mg/kg/day), and captopril (50 mg/kg/day) for 1 week, the blood pressure of SHRs was significantly reduced in the three groups and 54%, 46%, and 36% decreases in basal Ang II release were observed, respectively, compared with control. However, low-dose captopril (10 mg/kg/day) had no effect on blood pressure or basal Ang II release. These results provide clear evidence that ACE inhibitors suppress vascular renin-angiotensin activity of SHRs, and the possible contribution of the tissue renin-angiotensin system to spontaneous hypertension is suggested.