delapril and candesartan-cilexetil

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

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

We previously demonstrated that angiotensin converting enzyme (ACE) inhibitor normalizes the up-regulated gene expression of vascular natriuretic peptide type A (NP-A) receptor in hypertensive rats. To elucidate the mechanism, we examined the effect of angiotensin II receptor (AT1) antagonist (TCV-116) and bradykinin receptor (B2) antagonist (Hoe 140) on the NP-A receptor mRNA level in the aorta of genetically hypertensive rats (SHR-SP/Izm) using ribonuclease protection assay. The effect of ACE inhibitor on the NP-A receptor mRNA level was completely abolished by a concomitant administration of Hoe 140, while TCV-116 did not show any significant effect on the NP-A receptor mRNA level. These results suggest that bradykinin plays an important role in the regulation of the vascular NP-A receptor gene expression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Gene Expression; Indans; Rats; Rats, Inbred SHR; Receptor, Bradykinin B2; Receptors, Atrial Natriuretic Factor; Tetrazoles

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

We investigated the effect of chronic administration of an angiotensin II type-1 receptor antagonist in the development of heart failure due to volume overload in rats.. Aortocaval fistula (AVF), a model of volume overloaded heart failure, was induced in rats by our newly developed technique using a simple and rapid 18-gauge needle multipuncture. After 3 weeks of oral administration of an angiotensin II receptor antagonist TCV-116, 1 mg/kg per day, we evaluated the hemodynamics, heart weight, and degree of left ventricular dilatation. We also compared the effect of TCV-116 with that of an angiotensin-converting enzyme inhibitor delapril, 1 g/L in drinking water.. AVF heart failure produced by our technique exhibited significant increases in the left ventricular end-diastolic pressure (LVEDP) (12 = 1 vs 4 +/- 1 mmHg, p < 0.05), right atrial pressure (RAP) (5.0 +/- 0.6 vs 1.0 +/- 0.4 mmHg, p < 0.05), right ventricular systolic pressure (RVSP) (58 +/- 6 vs 33 +/- 1 mmHg, p < 0.05), left ventricular weight (LVW) (3.00 +/- 0.13 vs 2.09 +/- 0.04 g/kg BW, p < 0.05), right ventricular weight (RVW) (0.93 +/- 0.05 vs 0.59 +/- 0.01 g/kg BW, p < 0.05), and left ventricular end-diastolic volume index (LVEDVI) (2.55 +/- 0.14 vs 0.80 +/- 0.12 ml/kg BW, p < 0.05) as compared with these values in sham-operated rats. There were no differences in shunt ratio between untreated and TCV-116- and delapril-treated AVF groups. TCV-116 improved these hemodynamics, as did delapril (TCV-116 vs delapril: LVEDP 8 +/- 1 vs 8 +/- 1, RAP: 3.8 +/- 0.6 vs 2.3 +/- 1.4, RASP: 50 +/- 2 vs 46 +/- 3, LVW: 2.53 +/- 0.11 vs 2.52 +/- 0.15, RVW: 0.80 +/- 0.04 vs 0.77 +/- 0.06, LVEDVI: 1.67 +/- 0.15 vs 1.70 +/- 0.17).. These results suggest that AVF rats with volume overload produced by a new multipuncture method exhibit both right- and left-side heart failure. Angiotensin II type-1 receptor antagonist as well as angiotensin converting enzyme inhibitor attenuate the development of this type of heart failure in rats.

Topics: Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Aortic Diseases; Arteriovenous Fistula; Benzimidazoles; Biphenyl Compounds; Heart Failure; Hemodynamics; Indans; Linear Models; Male; Rats; Rats, Wistar; Tetrazoles; Vena Cava, Inferior

The aim was to investigate changes in cardiac transforming growth factor beta 1 (TGF-beta 1), fibronectin, and collagen types I and III mRNA levels in isoprenaline induced cardiac hypertrophy, and the effects of delapril, an angiotensin converting enzyme inhibitor, and TCV-116, an angiotensin II type 1 receptor antagonist, on this hypertrophy.. Rats were continuously infused with saline and low or high dose of isoprenaline (0.5 or 3 mg.kg-1.d-1) by an osmotic minipump for 24 h, 48 h or 7 d. Treatment with delapril (100 mg.kg-1.d-1) or TCV-116 (10 mg.kg-1.d-1) was started from 1 d before the implantation of minipump to the end of experiments. After the experimental periods, left ventricular weight was measured and the mRNA was extracted and measured by northern blot hybridisation.. Both low and high doses of isoprenaline infusion resulted in increased left ventricular weight. With low dose infusion, cardiac TGF-beta 1 mRNA was not stimulated throughout the infusion, while fibronectin mRNA and collagen types I and III mRNAs began to increase at 24 h and 48 h, respectively, after the infusion. In high dose isoprenaline infusion, not only was extracellular matrix mRNA but also TGF-beta 1 mRNA in the ventricle significantly increased. TCV-116 prevented isoprenaline induced left ventricular hypertrophy as much as delapril. However, with delapril or TCV-116, the time course of TGF-beta 1 and ECM mRNA expression was almost similar to isoprenaline infusion only.. The extracellular matrix mRNA expressions are enhanced in myocardial hypertrophy by a low dose of isoprenaline, which is probably not mediated by TGF-beta 1. The preventive effects of TCV-116 on this hypertrophy indicate that the inhibitory effects of angiotensin converting enzyme inhibitor on cardiac hypertrophy are due to the inhibition of angiotensin II and that angiotensin II type I receptor plays an important role in isoprenaline induced left ventricular hypertrophy. However, the renin-angiotensin system may play a minor role in isoprenaline induced cardiac fibrosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blotting, Northern; Cardiomegaly; Collagen; Extracellular Matrix; Fibronectins; Gene Expression; Indans; Isoproterenol; Male; Rats; Rats, Wistar; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta

To evaluate the biosynthesis of the type-1 angiotensin II (AT1) receptor and the regulation of AT1 receptor subtypes in the rat adrenal gland, we performed non-radioisotope in situ hybridisation histochemistry with an AT1 receptor complementary RNA (cRNA) probe and a messenger RNA (mRNA) probe. The levels of AT1A and AT1B receptor mRNAs were measured by the reverse transcriptase-polymerase chain reaction method after 4-week treatment with a selective AT1 receptor antagonist, TCV-116, and an angiotensin-converting enzyme inhibitor, delapril. Specific hybridisation signals were observed with the cRNA probe in both the cortex and medulla of the rat adrenal gland. An especially strong signal was observed in the zona glomerulosa. TCV-116 did not affect the levels of expression of AT1A and AT1B receptor mRNAs in the adrenal gland. Delapril, on the other hand, significantly reduced the levels of expression of AT1A and AT1B receptor mRNAs. These results indicate that the sites of biosynthesis of the AT1 receptor are mainly distributed in the adrenal zona glomerulosa. The observed differences in levels of expression of AT1 receptor mRNAs following treatment with TCV-116 and delapril suggest the involvement of the AT2 receptor in the regulation of AT1 receptor subtypes.

Topics: Adrenal Glands; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Benzimidazoles; Biphenyl Compounds; DNA, Complementary; Gene Expression; In Situ Hybridization; Indans; Male; Polymerase Chain Reaction; Prodrugs; Rats; Rats, Wistar; Receptors, Angiotensin; RNA Probes; RNA, Messenger; Tetrazoles

We investigated the protective effect of angiotensin II (Ang II) type 1 receptor antagonist on myocardial ischemia-reperfusion injury and the role of exogenous Ang II to this injury in perfused hearts. We orally administered TCV-116 (Ang II type 1 receptor antagonist) and delapril (angiotensin converting enzyme inhibitor) to Wistar rats for 1 week and measured the immunoreactive cardiac Ang II. Immunoreactive cardiac Ang II (pg/gm tissue) was 14.3 +/- 2.0 in control group, 11.8 +/- 0.8 in TCV-116-treated group, and 7.3 +/- 0.6 in delapril-treated group (p < 0.05 compared to TCV-116-treated group; p < 0.01 compared to control group). The 15 hearts (five rats in each group) were perfused by a langendorff method and global ischemia was maintained for 30 min. Both TCV-116 and delapril were found to improve postischemic cardiac function and decrease reperfusion creatine kinase (CK) release. Ang II injection before ischemia worsened postischemic cardiac function and increased reperfusion CK release. Only TCV-116 prevented this injury. These data indicated that TCV-116 Ang II type 1 receptor antagonist was effective against myocardial ischemia-reperfusion injury, and exogenous Ang II accelerated this injury through Ang II type 1 receptor.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Coronary Circulation; Creatine Kinase; Heart; Heart Rate; Heart Ventricles; Indans; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Wistar; Tetrazoles; Ventricular Pressure

The present study was undertaken to examine an effect of an angiotensin II type 1 (AT1) receptor antagonist on urinary prostaglandin E2 (PGE2) excretion following furosemide, a loop diuretic, in rats. Furosemide (30 mg/kg) was given orally with or without pretreatment with derapril (30 mg/kg), an angiotensin converting enzyme inhibitor, TCV-116 (1 mg/kg), an AT1 receptor antagonist, or losartan (10 mg/kg), another AT1 receptor antagonist. The 6-hour urine was collected following furosemide, and the urinary excretion of PGE2 was determined. The urinary PGE2 increased significantly following furosemide alone. However, such a furosemide-induced increase was not observed with pretreatment with derapril, TCV-116 or losartan. These results suggest that the increased urinary excretion of PGE2 following furosemide is blunted by derapril, TCV-116 and losartan. As TCV-116 and losartan are selective AT1 receptor antagonists, the effect of furosemide on renal PGE2 production, as reflected by the urinary PGE2, might be mediated by an activation of AT1 receptors.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Dinoprostone; Furosemide; Imidazoles; Indans; Losartan; Male; Prodrugs; Rats; Rats, Wistar; Tetrazoles

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.. 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.. 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.. 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.

Topics: Actins; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Thoracic; Benzimidazoles; Biphenyl Compounds; DNA; Hydralazine; Hypertension, Renovascular; Hypertrophy; Indans; Male; Muscle, Smooth, Vascular; Rats; Rats, Wistar; Tetrazoles

To investigate the contribution of the cardiac renin-angiotensin system to ventricular dilatation after myocardial infarction, we examined the effects of 3-week treatments with an angiotensin converting enzyme inhibitor, delapril, and a selective angiotensin II type 1 (AT1) receptor antagonist, TCV-116, on haemodynamics and ventricular angiotensin II contents in myocardial-infarcted rats. TCV-116 reduced mean aortic pressure, and prevented the increase of right and left ventricular weight, left ventricular end-diastolic pressure and volume of myocardial-infarcted rats, to a similar extent to delapril. Thus, AT1 receptor-mediated action of angiotensin II plays a central role in the development of ventricular dilatation. Angiotensin II contents in the right and non-infarcted left ventricles (6.0 +/- 1.0 and 5.9 +/- 0.7 pg/g tissue, respectively, mean +/- S.E.M.) of myocardial-infarcted rats were not different from those of sham-operated rats. However, angiotensin II contents in the infarcted scar (21.7 +/- 3.5 pg/g) of myocardial-infarcted rats were 4.2-fold higher than those in the left ventricle of sham-operated rats. Delapril reduced angiotensin II contents in the right and non-infarcted left ventricles, and the scar by 48, 81 and 60%, respectively, but did not reduce plasma angiotensin II in myocardial-infarcted rats. TCV-116 also decreased angiotensin II in the right and non-infarcted left ventricles by 57 and 56%, respectively, while increased plasma angiotensin II by 4.3-fold. Thus, the prevention of ventricular dilatation by these two agents was associated with the decrease in ventricular angiotensin II contents. These observations suggest that the cardiac renin-angiotensin system rather than the circulating system may play an important role in ventricular dilatation after myocardial infarction.

Topics: Analysis of Variance; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Hemodynamics; Indans; Male; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Receptors, Angiotensin; Tetrazoles

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