temocapril-hydrochloride and Cardiomegaly

To investigate the time course of cardiovascular structural changes in patients with essential hypertension after angiotensin-converting enzyme (ACE) inhibition, we determined left ventricular structure, minimal vascular resistance in the forearm as an index of resistance vessel structure and stiffness beta of carotid artery in 15 essential hypertensive subjects during a placebo period and after 2, 6, and 12 months of temocapril treatment. Blood pressure decreased within 2 weeks, and the antihypertensive effects were noted throughout the 12-month administration period. Left ventricular mass index decreased significantly after 2 months (120+/-12 to 106+/-9 g/m2; p < 0.01) and was normalized after 12 months (88+/-6 g/m2). Postischemic minimal vascular resistance in the forearm decreased gradually from 2.1+/-0.5 to 1.6+/-0.4 PRU at month 12 of temocapril treatment. In contrast, increased stiffness index beta of carotid artery was not altered during a 1-year treatment period (11.4+/-4.9 to 11.6+/-3.8 at month 12 of treatment). These data indicated that the regression of structural changes of left ventricle and arterioles occurred gradually and progressively for 1-year treatment with ACE inhibition, but large arteries were not affected.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiomegaly; Echocardiography; Female; Forearm; Heart Ventricles; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Placebos; Plethysmography; Thiazepines; Time Factors; Vascular Resistance

CGS 26303 is a vasopeptidase inhibitor that simultaneously inhibits endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP). We compared the effects of chronic treatment with CGS 26303 to the selective inhibition of angiotensin-converting enzyme (ACE) and NEP during the transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF) in hypertensive rats. LV geometry and function were assessed in Dahl salt-sensitive rats placed on a high-salt diet from age 6 weeks (hypertensive rats) and in control rats fed a low-salt diet. The hypertensive rats were randomized into groups that received no treatment or were treated with an ACE inhibitor (temocapril), an ECE/NEP inhibitor (CGS 26303), or a NEP inhibitor (CGS 24592) from the LVH stage (11 weeks) to the CHF stage (17 weeks). All treatments decreased the systolic blood pressure equally and significantly improved LV fractional shortening. Both temocapril and CGS 26303 ameliorated LV perivascular fibrosis, reduced mRNA levels of types I and III collagen, and decreased the heart weight/body weight ratio. CHF rats had increased plasma ET-1 levels compared with control rats. Only CGS 26303 reduced ET-1 to normal levels. ET-1 levels were found to correlate with heart/body weight, right ventricle/body weight and perivascular fibrosis ratios. During the transition to CHF, CGS 26303 produces effects that are comparable to temocapril and superior to CGS 24592. The beneficial effects of CGS 26303 are likely caused in part by the greater reduction of plasma ET-1. Dual ECE/NEP inhibitor may provide a new strategy for the treatment of human heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Cardiac Output, Low; Cardiomegaly; Collagen; Echocardiography; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Fibrosis; Heart; Male; Metalloendopeptidases; Myocardium; Neprilysin; Neurotransmitter Agents; Organophosphonates; Phenylalanine; Rats; Rats, Inbred Dahl; RNA, Messenger; Tetrazoles; Thiazepines

We investigated the effects of an angiotensin-converting enzyme inhibitor (temocapril) and an angiotensin II type 1 receptor blocker (olmesartan) on changes in myocardial sympathetic nervous activity, fatty acid metabolism and myocardial blood flow using 131I-meta-iodobenzylguanidine, 125I-beta-methyl-iodophenyl pentadecanoic acid and 99mTc-tetrofosmin, respectively, in rats with isoproterenol-induced cardiac hypertrophy. Male Sprague-Dawley rats underwent isoproterenol administration (3 mg/kg per day) for 1 week by osmotic mini-pump. The hearts were excised and analyzed for the uptake of meta-iodobenzylguanidine. Beta-methyl-iodophenyl pentadecanoic acid and tetrofosmin in 11 segments in four groups; sham group (saline), isoproterenol group (isoproterenol alone), angiotensin-converting enzyme inhibitor group (isoproterenol and temocapril), and angiotensin II type 1 receptor blocker group (isoproterenol and olmesartan). Isoproterenol significantly increased the heart weight compared with the sham group, whereas it was significantly blunted in the angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker groups. The ratio of the percent kilogram dose per gram of meta-iodobenzylguanidine to tetrofosmin, an index of myocardial sympathetic nervous activity, was significantly decreased in the isoproterenol group (0.18 +/- 0.01) compared with the sham group (0.41 +/- 0.03). Importantly, these changes were significantly improved in the angiotensin-converting enzyme inhibitor (0.28 +/- 0.01) and the angiotensin II type 1 receptor blocker groups (0.32 +/- 0.01). The ratio of the percent kilogram dose per gram of beta-methyl-iodophenyl pentadecanoic acid to tetrofosmin, an index of myocardial fatty acid metabolism, was significantly decreased in the isoproterenol group (1.30 +/- 0.03) compared with the sham group (1.60 +/- 0.10). In contrast, there were no significant differences in beta-methyl-iodophenyl pentadecanoic acid to tetrofosmin ratios between the sham and angiotensin-converting enzyme inhibitor groups, or the angiotensin II type 1 receptor blocker group. Cardiac hypertrophy induced by chronic beta-adrenergic stimulation is accompanied by impairment of sympathetic nervous activity and fatty acid metabolism. These abnormalities are effectively prevented by the angiotensin-converting enzyme inhibitor and the angiotensin II type 1 receptor blocker.

Topics: Adrenergic Fibers; Animals; Cardiomegaly; Fatty Acids; Imidazoles; Male; Myocardium; Olmesartan Medoxomil; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Tetrazoles; Thiazepines

Previous studies have demonstrated that integrins link the extracellular matrix to the hypertrophic response pathway of cardiac myocytes in vitro. To examine the direct relation between integrin beta1 and cardiac hypertrophy in vivo, we studied the effects of a newly developed angiotensin II type 1 (AT1) blocker, CS866 (ARB; 10 mg/kg/day), an angiotensin-converting enzyme inhibitor, temocapril (ACEI, 10 mg/kg/day), or both on modulation of integrin beta1 in the hypertrophied hearts of stroke-prone spontaneously hypertensive rats (SHRSP) 6 to 12 weeks of age. Treatments with ARB, ACEI, and combination therapy significantly reduced systolic blood pressure. However, the reduction in cardiac hypertrophy was greater in SHRSP treated with ARB or combination therapy than in those treated with ACEI. Multiplex reverse transcription-polymerase chain reaction revealed significantly higher mRNA expression of atrial natriuretic factor, AT1 receptor, and integrin beta1 in untreated SHRSP than in normotensive Wistar-Kyoto rats (WKY). The mRNA levels of ANP, AT1 receptor, and integrin B1 in SHRSP were significantly decreased by treatment with ARB, ACEI, or combination therapy. Decreased mRNA expression of ANP, AT1 receptor, and integrin beta1 in the treated SHRSP was associated with reductions in blood pressure; ARB and combination therapy produced greater decreases in expression than did ACEI. These observations suggest that CS866 has a beneficial effect on myocyte hypertrophy and that down-regulation of AT1 receptor and suppression of integrin beta1 participate in the regression of pressure-induced cardiac hypertrophy in vivo. The correlation between the expression of integrin beta1 and AT1 receptor was significant. Our results also suggest that integrin expression by myocytes might be modulated by angiotensin II via AT1 receptor.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Down-Regulation; Drug Therapy, Combination; Imidazoles; Integrin beta1; Male; Myocytes, Cardiac; Olmesartan Medoxomil; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; RNA, Messenger; Tetrazoles; Thiazepines

Chronic inhibition of NO synthesis induces cardiac hypertrophy independent of systemic blood pressure (SBP) by increasing protein synthesis in vivo. We examined whether ACE inhibitors (ACEIs) enalapril and temocapril and angiotensin II type-I receptor antagonists (angiotensin receptor blockers [ARBs]) losartan and CS-866 can block cardiac hypertrophy and whether changes in activation of 70-kDa S6 kinase (p70S6K) or extracellular signal-regulated protein kinase (ERK) are involved. The following 13 groups were studied: untreated Wistar-Kyoto rats and rats treated with NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME), D-NAME (the inactive isomer of L-NAME), L-NAME plus hydralazine, L-NAME plus enalapril (3 mg. kg(-1). d(-1)) or temocapril (1 or 10 mg. kg(-1). d(-1)), L-NAME plus losartan (10 mg. kg(-1). d(-1)) or CS-866 (1 or 10 mg. kg(-1). d(-1)), L-NAME plus temocapril-CS866 in combination (1 or 10 mg. kg(-1). d(-1)), and L-NAME plus rapamycin (0.5 mg. kg(-1). d(-1)). After 8 weeks of each experiment, ratios of coronary wall to lumen (wall/lumen) and left ventricular weight to body weight (LVW/BW) were quantified. L-NAME increased SBP, wall/lumen, and LVW/BW compared with that of control. ACEIs, ARBs, and hydralazine equally canceled the increase in SBP induced by L-NAME. However, ACEIs and ARBs equally (but not hydralazine) attenuated increase in wall/lumen and LVW/BW induced by L-NAME. The L-NAME group showed both p70S6K and ERK activation in myocardium (2.2-fold and 1.8-fold versus control, respectively). ACEIs inactivated p70S6K and ARBs inactivated ERK in myocardium, but hydralazine did not change activation of either kinase. Thus, ACEIs and ARBs modulate different intracellular signaling pathways, inhibiting p70S6K or ERK, respectively, to elicit equal reduction of cardiac hypertrophy induced by chronic inhibition of NO synthesis in vivo.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Cardiomegaly; Coronary Vessels; Enalapril; Enzyme Inhibitors; Heart Rate; Heart Ventricles; Imidazoles; Losartan; Male; Mitogen-Activated Protein Kinases; Myocardium; Neutrophil Infiltration; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Olmesartan Medoxomil; Organ Size; Rats; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Ribosomal Protein S6 Kinases; Tetrazoles; Thiazepines

Supplemental myocardial hypertrophy induced by insulin-like growth factor (IGF)-1 may prevent transition from hypertrophy to heart failure under chronic mechanical overload.. Several studies have suggested that IGF-1 treatment may be beneficial in chronic heart failure. In addition, recent studies indicated that the amount of alpha-myosin heavy chain (MHC) plays a significant hemodynamic role in large animals including humans.. We treated Dahl salt-sensitive hypertensive rats on a long-term basis with IGF-1. The effects were compared with those produced by treatment using a sub-antihypertensive dose of temocapril, an angiotensin-converting enzyme (ACE) inhibitor. At 11 weeks, when these rats displayed compensated left ventricular hypertrophy (LVH), they were randomized to three groups: 1) IGF group (3 mg/kg/day); 2) temocapril group (1 mg/kg/day); and 3) vehicle (control) group.. After 15 weeks, the control rats showed left ventricular (LV) enlargement and severe LV dysfunction and rapidly died of pulmonary congestion (mean survival time: 16.8+/-0.5 weeks). The survival time was significantly shortened (15.6+/-0.3 weeks) in the IGF-1 group but significantly prolonged (19.5+/-0.6 weeks) in the temocapril group. The rats in the IGF-1 group showed accelerated LV dilation and dysfunction. Of the several parameters investigated, it was found that the relative amounts of MHC isoforms differed among the three groups. The alpha-MHC mRNA level was decreased by 52% (p<0.01) in the IGF group, while it increased by 58% (p<0.01) in the temocapril group compared with the control group. These changes were related to the progression of LV dysfunction.. Supplemental myocardial hypertrophy with long-term IGF-1 treatment may not be beneficial if concentric LVH already exists. Our data suggest that IGF-1 may not protect myocardial performance when its hypertrophic effect aggravates the reduction of alpha-MHC. By contrast, the ACE inhibitor may improve myocardial function and prognosis by preventing the down-regulation of this isoform.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomegaly; Evaluation Studies as Topic; Insulin-Like Growth Factor I; Male; Myocardium; Myosin Heavy Chains; Random Allocation; Rats; Rats, Inbred Strains; Thiazepines; Ventricular Dysfunction, Left

We have shown previously that angiotensin-converting enzyme (ACE) inhibitors prevent coronary vascular remodeling (medial thickening and perivascular fibrosis) and myocardial remodeling (fibrosis and hypertrophy) in rats induced by long-term inhibition of nitric oxide (NO) synthesis with oral administration of N omega-nitro-L-arginine methyl ester (L-NAME). ACE inhibitors inhibit both the formation of angiotensin II and the catabolism of bradykinin. In this study, we aimed to determine the relative contribution of the latter two mechanisms to the beneficial effects of an ACE inhibitor on structural remodeling. First, we examined the effects of the ACE inhibitor temocapril and the angiotensin II AT1 subtype receptor antagonist CS-866 on the structural remodeling induced by administering L-NAME for 8 weeks. Temocapril and CS-866 were equally effective in preventing remodeling. Second, we examined whether the effect of temocapril on the remodeling induced by L-NAME was reduced by the bradykinin receptor antagonist HOE140. The latter drug did not alter the beneficial effect of temocapril on remodeling. In conclusion, although species differences must be considered to apply our conclusion to clinical conditions, the present results suggest that the inhibition of angiotensin II activity, mediated via the AT1 receptors, is responsible for the beneficial effects of an ACE inhibitor in our animal model of coronary vascular and myocardial remodeling induced by the long-term inhibition of NO synthesis.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Bradykinin; Cardiomegaly; Coronary Vessels; Fibrosis; Heart; Heart Rate; Imidazoles; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Olmesartan Medoxomil; Peptidyl-Dipeptidase A; Rats; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Tetrazoles; Thiazepines