angiotensin-i and Cardiomyopathy--Hypertrophic

The effects of des-aspartate-angiotensin I (DAA-I) on the expression of angiotensin AT1 and AT2 receptor in hearts of aortic coarcted rats were studied. The protocols used included competitive reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and receptor-ligand binding assays. mRNA of the AT1 and AT2 receptors increased significantly after 4 days of aortic coarctation (7- and 4-folds of sham-operated, respectively). However, the protein of the AT1 receptor was not altered, and only increase in protein of the AT2 receptor was detected. There was an increase in [125I]Sar1-Ile8-angiotensin II binding sites in the ventricular membranes of hypertrophic hearts, which was attributed to an upregulation of the AT2 receptor. Treatment with i.p. DAA-I resulted in a significant reduction of cardiac hypertrophy, the maximum effect was achieved with a dose of 200 nmol/kg/day. The anti-cardiac hypertrophy effect appeared to be U-shape, and at a higher dose of 800 mol/kg/day, there was a loss of effect. DAA-I had no effect on the receptor protein in ventricles of hypertrophic hearts. However, DAA-I dose-dependently decreased the binding of [125I]Sar1-Ile8-angiotensin II to ventricular membranes. The decrease was due to a likely desensitization by internalization of the AT1 receptor, and this probably contributed to the loss of hypertrophic effects at 800 nmol/kg/day. Treatment of DAA-I also resulted in a remarkable increase in AT2 receptor mRNA (24-fold increase over the sham-operated), which was not coupled to translation. The present findings provide new information regarding the relationship between cardiac hypertrophy and the angiotensin receptors, and the anti-cardiac hypertrophic actions of DAA-I via the AT1 receptors.

Topics: Angiotensin I; Angiotensin III; Animals; Aortic Coarctation; Cardiomyopathy, Hypertrophic; Heart Ventricles; Male; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2

The in vitro anti-hypertrophic and hyperplastic actions of des-aspartate-angiotensin I (DAA-I) on cultured cardiovascular cells have been demonstrated in earlier experiments. The present study investigated its effects on the development of neointima in balloon catheter-injured carotid artery of the Sprague-Dawley (SD) rat and the development of cardiovascular hypertrophy in the spontaneously hypertensive rat. Treatment with i.v. DAA-I for 14 days post-injury dose-dependently attenuated the development of neointima. The maximum effect was obtained at 34 pmol/kg/day. The data support the possibility that endogenous angiotensins could inhibit neointima growth. This opens up avenues for their therapeutic elevation in combating neointima-related restenosis of which current drugs are not fully effective in suppressing. Five-week-old pre-hypertensive SHR, when orally administered with a dose of 769 nmol/kg/day DAA-I for a duration of 47 weeks, showed significant reduction in the development of cardiac and vascular hypertrophy compared to the untreated controls. Similar treatment with DAA-I had no effect on the Wistar Kyoto rats. The present findings support the contention that, besides angiotensin II, other endogenous angiotensins are also involved in the regulation and/or pathophysiology of the cardiovascular system.

Topics: Angiotensin I; Angiotensin III; Animals; Arterial Occlusive Diseases; Arteriosclerosis; Cardiomegaly; Cardiomyopathy, Hypertrophic; Dose-Response Relationship, Drug; Hypertension; Injections, Intravenous; Male; Rats; Tunica Intima

We investigated in Lewis normotensive rats the effect of coronary artery ligation on the expression of cardiac angiotensin-converting enzymes (ACE and ACE 2) and angiotensin II type-1 receptors (AT1a-R) 28 days after myocardial infarction. Losartan, olmesartan, or the vehicle (isotonic saline) was administered via osmotic minipumps for 28 days after coronary artery ligation or sham operation. Coronary artery ligation caused left ventricular dysfunction and cardiac hypertrophy. These changes were associated with increased plasma concentrations of angiotensin I, angiotensin II, angiotensin-(1-7), and serum aldosterone, and reduced AT1a-R mRNA. Cardiac ACE and ACE 2 mRNAs did not change. Both angiotensin II antagonists attenuated cardiac hypertrophy; olmesartan improved ventricular contractility. Blockade of the AT1a-R was accompanied by a further increase in plasma concentrations of the angiotensins and reduced serum aldosterone levels. Both losartan and olmesartan completely reversed the reduction in cardiac AT1a-R mRNA observed after coronary artery ligation while augmenting ACE 2 mRNA by approximately 3-fold. Coadministration of PD123319 did not abate the increase in ACE 2 mRNA induced by losartan. ACE 2 mRNA correlated significantly with angiotensin II, angiotensin-(1-7), and angiotensin I levels. These results provide evidence for an effect of angiotensin II blockade on cardiac ACE 2 mRNA that may be due to direct blockade of AT1a receptors or a modulatory effect of increased angiotensin-(1-7).

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Carboxypeptidases; Cardiomyopathy, Hypertrophic; Coronary Vessels; Disease Models, Animal; Enzyme Induction; Imidazoles; Ligation; Losartan; Male; Myocardial Infarction; Myocardium; Olmesartan Medoxomil; Peptide Fragments; Peptidyl-Dipeptidase A; Pyridines; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Ventricular Remodeling

Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure.. To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT1-RA) is sufficient to prevent the development of hypertensive cardiomyopathy and cardiac contractile dysfunction. Special emphasis was placed on the effects of both treatments on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a) gene expression as a major cause of impaired diastolic cardiac relaxation.. Eight-week-old rats harboring the mouse renin 2d gene [TG(mREN2)27] were treated for 8 weeks with 100 mg/kg captopril (Cap) in their food and 100 mg/kg of the AT1-RA Bay 10-6734 (Bay) in their food. Untreated TG(mREN2)27 and Sprague-Dawley rats (SDR) were used as controls. Both treatment regimens normalized the left ventricular weight, which was increased significantly (P < 0.001) in TG(mREN2)27. Both treatments normalized the left ventricular end-systolic and end-diastolic pressures, which were significantly (P < 0.001) higher in TG(mREN2)27 than they were in SDR, and they improved the velocity of the decrease in pressure [P < 0.05, Bay and Cap versus TG(mREN2)27]. Decreased left ventricular SERCA 2a mRNA and protein levels and increased atrial natriuretic peptide messenger RNA levels were normalized by Bay and Cap treatments (P < 0.05, Bay and Cap versus TG(mREN2)27, by Northern and Western blotting). According to radioimmunoassay and an enzyme assay, respectively, Bay, but not Cap, increased plasma angiotensin I concentrations and the renin activity above normal levels (P < 0.05), whereas myocardial angiotensin II concentrations (determined by radioimmunoassay), which were significantly (P < 0.05) increased in TG(mREN2)27, were normalized equally by Bay and Cap.. In renin-induced hypertensive cardiomyopathy, left ventricular diastolic dysfunction occurs at the stage of compensated myocardial hypertrophy. The decreased left ventricular relaxation velocity might be due to reduced SERCA 2a gene expression. In this model of hypertensive cardiomyopathy, AT1-RA and ACEI treatments are similarly effective at reducing the arterial pressure, preventing myocardial hypertrophy and diastolic contractile dysfunction. Normalization of SERCA 2a gene expression, either by AT1-RA or by ACEI treatment, might contribute to the improvement in diastolic function.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blotting, Northern; Blotting, Western; Calcium-Transporting ATPases; Captopril; Cardiomyopathy, Hypertrophic; Diastole; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hemodynamics; Hypertension; Mice; Mice, Transgenic; Myocardium; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Sarcoplasmic Reticulum; Tetrazoles

We compared the activity and physiologic effects of cardiac angiotensin converting enzyme (ACE) using isovolumic hearts from male Wistar rats with left ventricular hypertrophy due to chronic experimental aortic stenosis and from control rats. In response to the infusion of 3.5 X 10(-8) M angiotensin I in the isolated buffer perfused beating hearts, the intracardiac fractional conversion to angiotensin II was higher in the hypertrophied hearts compared with the controls (17.3 +/- 4.1% vs 6.8 +/- 1.3%, P less than 0.01). ACE activity was also significantly increased in the free wall, septum, and apex of the hypertrophied left ventricle, whereas ACE activity from the nonhypertrophied right ventricle of the aortic stenosis rats was not different from that of the control rats. Northern blot analyses of poly(A)+ purified RNA demonstrated the expression of ACE mRNA, which was increased fourfold in left ventricular tissue obtained from the hearts with left ventricular hypertrophy compared with the controls. In both groups, the intracardiac conversion of angiotensin I to angiotensin II caused a comparable dose-dependent increase in coronary resistance. In the control hearts, angiotensin II activation had no significant effect on systolic or diastolic function; however, it was associated with a dose-dependent depression of left ventricular diastolic relaxation in the hypertrophied hearts. These novel observations suggest that cardiac ACE is induced in hearts with left ventricular hypertrophy, and that the resultant intracardiac activation of angiotensin II may have differential effects on myocardial relaxation in hypertrophied hearts relative to controls.

Topics: Angiotensin I; Angiotensin II; Animals; Blotting, Northern; Cardiomyopathy, Hypertrophic; Coronary Circulation; Gene Expression; Hemodynamics; Male; Myocardial Contraction; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Strains; RNA, Messenger; Vascular Resistance