angiotensin-iii 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