Effects of des-aspartate-angiotensin I on angiotensin II-induced incorporation of phenylalanine and thymidine in cultured rat cardiomyocytes and aortic smooth muscle cells.
Des-aspartate-angiotensin I, a pharmacologically active nine-amino acid angiotensin peptide, and losartan, an AT(1) angiotensin receptor antagonist, but not angiotensin-(1-7), another active angiotensin peptide, completely attenuated the angiotensin II-induced incorporation of [3H]phenylalanine in cultured rat cardiomyocytes. The attenuation by des-aspartate-angiotensin I but not that of losartan was inhibited by indomethacin. The data support an earlier suggestion that the nonapeptide attenuates cardiac hypertrophy in rats via an indomethacin-sensitive angiotensin AT(1) receptor subtype. In rat aortic smooth muscle cells, both des-aspartate-angiotensin I and angiotensin-(1-7) had no effect on the angiotensin II-induced [3H]phenylalanine incorporation. However, the two peptides significantly attenuated the angiotensin II-induced [3H]thymidine incorporation in the smooth muscle cells. The attenuation by angiotensin-(1-7) but not by des-aspartate-angiotensin I was inhibited by (D-Ala(7))-angiotensin-(1-7), a specific angiotensin-(1-7) antagonist. Des-aspartate-angiotensin I also attenuated FCS-stimulated [3H]thymidine incorporation. This attenuation was inhibited by the peptide angiotensin receptor antagonist, (Sar(1), Ile(8))-angiotensin II, but not by losartan. These data indicate that des-aspartate-angiotensin I and angiotensin-(1-7) do not participate in the process of protein synthesis in vascular smooth muscle cells and that the nonapeptide and heptapeptide act on different non-AT(1) receptors to mediate their anti-hyperplasic action. Although the exact mechanisms of action remain to be elucidated, the findings indicate that des-aspartate-angiotensin I acts as an agonist on angiotensin AT(1) and non-AT(1) receptor subtypes and induces responses that oppose the actions of angiotensin II.
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Department of Pharmacology, Faculty of Medicine, National University of Singapore, 119260, Singapore, Singapore.
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Xu
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D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000494:pharmacology; D000803:Angiotensin I / Q000031:analogs & derivatives* / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000831:Animals, Newborn; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010649:Phenylalanine / Q000378:metabolism*; D014176:Protein Biosynthesis; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000819:agonists; D013936:Thymidine / Q000378:metabolism*
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C073402:PD 123319; D010649:Phenylalanine; C011437:angiotensin I, des-Asp(1)-; D004247:DNA; D000803:Angiotensin I; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; C118790:angiotensin I (1-7); D019808:Losartan; D013936:Thymidine; D007213:Indomethacin