Role of type 1 and type 2 angiotensin receptors in angiotensin II-induced cardiomyocyte hypertrophy.
We compared the ability of angiotensin II (Ang II) to induce hypertrophy of neonatal rat ventricular myocytes with that of endothelin-1. Over 72 hours, Ang II (1 mumol/L) increased the ratio of protein to DNA by less than 10%, whereas endothelin-1 (100 nmol/L) produced a 28% increase. The growth effects of either agonist occurred independently of chronotropic actions. Radioligand binding studies showed that myocytes have nearly 300-fold more receptors for endothelin-1 than Ang II, and type 1 and type 2 Ang II receptor subtypes (AT1 and AT2) are present in near equal proportions. Cotreatment with a 10-fold molar excess of AT2 antagonists (PD 123177 or CGP 42112) for 72 hours augmented the Ang II-induced increase in the protein-to-DNA ratio to levels nearly as high (23%) as those with endothelin-1 (28%). AT2 antagonists enhanced Ang II stimulation of protein synthesis, as indexed by [3H]leucine incorporation, whereas an AT1 antagonist blocked Ang II-induced incorporation. An AT2 antagonist also prevented Ang II-induced protein degradation. In conclusion, Ang II-induced myocyte growth is tempered because of low AT1 levels and an antigrowth effect of AT2. These findings have potential clinical significance in that regression of hypertension-induced cardiac hypertrophy by AT1 antagonists may be in part due to an unopposed antigrowth effect of Ang II mediated via AT2.
Booz
G W
GW
Weis Center for Research, Geisinger Clinic, Danville, Pa. 17822, USA. gbooz@smtp.geisinger.edu
Baker
K M
KM
D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced*; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000145:classification / Q000502:physiology*
D007093:Imidazoles; D011506:Proteins; D011725:Pyridines; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C066253:PD 123177