Angiotensin II-mediated growth and antigrowth effects in cultured neonatal rat cardiac myocytes and fibroblasts.
Angiotensin II (Ang II) stimulates cardiovascular growth and remodeling via AT1 receptors. Recent experiments have shown that Ang II may also exert antiproliferative effects via AT2 receptors. We studied the effects of Ang II on protein and DNA content and synthesis rate in unstimulated and endothelin-1 (ET-1)-stimulated neonatal rat cardiomyocytes and fibroblasts, isolated from 1-3-day-old Wistar strain pups. Total protein and total DNA, as well as [3H]leucine and [3H]thymidine incorporation were measured following incubation with either vehicle, Ang II, ET-1 or Ang II+ET-1, both in the presence or absence of the AT1 receptor blocker losartan or the AT2 receptor blocker PD123319. In myocytes, ET-1 increased total protein (+38% relative to control) as well as [3H]leucine (+66%) and [3H]thymidine (+77%) incorporation. Ang II did not affect any of these parameters, nor did it influence the ET-1-induced responses. However, in the presence of PD123319 Ang II stimulated [3H]leucine (+24%) and [3H]thymidine (+30%) incorporation. In fibroblasts, ET-1 and Ang II did not significantly affect total DNA and [3H]thymidine incorporation. Ang II tended to increase total protein in these cells, an effect which was significant only in the presence of PD123319 (+17%). Ang II stimulated [3H]leucine incorporation (+24%) in fibroblasts. This effect was absent with losartan and enhanced in the presence of PD123319. These data demonstrate that AT1 receptor-mediated proliferative effects of Ang II in neonatal cardiac cells may become apparent only when its AT2 receptor-mediated antigrowth effects are blocked. The net growth effect of Ang II therefore depends on the cellular AT1/AT2 receptor ratio. Ang II does not appear to interfere with ET-1-induced effects.
van Kesteren
C A
CA
Department of Pharmacology, Cardiovascular Research Institute COEUR, Erasmus University Rotterdam, Rotterdam, The Netherlands.
van Heugten
H A
HA
Lamers
J M
JM
Saxena
P R
PR
Schalekamp
M A
MA
Danser
A H
AH
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000502:physiology
D057911:Angiotensin Receptor Antagonists; D019332:Endothelin-1; D006131:Growth Inhibitors; D006133:Growth Substances; D007093:Imidazoles; D007295:Inositol Phosphates; D011725:Pyridines; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C073402:PD 123319; D019808:Losartan