Stimulation of adult rat ventricular myocyte protein synthesis and phosphoinositide hydrolysis by the endothelins.
The effects of endothelin-1 (ET-1) on protein synthesis and phosphoinositide (PI) hydrolysis were investigated in ventricular myocytes isolated by collagenase digestion of adult rat hearts. The maximum stimulation of protein synthesis by ET-1 was about 35% and the EC50 value was about 0.3 nM. The stimulation was exerted at the translational stage since it was insensitive to inhibition by actinomycin D. The maximum stimulation of PI hydrolysis by ET-1 as measured by the formation of [3H]inositol phosphates was about 11-fold and the EC50 value was about 0.7 nM. The ET-1 analogue sarafotoxin-6b stimulated protein synthesis by a maximum of 27% and stimulated PI hydrolysis about 8- to 9-fold. The EC50 values were 1.6 nM and 0.6 nM, respectively. Other endothelins stimulated protein synthesis and PI hydrolysis in the following order of potency: ET-1 approximately ET-2 > ET-3. This order of potency suggests that the stimulation of both protein synthesis and PI hydrolysis is mediated through the ETA receptor. Although both angiotensin II and [Arg]vasopressin stimulated PI hydrolysis significantly, the stimulation was less than 60%, i.e., much less than the stimulation by ET-1 and its analogues. Neither insulin nor substance P stimulated PI hydrolysis. Stimulation of protein synthesis by ET-1 and its analogues correlated strongly with the stimulation of PI hydrolysis and we suggest that the stimulation of protein synthesis may be dependent on the stimulation of PI hydrolysis. We hypothesize that the mechanism may involve a protein kinase C-mediated increase in intracellular pH.
Department of Cardiac Medicine, National Heart and Lung Institute, University of London, UK.
P H
PH
Sugden
S J
SJ
Fuller
J R
JR
Mynett
R J
RJ
Hatchett
M A
MA
Bogoyevitch
M C
MC
Sugden
D000818:Animals; D003609:Dactinomycin; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles; D006868:Hydrolysis / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D016232:Endothelins; D010716:Phosphatidylinositols; D003609:Dactinomycin