The relationship between activation of phosphoinositide-specific phospholipase C and growth stimulation by Ca2+-mobilizing hormones in hepatocytes

Previous studies have shown that while vasopressin and angiotensin II are m arkedly more effective than norepinephrine and prostaglandin F-2 alpha in e liciting an acute elevation of inositol 1,4,5-trisphosphate (IP3), norepine phrine and prostaglandin F-2 alpha produce larger enhancement of DNA synthe sis. This suggests that the initial activation of phosphoinositide-specific phospholipase C is not a common factor for the growth response to these ag onists, but does not exclude a role of the integral of phospholipase C acti vity over a prolonged part of the prereplicative period, during which agoni st-specific changes in responsiveness might occur. We show that vasopressin and angiotensin II also cause a prolonged elevation of cellular Ig levels, which remain elevated for at least 60 min., while norepinephrine and prost aglandin F-2a elevate IP3 levers slightly and transiently For vasopressin t he dose-effect curves for IP3 accumulation and stimulation of DNA synthesis were closely parallel, while this was not the case for angiotensin II, nor epinephrine, or prostaglandin F-2 alpha After cultivation of the hepatocyte s, hormone-stimulated IP3 accumulation rapidly declined, particularly in re sponse to norepinephrine and prostaglandin F-2 alpha. When the IP3 response to norepinephrine and prostaglandin F-2 alpha was completely down-regulate d, these agonists still enhanced the DNA synthesis. These results suggest t hat other mechanisms in addition to IP3 accumulation and Ca2+ release are l ikely to be involved in the growth stimulatory effects of the Ca2+-mobilizi ng: agonists studied here, ia particular For angiotensin II, norepinephrine , and prostaglandin F-2a.