Previous studies have shown that while vasopressin and angiotensin II are markedly more effective than norepinephrine and prostaglandin F2alpha in eliciting an acute elevation of inositol 1,4,5-trisphosphate (IP3), norepinephrine and prostaglandin F2alpha produce larger enhancement of DNA synthesis. This suggests that the initial activation of phosphoinositide-specific phospholipase C is not a common factor for the growth response to these agonists, but does not exclude a role of the integral of phospholipase C activity over a prolonged part of the prereplicative period, during which agonist-specific changes in responsiveness might occur. We show that vasopressin and angiotensin II also cause a prolonged elevation of cellular IP3 levels. which remain elevated for at least 60 min., while norepinephrine and prostaglandin F2alpha elevate IP3 levels slightly and transiently For vasopressin the dose-effect curves for IP3 accumulation and stimulation of DNA synthesis were closely parallel, while this was not the case for angiotensin II, norepinephrine, or prostaglandin F2alpha. After cultivation of the hepatocytes, hormone-stimulated IP3 accumulation rapidly declined, particularly in response to norepinephrine and prostaglandin F2alpha. When the IP3 response to norepinephrine and prostaglandin F2alpha was completely down-regulated, these agonists still enhanced the DNA synthesis. These results suggest that other mechanisms in addition to IP3 accumulation and Ca2+ release are likely to be involved in the growth stimulatory effects of the Ca2+-mobilizing agonists studied here, in particular for angiotensin II, norepinephrine, and prostaglandin F2alpha.