Stimulation of inositol trisphosphate formation in hepatocytes by vasopressin, adrenaline and angiotensin II and its relationship to changes in cytosolic free Ca2+

Abstract

At maximally effective concentrations, vasopressin (10(-7) M) increased myo-inositol trisphosphate (IP3) in isolated rat hepatocytes by 100% at 3 s and 150% at 6 s, while adrenaline (epinephrine) (10(-5) M) produced a 17% increase at 3 s and a 30% increase at 6 s. These increases were maintained for at least 10 min. Both agents increased cytosolic free Ca2+ [( Ca2+]i) maximally by 5 s. Increases in IP3 were also observed with angiotensin II and ATP, but not with glucagon or platelet-activating factor. The dose-responses of vasopressin and adrenaline on phosphorylase and [Ca2+]i showed a close correspondence, whereas IP3 accumulation was 20-30-fold less sensitive. However, significant (20%) increases in IP3 could be observed with 10(-9) M-vasopressin and 10(-7) M-adrenaline, which induce near-maximal phosphorylase activation. Vasopressin-induced accumulation of IP3 was potentiated by 10mM-Li+, after a lag of approx. 1 min. However the rise in [Ca2+]i and phosphorylase activation were not potentiated at any time examined. Similar data were obtained with adrenaline as agonist. Lowering the extracellular Ca2+ to 30 microM or 250 microM did not affect the initial rise in [Ca2+]i with vasopressin but resulted in a rapid decline in [Ca2+]i. Brief chelation of extracellular Ca2+ for times up to 4 min also did not impair the rate or magnitude of the increase in [Ca2+]i or phosphorylase a induced by vasopressin. The following conclusions are drawn from these studies. IP3 is increased in rat hepatocytes by vasopressin, adrenaline, angiotensin II and ATP. The temporal relationships of its accumulation to the increases in [Ca2+]i and phosphorylase a are consistent with it playing a second message role. Influx of extracellular Ca2+ is not required for the initial rise in [Ca2+]i induced by these agonists, but is required for the maintenance of the elevated [Ca2+]i.

Calcium: its modulation in liver by cross-talk between the actions of glucagon and calcium-mobilizing agonists

“…The interesting observation of Assimacoupoulus-Jeanett et al (1982) and Morgan et al (1983) that increases in dibutyryl cyclic AMP are able to reverse vasopressin-induced Ca2+ mobilization (see also Crane et al, 1982) appears to be consistent with the finding (Keppens and De Wulf, 1984) that vasopressin inhibits the maintenance of cyclic AMP levels in hepatocytes by activating phosphodiesterase. Charest et al (1985b) have shown that glucagon is able to potentiate Ca2+ inflow induced by extracellular ATP.…”

“…Earlier studies from a number of laboratories indicated that glucagon alone has no significant effect on Ins(1,4,5)P3 generation in hepatocytes (Prpic et al, 1982;Kaibuchi et al, 1982;Charest et al, 1985b) and fails to increase Ins(1,4,5)P3 breakdown (Creba and Hansen (1987) showed that glucagon, while enhancing adrenaline-induced Ca2+ inflow in hepatocytes, had no effect on the generation of Ins(1,4,5)P3. Burgess et al (1986Burgess et al ( , 1991 found (like Cocks et al, 1984) that isoprenaline administration to guinea pig hepatocytes caused little, if any, increase in Ins(1,4,5)P3 formation in the absence or presence of angiotensin II.…”

Angiotensin II stimulates angiotensinogen synthesis in hepatocytes by a pertussis toxin‐sensitive mechanism

“…angiotensinogen secretion The major signal transduction pathway by which angiotensin II influences intracellular functions in hepatocytes seems to be the activation of phospholipase C, release of both inositol trisphosphate and diacylglycerol, and the subsequent increase in intracellular calcium and activation of the Ca'+-activated, phospholipid-dependent protein kinase (protein kinase C), respectively [12,13]. In addition, angiotensin II has been shown to inhibit adenylate cyclase and reduce intracellular CAMP [14,15].…”

Glycogenolytic and antiglycogenolytic prostaglandin E2 actions in rat hepatocytes are mediated via different signalling pathways

“…Hence, a submaximal increase (35%) in cAMP formation already yielded a maximal activation of glycogen phosphorylase. This lack of a strict correlation of cAMP formation and activation of glycogen phosphorylase, where cAMP apparently is produced in excess, is a well-known phenomenon [57, 581 which is also observed with the second messenger InsP, [59].…”