Effect of H-7 on the modulation of glucagon actions by activators of protein kinase-C.

The stimulations of ureagenesis and cyclic AMP accumulation induced by glucagon were inhibited by 10 nM vasopressin or 100 nM phorbol 12-myristate 13-acetate (PMA). The maximal accumulation of cyclic AMP induced by glucagon was clearly diminished by these agents without change in the EC50 for the peptide hormone suggesting a non-competitive type of inhibition. H-7 blocked the inhibition of glucagon-stimulated ureagenesis induced by PMA and vasopressin and diminished their effect on the accumulation of cyclic AMP induced by glucagon. It is concluded that activation of protein kinase C inhibits the stimulation of ureagenesis and the accumulation of cyclic AMP induced by glucagon in liver cells from hypothyroid rats; H-7 inhibits the effects of protein kinase C activation.

Effects of histamine on the metabolism of isolated rat hepatocytes: roles of H1- and H2-histamine receptors.

In isolated rat hepatocytes histamine stimulates in a dose-dependent fashion three of the major metabolic pathways: glycogenolysis (70-80% increase over basal), gluconeogenesis from lactate (50-60%), and ureagenesis (50-60%). It was observed that both H1 and H2 receptors mediate the action of histamine and that, in control hepatocytes, the H1-mediated action predominates over the H2. The H1-mediated effect diminished in the absence of extracellular calcium, whereas the H2-mediated action did not. Interestingly, in hepatocytes from hypothyroid rats, the H2 action increased and the H1-mediated effect decreased as compared to those in the controls, with an inversion in efficacy (i.e., H1 greater than H2 in the controls and H2 greater than H1 in cells from hypothyroid rats). Furthermore, it was observed that pertussis toxin treatment and forskolin both enhance the H2-mediated effects without altering the H1-mediated actions of histamine (i.e., H1 approximately equal to H2). The active phorbol ester, phorbol 12-myristate 13-acetate, did not alter the effect of the autacoid. In summary, the data show that histamine modulates liver metabolism through H1 and H2 receptors. The relative importance of the two receptor types in mediating the actions of histamine varies depending on the specific conditions used.

Possible existence of two mechanisms involved in alpha 1-adrenergic action: effect of Sgd 101/75.

The effect of 2-(2-methyl-indazol-4-imino)-imidazoline (Sgd 101/75) on the rate of urea synthesis by isolated rat hepatocytes was studied. This agent was observed to stimulate ureagenesis through the activation of alpha 1-adrenoceptors (prazosin-sensitive). The effect of Sgd 101/75 was dependent on the presence of calcium and was not affected by insulin. The active phorbol ester, phorbol 12-myristate 13-acetate, blocked the effect of Sgd 101/75. It was also observed that this adrenoceptor agonist was unable to stimulate ureagenesis in hepatocytes obtained from hypothyroid rats but produced clear stimulation of this metabolic pathway in cells obtained from adrenalectomized rats. The data indicate that this agonist stimulates hepatic metabolism through a calcium-dependent, insulin-insensitive pathway for alpha 1-adrenergic action, modulated by the thyroid status of the animal.