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Recently we reported the presence of both the guanylyl cyclase-linked (116 kDa) and the ANF-C (66 kDa) atrial natriuretic peptide receptors in the rat liver. Since ANF 103-125 (atriopeptin II) stimulates cGMP production in livers and because cGMP has previously been shown to mimic the actions of cAMP in regulating hepatic carbohydrate metabolism, studies were performed to investigate the effects of atriopeptin II on hepatic glycolysis and gluconeogenesis. Additionally, employing analogs of atrial natriuretic hormone [des-(Q116, S117, G118, L119, G120) ANF 102-121 (C-ANF) and des-(C105,121) ANF 104-126 (analog I)] which bind only the ANF-C receptors, the role of the ANF-C receptors in the hepatic actions of atriopeptin II was evaluated. In perfused livers of fed rats atriopeptin II, but not C-ANF and analog I, inhibited hepatic glycolysis and stimulated glucose production. Moreover, analog I did not alter the ability of atriopeptin II to inhibit hepatic glycolysis. Atriopeptin II, but not C-ANF and analog I, also stimulated cGMP production in perfused rat livers. Furthermore, while atriopeptin II inhibited the activity ratio of pyruvate kinase by 30%, C-ANF did not alter hepatic pyruvate kinase activity. Finally, in rat hepatocytes, atriopeptin II stimulated the synthesis of [14C]glucose from [2-14C]pyruvate by 50% and this effect of atriopeptin II was mimicked by the exogenously supplied cGMP analog, 8-bromo cGMP. Thus atriopeptin II increases hepatic gluconeogenesis and inhibits glycolysis, in part by inhibiting pyruvate kinase activity, and the effects of atriopeptin II are mediated via activation of guanylyl cyclase-linked ANF receptors which elevate cGMP production.

The effect of veratridine-mediated depolarization on rat brain synaptosomal respiration in the presence and absence of calcium was investigated. Studies on respiration were performed employing three different pretreatments of the synaptosomes which attempted to deplete endogenous substrates. First, synaptosomes were preincubated for 10 min in the absence of any substrates in medium either containing or devoid of calcium. Second, synaptosomes were preincubated for either 15 or 60-min periods in the presence and absence of calcium, and the incubation medium was changed by centrifugation and resuspension of synaptosomes in their respective media. Irrespective of the prior treatment, maximal stimulation of respiration (400-600%) during veratridine (100 microM) elicited depolarization was observed only when calcium was present in the incubation media. In incubations performed in the absence of calcium, veratridine addition either modestly stimulated (10- and 15-min preincubated synaptosomes) or did not affect (60-min preincubated synaptosomes) the rate of respiration. However, when calcium was added back to these incubations the rate of respiration in the presence of veratridine was stimulated by five- to six-fold. Similarly, the rates of 14CO2 production from [1-14C]- and [2-14C]pyruvate were increased by veratridine only when synaptosomes were incubated in calcium-replete medium. These data indicate that calcium plays an obligatory role in depolarization-elicited stimulation of synaptosomal oxidative processes.