MODULATION OF BASAL HEPATIC GLYCOGENOLYSIS BY NITRIC-OXIDE

We perfused Livers from fed rats with a balanced salt solution contain ing 1 mmol/L glucose. Under these conditions a low steady rate of glyc ogenolysis was observed (approximately 1.7 mu mol glucose equivalents/ g/min; 20% of the maximal glycogenolytic activity). Nitric oxide (NO) transiently stimulated hepatic glucose production. A maximal response( on average doubling basal glucose output) was observed with 34 mu mol/ L NO. The same concentration of nitrite (NO2-) was ineffective. Half-m aximal effects were seen at 8 to 10 mu mol/L NO, irrespective of the f low direction (portocaval or retrograde). This glycogenolytic response to NO corresponded to a partial. activation of phosphorylase. The NO effect was not additive to maximal stimulation of glycogenolysis (7.7 +/- 0.2 mu mol hexose equivalents/g/min; n = 4) by 100 mu mol/L dibuty ryl cyclic adenosine monophosphate (Bt(2)cAMP). The requirement for ac tivation of phosphorylase was also evidenced by the ineffectiveness of NO in phosphorylase-kinase-deficient livers of gsd/gsd rats. The NO e ffect was blocked by co-administration of cyclooxygenase inhibitors (5 0 mu mol/L ibuprofen, 50 mu mol/L indomethacin, or 2 mmol/L aspirin), suggesting a mediatory role of prostanoids from nonparenchymal cells. This conclusion was confirmed by the fact that NO did not activate pho sphorylase in isolated hepatocytes. Moreover, NO was no longer glycoge nolytic in livers perfused with Ca2+-free medium, in agreement with th e known mediatory role of Ca2(+) in prostanoid-mediated responses. Sur prisingly, in Ca2+-free medium NO inhibited the basal glucose producti on. This coincided with an increased elution of cyclic guanosine monop hosphate (cGMP). Inhibition of glycogenolysis by NO under these condit ions was blocked by 1 mmol/L theophylline, suggestive for involvement of cGMP-stimulated cAMP phosphodiesterase. However, we could not confi rm that an increase in cGMP resulted in a drop in cAMP. In conclusion, NO recruits opposing mechanisms with respect to modulation of basal h epatic glycogenolysis. In the presence of Ca2+, activation of phosphor ylase with stimulation of glycogenolysis dominates, Cyclooxygenase inh ibitors abolish this effect. Activation by NO of the cyclooxygenase in nonparenchymal cells is a distinct possibility. In the absence of Ca2 +, inhibition of basal glycogenolysis becomes observable. It remains t o be established whether this results from cGMP-mediated stimulation o f hydrolysis of cAMP.