ROLE OF CA2-INDUCED GLUCOSE AND ADENOSINE-3',5'-MONOPHOSPHATE PRODUCTION IN THE ISOLATED PERFUSED-RAT-LIVER( ON VASOACTIVE INTESTINAL PEPTIDE)

Livers from fed rats (180-240 g) were perfused noncyclically with a he moglobin-free medium in vitro to determine whether vasoactive intestin al peptide (VIP) increases hepatic glucose production through a cAMP- or a Ca2+-dependent mechanism. Glucose output did not increase, but cA MP increased maximally during 10(-9) M VIP infusion. When VIP was perf used at 10(-8) M or more, glucose output increased dose dependently, w hereas cAMP increased only a little during the VIP infusion, but incre ased greatly after the infusion. When Ca2+ was excluded from the perfu sate, glucose output produced by 10(-8)-10(-7) M VIP was only 40% of t hat observed in the Ca2+-containing perfusion, and the increase in cAM P was abolished almost completely. By adding 10(-7) M A23187 for 10 mi n during the infusion of 10(-9) M VIP, cAMP, which increased with VIP alone, decreased during the A23187 infusion and increased again after the cessation of the A23187 infusion, whereas glucose output increased during the A23187 infusion. These results were similar to those obser ved with higher concentrations of VIP. When 10(-4) M isobutylmethylxan thine and 10(-8) M VIP were infused concurrently, cAMP increased rapid ly during the infusion and decreased after the infusion. In conclusion , 1) glycogenolysis is produced by VIP through a Ca2+-dependent mechan ism, rather than a cAMP-dependent one; and 2) the restriction of cAMP accumulation during the infusion of high concentrations of VIP is caus ed by Ca2+-induced phosphodiesterase activation.