The effects of pyrazinoylguanidine (PZG) on lipolysis and intracellular cyclic AMP concentrations were investigated in isolated rat adipocytes. PZG reduced basal cyclic AMP concentrations and blocked in a concentration-dependent manner forskolin (1 mumol/l) and isoproterenol (1 mumol/l) stimulatory effects on intracellular cyclic AMP production and lipolysis. PZG's effects on hormone-sensitive lipase were investigated in the presence and absence of glucagon (1 mumol/l) or isoproterenol (1 mumol/l). PZG inhibited uncompetitively the induction of hormone-sensitive lipase by either glucagon or isoproterenol. PZG's antilipolytic effects appeared to result from downregulation of intracellular cyclic AMP concentrations. In adipose tissue, cyclic AMP controls lipolysis through hormone-sensitive lipase. PZG's downregulation of lipolysis and cyclic AMP concentrations was unaffected by adenosine deaminase or pertussis toxin, suggesting that PZG did not activate Gi, the inhibitory guanyl nucleotide regulatory protein.
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