Effects of DN-9693, a synthesized phosphodiesterase inhibitor, on pancreatic exocrine secretion in dogs.

Abstract

Abstract-The effects of DN-9693, a synthesized phosphodiesterase inhibitor, on the secretion of pancreatic juice were investigated in preparations of the isolated and blood-perfused dog pancreas. DN-9693 injected intraarterially caused a dose-dependent increase in the secretion of pancreatic juice and decrease in the perfusion pressure.The threshold doses to increase the pancreatic secretion and to decrease the perfusion pressure were about 100 ,ug and 1 ,cg, respectively. Thus, the secretory response was less effective than the vascular response.The secretory activity of was approximately equal to that of 0.03 mg of 3 isobutyl-1 -methylxanthine, 0.5 mg of papaverine, 5 mg of theophylline, 0.08 units of secretin and 0.2 units of cholecystokinin.The concentration of bicarbonate in the pancreatic juice induced by DN-9693 was increased, but protein concentration was not. DN-9693-induced pancreatic secretion was not modified by pretreat ments with phentolamine, propranolol, atropine, sulpiride and cimetidine. Secretin induced pancreatic secretion was significantly potentiated by infusion of DN-9693 (10 ,eg/min), but cholecystokinin-induced one was not. From these results, it is concluded that DN-9693 may produce an increase in pancreatic secretion by acting directly on the pancreatic exocrine gland of the dog, which might be mediated through an increase of intracellular cyclic AMP concentration by inhibiting phos phodiesterase activity.It was reported that adenosine 3",5 cyclic monophosphate (cyclic AMP) stimulated the pancreatic secretion of water and electrolytes in cats and dogs (1, 2). Additionally, secretin stimulated the pancreatic secretion concomi tant with the increase in the cyclic AMP con tent in the pancreas (3, 4). Phosphodiesterase inhibitors such as theophylline, papaverine and 3-isobutyl-1-methylxanthine (IBMX) were also shown to stimulate the pancreatic secretion (2, 5, 6). Thus, cyclic AMP may be an intracellular mediator in the process of pancreatic secretion. Along this line, it is of interest to investigate the effect of phospho diesterase inhibitors on pancreatic secretion. (1,5-dihydro-7-(1-piperidinyl) imidazo[2,1-b]quinazoline-2(3H)-one dihy drochloride hydrate) is a newly synthesized phosphodiesterase inhibitor and its potency was about 5 times as potent as papaverine in platelets (7). However, there is no available reports on the effect of DN-9693 on pancre atic exocrine secretion. The present experi ments were, therefore, undertaken to inves tigate the effects of DN-9693 on pancreatic secretion in isolated and blood-perfused day pancreas preparations in situ and to compare DN-9693 with secretin and cholecystokinin in the same preparations. Materials and MethodsTwenty-two mongrel dogs of either sex, weighing from 12-16 kg, were fasted 24 hr and anesthetized with sodium pentobarbital (30 mg/kg, i.v.). During the experimental periods, anesthesia was maintained by ad ditional injection of sodium pentobarbital (5 mg/kg, i.m.) at hourly intervals. The dogs

Inotropic Effects of DN‐9693: A Selective Cyclic AMP Phosphodiesterase Inhibitor

“…DN-9693 increases pancreatic secretion in the isolated blood-perfused dog pancreas, which can be explained by an increase in intracellular cAMP concentration (16).…”