EFFECTS OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE IV INHIBITOR, Ro20,1724, ON PANCREATIC EXOCRINE SECRETION IN DOG

Abstract

1. The effects of the cyclic nucleotide phosphodiesterase (PDE) inhibitors, Ro20,1724, 3-isobutyl-1-methylxanthine (IBMX), trifluoperazine (TFP) and amrinone on pancreatic exocrine secretion were investigated in anaesthetized dogs in comparison with those of secretion and cholecystokinin octapeptide (CCK-8). 2. Ro20,1724 (1-30 nmol/kg), IBMX (3-30 nmol/kg), secretin (0.01-0.1 pmol/kg) or CCK-8 (0.1-1 pmol/kg) injected i.a. elicited a dose-dependent increase in the secretion of pancreatic juice, but TFP and amrinone (up to 1 mumol/kg) did not. 3. The bicarbonate concentration in pancreatic juice was increased and the protein concentration was decreased by Ro20,1724, IBMX and secretin. Cholecystokinin octapeptide increased the protein concentration but did not alter the bicarbonate concentration. 4. Ro20,1724 and IBMX elicited more than the respective additive secretory response when added together with secretin, although the stimulatory effects of CCK-8 with Ro20,1724 and IBMX were additive. 5. Ro20,1724 and IBMX increased cyclic AMP concentration but did not affect cyclic GMP concentration. 6. These results suggest that Ro20,1724 and IBMX have secretory properties on pancreatic exocrine glands of the dog, which may be mediated through an increase in cyclic AMP subsequent to inhibition of PDE activity. Furthermore, pancreatic PDE enzymes in the dog may be mainly type IV.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

“…Among 17 NMNAT2 positive modulators confirmed by Western analysis, 5 compounds are known to increase cAMP signaling. These include 8-Br-cAMP, Ro20–17243940, caffeine41, the caffeine analog dipropyl-7-methylxanthine42, and rolipram4344. Both caffeine and rolipram act as phosphodiesterase inhibitors to reduce cAMP degradation and thus increase cAMP concentrations.…”

Immunohistochemical Localization of cGMP-binding cGMP-specific Phosphodiesterase (PDE5) in Rat Tissues

“…The bicarbonate concentration in pancreatic juice is increased by Ro20,1724, a potent PDE4 inhibitor, and by 3-isobutyl-1-methylxanthine, a nonselective PDE inhibitor (Iwatsuki et al 1994), via the elevation of the intracellular concentration of cAMP. With regard to cGMP function, KRN2391, a synthesized vasodilator, and nitroprusside, which produces NO, increase the secretion of pancreatic juice with a high concentration of protein and a low concentration of bicarbonate with the increase of the cGMP levels in pancreatic tissues in anesthetized dogs (Iwatsuki et al 1993).…”

A factorial design to identify process parameters affecting whole mechanically disrupted rat pancreata in a perfusion bioreactor

“…(3) Pancreatic islets lost their sensitivity to secrete insulin to high glucose concentrations over the 12 h stimulatory time and IBMX is solely responsible for the stimulation observed in the final 6 h of stimulation (non‐glucose‐stimulated insulin secretion) . (4) IBMX has previously been shown to stimulate pancreatic exocrine secretions in dog pancreata which could prove toxic to pancreatic beta cells ultimately impairing their insulin release …”

“…21,22,[26][27][28] (4) IBMX has previously been shown to stimulate pancreatic exocrine secretions in dog pancreata which could prove toxic to pancreatic beta cells ultimately impairing their insulin release. 29 In a traditional glucose-stimulated insulin secretion assay, a low glucose concentration (2.8 mM) step would normally follow the high glucose concentration, and high glucose concentration 1 IBMX steps described here. However, this was not envisioned here as this would have involved replacing the circulating supplemented rat pancreatic medium with fresh medium.…”