Effects of type‐selective phosphodiesterase inhibitors on glucose‐induced insulin secretion and islet phosphodiesterase activity

• Published in: British journal of pharmacology 1995-08, Vol.115 (8), p.1486-1492
• Main Authors: Shafiee‐Nick, R., Pyne, N.J., Furman, B.L.
• Format: Article
• Language: English
• Subjects: 1-Methyl-3-isobutylxanthine - pharmacology; 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Analysis of Variance; Animals; Biological and medical sciences; Colforsin - pharmacology; cyclic AMP; Cyclic AMP - metabolism; Dose-Response Relationship, Drug; Drug Interactions; Endocrine pancreas; forskolin; Fundamental and applied biological sciences. Psychology; Glucose - pharmacology; Guanidines - pharmacology; Hormones. Régulation; Insulin - metabolism; Insulin Secretion; Islets of Langerhans; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Isoenzymes - metabolism; Male; phosphodiesterase inhibitors; Phosphodiesterase Inhibitors - pharmacology; phosphodiesterase isoforms; Phosphoric Diester Hydrolases - metabolism; Purinones - pharmacology; Pyrazines - pharmacology; Pyridazines - pharmacology; Pyrrolidinones - pharmacology; Rats; Rats, Sprague-Dawley; Rolipram; Thiophenes - pharmacology; Vertebrates: endocrinology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb16641.x

1 We examined various type‐selective phosphodiesterase (PDE) inhibitors on glucose‐induced insulin secretion from rat isolated islets, on islet PDE activity and on islet cyclic AMP accumulation in order to assess the relationship between type‐selective PDE inhibition and modification of insulin release. 2 The nonselective PDE inhibitor, 3‐isobutyl‐l‐methylxanthine (IBMX, 10−5‐10−3 M), as well as the type III selective PDE inhibitors SK&F 94836 (10−5‐10−3 M), Org 9935 (10−7‐10−4 M), SK&F 94120 (10−5‐10−4 M) and ICI 118233 (10−6‐10−4 M) each caused concentration‐dependent augmentation (up to 40% increase) of insulin release in the presence of a stimulatory glucose concentration (10 mM), but not in the presence of 3 mM glucose. 3 Neither the type IV PDE inhibitor rolipram (10−4 M) nor the type I and type V PDE inhibitor, zaprinast (10−4‐10−3 M) modified glucose‐induced insulin release when incubated with islets, although a higher concentration of rolipram (10−3 M) inhibited secretion by 55%. However, when islets were preincubated with these drugs followed by incubation in their continued presence, zaprinast (10−6‐10−4 M) produced a concentration‐dependent inhibition (up to 45% at 10−4 M). Under these conditions, rolipram inhibited insulin secretion at a lower concentration (10−4 M) than when simply incubated with islets. 4 A combination of SK&F 94836 (10−5 M) and forskolin (5 × 10−8 M) significantly augmented glucose‐induced insulin secretion (30% increase), although neither drug alone, in these concentrations, produced any significant effect. 5 Islet cyclic AMP levels, which were not modified by forskolin (10−6 M), SK&F 94836 (10−4 M) or Org 9935 (10−5 M) were significantly elevated (approximately 3.7 fold increase) by forskolin in combination with either SK&F 94836 or Org 9935. 6 Homogenates of rat islets showed a low Km (1.7 μm) and high Km (13 μm) cyclic AMP PDE in the supernatant fractions (from 48, 000 g centrifugation), whereas the particulate fraction showed only a low Km (1.4 μm) cyclic AMP PDE activity. 7 The PDE activity of both supernatant and pellet fractions were consistently inhibited by SK&F 94836 or Org 9935, the concentrations required to reduce particulate PDE activity by 50% being 5.5 and 0.05 μm respectively. 8 Rolipram (10−5‐10−4 M) did not consistently inhibit PDE activity in homogenates of rat islets and zaprinast (10−4 M) consistently inhibited activity by 30% in the supernatant fraction, but not consistently in the pellet. 9 These da