Effects of type-selective phosphodiesterase inhibitors on glucose-induced insulin secretion and islet phosphodiesterase activity.
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 non-selective PDE inhibitor, 3-isobutyl-1-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 x 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 inc ombination with either SK&F 94836 or Org 9935.6 Homogenates of rat islets showed a low Km (1.7 microM) and high Km (13 microM) cyclic AMP PDE in the supernatant fractions (from 48,000 g centrifugation), whereas the particulate fraction showed only a low Km (1.4 microM) cyclic AMP PDE activity.7. The PDE activity of both supernatant and pellet fractions were consistently inhibited by SK&F94836 or Org 9935, the concentrations required to reduce particulate PDE activity by 50% being 5.5 and 0.05 microM 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 data are consistent with the presence of a type III PDE in rat islets of Langerhans.
Shafiee-Nick
R
R
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow.
Pyne
N J
NJ
Furman
B L
BL
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000704:Analysis of Variance; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005947:Glucose / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011688:Purinones / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram; D013876:Thiophenes / Q000494:pharmacology
D006146:Guanidines; D007328:Insulin; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011719:Pyrazines; D011724:Pyridazines; D011760:Pyrrolidinones; D013876:Thiophenes; C097915:Org 9935; D005576:Colforsin; C056215:siguazodan; C048350:5-(4-acetamidophenyl)pyrazin-2(1H)-one; C054775:ICI 118233; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C011145:zaprinast; D005947:Glucose; D020889:Rolipram; D015056:1-Methyl-3-isobutylxanthine