Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the effects of cyclic nucleotide phosphodiesterase (PDE) isoenzyme inhibition on airway responsiveness, we studied the effects of a selective PDE isoenzyme type III inhibitor, SDZ MKS 492, on airway responsiveness to inhaled methacholine (Mch) in 6 beagles. Base-line respiratory resistance and airway responsiveness to Mch were determined by modified Astograph (7 Hz oscillation method). SDZ MKS 492 (1.0 mg/kg, 0.3 mg/kg or 0.1 mg/kg) was orally administered 1 hr prior to the determination of airway responsiveness at intervals of one week. Base-line respiratory resistance was decreased in a dose-dependent manner by SDZ MKS 492. SDZ MKS 492 significantly decreased airway responsiveness to Mch (log D min) in a dose-dependent manner, and the airway responsiveness (log PD2.0 Mch) was significantly decreased by 1.0 mg/kg of SDZ MKS 492. These results indicate that selective inhibition of PDE isoenzyme type III results in a decrease in respiratory resistance and airway responsiveness.
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PMID:[Effects of a cyclic nucleotide phosphodiesterase isoenzyme type III inhibitor, SDZ MKS 492 on airway responsiveness in beagles]. 825 Jul 32

The effect of 1-cyclopentyl-3-ethyl-6-(3-ethoxypyrid-4-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-one (SR 265579), a potent inhibitor of guanosine 3',5'-cyclic monophosphate (cyclic GMP) phosphodiesterase (PDE5), was examined regarding its specificity toward the other cyclic nucleotide phosphodiesterases, the effect on cyclic nucleotide levels and the bronchodilatory activity, both in vitro and in vivo in guinea-pigs. The effects were compared to those obtained with zaprinast (CAS 37762-06-4), a known PDE5 inhibitor. Anion-exchange chromatography of the soluble fraction of guinea-pig homogenates revealed 5 peaks which corresponded to PDE1, PDE2, PDE3, PDE4 and PDE5. SR 265579 produced a potent and competitive inhibition, with respect to cyclic GMP, of PDE5 with a Ki of 6.4 nmol/l. The compound was 25 fold more potent than zaprinast and demonstrated selectivity toward PDE5. The selectivity index was 14 and 33 with respect to PDE4 and 3, respectively. PDE1 and 2 were only inhibited at considerably higher concentrations. SR 265579 specifically increased the intracellular cyclic GMP levels in guinea-pig tracheal epithelial cells (EC50 = 117 nmol/l). Moreover, in the guinea pig, plasma cyclic GMP levels were significantly increased after the intravenous or oral administration of doses as low as 1 mg/kg. Isolated guinea-pig trachea were relaxed by the addition of SR 265579 as evaluated by measuring either spontaneous tone or relaxation of histamine and acetylcholine-precontracted preparations. PD2 values were of 7.64, 6.52 and 5.25, respectively. In vivo, after i.v. administration, bronchodilatory activity was demonstrated in an artificially-ventilated guinea-pig histamine-induced bronchospasm model with an ED50 of 0.63 mg/kg. In all experiments, SR-265579 was proved to be more active than zaprinast. These results demonstrate that SR 265579 is an orally active, potent and specific inhibitor of PDE5.
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PMID:Experimental studies on guanosine 3',5'-cyclic monophosphate levels and airway responsiveness of the novel phosphodiesterase type 5 inhibitor SR 265579 in guinea-pigs. 1048 15