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)

The effects of intratracheal administration of MKS 492, a selective phosphodiesterase (PDE) III inhibitor, were studied in five anesthetized bronchoconstricted cats. The animals were challenged by four repeated doses of intratracheal methacholine (67 micrograms/kg), and the degree of bronchoconstriction was assessed from increases in respiratory system resistance (Rrs). All animals demonstrated good bronchoconstrictive responses (i.e., 86-99% increases in Rrs) to methacholine without tachyphylaxis. On a separate day, the cats received the same four doses of methacholine after being pretreated with either intratracheal saline or three different doses of MKS 492 (0.17, 1.7, and 17 micrograms/kg). The increases in Rrs with 1.7 micrograms/kg [52.6 +/- 8.4% (SE)] and 17 micrograms/kg of MKS 492 (44.4 +/- 10.1%) were smaller than those with saline pretreatment (88.1 +/- 16.8%) (P < 0.05). There were no treatment-associated changes in mean arterial pressure or heart rate during administration of MKS 492. We conclude that intratracheal MKS 492 effectively reduced methacholine-induced bronchoconstriction in a dose-dependent fashion without substantial systemic effects. These preliminary results suggest that inhalation of isozyme-selective PDE inhibitors may deserve consideration for clinical trials provided that more extensive preclinical investigations justify such trials.
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PMID:Intratracheal administration of phosphodiesterase III inhibitor attenuates bronchoconstriction in cats: a preliminary report. 756 16

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 effects of pretreatment with murine recombinant interleukin 5 (mrIL-5) on platelet activating factor (PAF)-induced bronchoconstriction and airway hyperreactivity were investigated in guinea pigs. The intratracheal administration of mrIL-5 (2.5-10 micrograms) augmented platelet activating factor (PAF; 50 ng/kg)-induced bronchoconstriction in guinea pigs. When IL-5 (2.5 micrograms) was injected intratracheally, PAF (25 ng/kg)-induced bronchoconstriction was not affected, but PAF-induced airway hyperresponsiveness to histamine was exacerbated. Airway inflammation, in terms of increased capillary permeability and the accumulation of leukocytes in bronchoalveolar lavage fluid, was not produced by pretreatment with PAF (25 ng/kg), mrIL-5 (2.5 micrograms), or by a combination of these agents. This mrIL-5-induced augmentation of airway hyperreactivity by PAF was clearly inhibited by the phosphodiesterase-type III inhibitors, SDZ-MKS-492 and AH 21-132, but not by aminophylline.
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PMID:Priming with murine recombinant interleukin-5 resulted in the augmentation of PAF-induced airway hyperresponsiveness to histamine in guinea pigs. 846 39

Reactive oxygen-derived free radical species have been implicated in the pathogenesis and pathophysiology of inflammatory lung diseases. In a guinea pig model of aerosolized endotoxin-induced bronchial hyperresponsiveness to substance P, a possible involvement of oxidative lung injury was assessed by measuring the changes in membrane-bound neutral endopeptidase activity in the airway tissues and the level of lipid peroxides in the plasma. Vehicle-treated animals developed a neutrophilic airway inflammation, bronchial hyperresponsiveness to substance P associated with neutral endopeptidase hypoactivity, and elevation of lipid peroxides at 18 to 24 h after an exposure to endotoxin (75 microgram/ml, 40 min). A nonselective phosphodiesterase inhibitor, aminophylline, and selective phosphodiesterase isoenzyme inhibitors, SDZ-ISQ-844 (type III/IV) and SDZ-MKS-492 (type III), attenuated the neutrophilic airway inflammation induced by endotoxin. Aminophylline, SDZ-MKS-492, and a superoxide anion-generating NADPH-oxidase inhibitor apocynin inhibited bronchial hyperresponsiveness to substance P with attenuation of neutral endopeptidase inactivation induced by endotoxin. SDZ-ISQ-844, SDZ-MKS-492, and apocynin attenuated the elevation of lipid peroxides. The generation of hypochlorite (OCl-) from whole blood leukocytes was attenuated by aminophylline, SDZ-ISQ-844, SDZ-MKS-492, and apocynin at 1 to 2 h after exposure. These results suggest that reactive oxygen-derived free radical species-mediated oxidative lung injury may play an important role in endotoxin-induced bronchial hyperresponsiveness to substance P, and that phosphodiesterase isoenzyme inhibitors may be potentially useful as anti-inflammatory drugs.
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PMID:A possible involvement of oxidative lung injury in endotoxin-induced bronchial hyperresponsiveness to substance P in guinea pigs. 970 1