Studies on 3, 7-Dimethyl-1-(5-oxo-hexyl)-xanthine (BL 191). I. Cyclic 3', 5'-Nucleotide Phosphodiesterase (PDE) and the Inhibitory Effect of BL 191 on PDE in Rat Brain and Heart

• Published in: Chemical & pharmaceutical bulletin Vol. 22; no. 3; pp. 587 - 593
• Main Authors: HAYASHI, SHORYO, OZAWA, HIKARU
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 1974; Japan Science and Technology Agency
• Subjects: Animals; Brain - cytology; Brain - enzymology; Cyclic AMP; In Vitro Techniques; Male; Myocardium - cytology; Myocardium - enzymology; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases - metabolism; Rats; Subcellular Fractions - enzymology; Xanthines - pharmacology
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.22.587

Some properties of cyclic 3', 5'-nucleotide phosphodiesterase (PDE) in the rat cerebral cortex and heart muscle and inhibitory effect of 3, 7-dimethyl-1-(5-oxo-hexyl)-xanthine (BL 191) on PDE have been investigated by comparison with theophylline and caffeine as PDE inhibitor. 1) Cyclic adenosine monophosphate (AMP) hydrolysis in the supernate of the cerebral cortex and heart muscle is linear with respect to time (up to 30 min) and protein concentration (up to 150 μg and 400 μg in the incubation medium on the brain and heart respectively). 2) PDE activity obtained in the absence of Mg2+ could be increased up to 70 per cent by adding Mg2+ with the supernate of the cerebral cortex as the enzyme. 3) Substantial activity was present in all of the fraction although most was contained in the supernate. 4) From typical Lineweaver-Burk plots, Km values for the supernate of the cerebral cortex and heart muscle were found to be 130 μM and 74 μM respectively. 5) Inhibitory effect of BL 191 on PDE from the rat cerebral cortex supernate was similar to the action of theophylline and was slightly more potent than that of caffeine. The inhibition of BL 191, theophylline and caffeine was noncompetitive ; the Ki was calculated to be 3.0 mM, 3.1 mM and 5.1 mM respectively. The Ki values of 1.65 mM, 1.80 mM and 1.55 mM were found in the heart muscle supernate treated with BL 191, theophylline and caffeine respectively : the type of inhibition was competitive.