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Beecham-Wulfing Res. Labs., D3212 Gronau (Leine), F.R.G.1 Denbufylline has been examined for its ability to inhibit cyclic nucleotide phosphodiesterase isoenzymes from rat cardiac ventricle and cerebrum, as well as for its affinity for adenosine A1 and A2 receptors and the re-uptake site. For comparison, SK&F 94120, theophylline and 3-isobutyl-1-methyl-xanthine (IBMX) were examined as phosphodiesterase inhibitors whilst N6-cyclohexyladenosine, R(-)-N6-(2-phenylisopropyl)-adenosine, 5'-N-ethylcarboxamido-adenosine, 2-nitrobenzylthioinosine, theophylline and IBMX were examined for their affinity for adenosine binding sites. 2 This investigation confirmed the presence of four phosphodiesterase activities in rat cardiac ventricle; in rat cerebrum only three were present.3 Denbufylline selectively inhibited one form of Ca2"-independent, low Km cyclic AMP phosphodiesterase. The form inhibited was one of two present in cardiac ventricle and the sole one in cerebrum. This form was not inhibited by cyclic GMP. The inotropic agent SK&F 94120 selectively inhibited the form of cyclic AMP phosphodiesterase which was inhibited by cyclic GMP present in cardiac ventricle. Theophylline and IBMX were relatively non-selective phosphodiesterase inhibitors.4 Denbufylline was a less potent inhibitor of ligand binding to adenosine receptors than of cyclic AMP phosphodiesterase. This contrasted with theophylline, which had a higher affinity for adenosine receptors, and IBMX which showed no marked selectivity. Denbufylline, theophylline and IBMX all had a low affinity for the adenosine re-uptake site. 5 Denbufylline is being developed as an agent for the therapy of multi-infarct dementia. The selective inhibition of a particular low Km cyclic AMP phosphodiesterase may account for the activity of this compound.

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1 The ability of memantine (l-amino-3,5-dimethyladamantane)

The effect of treadmill physical training (PT) on rat gastrocnemius/plantaris muscle after bilateral femoral artery ligation was investigated. To enable a comparison to be made between the susceptibility of muscles with restricted blood flow and normally perfused skeletal muscle to PT, animals without ligated femoral arteries also underwent PT. PT increased the oxidative capacity of the gastrocnemius/plantaris muscle, as judged by the activity of citrate synthase, and reduced muscle fatigue in both groups of animals. Exercise also tended to lower the activity of a marker enzyme for glycolysis, glyceraldehyde-phosphate dehydrogenase in all animals, although this only reached the level of statistical significance in the animals with ligated femoral arteries. In the animals with restricted muscle blood flow, PT increased gastrocnemius skeletal muscle blood flow and pO2 and prolonged the time taken to attain maximum muscle twitch tension. The results indicate a great susceptibility of hindlimb skeletal muscles of rats with ligated femoral arteries to PT. They also suggest that the beneficial effect of PT observed in man with chronic occlusive arterial disease (COAD) may result both from an increase in muscle blood flow and from an enhanced mitochondrial respiratory activity in the afflicted muscle.