Pharmacodynamic Actions of (S)-2-[4, 5-Dihydro5-Propyl-2 (3h)-Furylidene]-1, 3-Cyclopentanedione (Oudenone)

Abstract

Abstract-The pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2(3H)-furyli dene]-l,3-cyclopentanedione (oudenone) were studied in both anesthetized animals and isolated organs. Oudenone (10-40 mg/kg i.v.) induced an initial rise in blood pressure followed by a prolonged hypotension in the anesthetized rats. In unanesthetized spontaneously hypertensive rats (SHR), oudenone (5-200 mg/kg p.o.) caused a dose related decrease in the systolic blood pressure. The initial pressor effect was dimi nished by pretreatments with phentolamine, guanethidine, hexamethonium and was abolished in the pithed rats. In addition, intracisternal administrations of oudenone (100-600 ,!g;'kg) showed a marked increase in blood pressure in the anesthetized rats, suggesting that the pressor effect may be due to centrally mediated actions. Oudenone, given intra-arterially into the femoral artery (400-800 pg/kg), caused a long-lasting vasodilation in anesthetized dogs. At a relatively high dose (40 mg/kg i.v.), oudenone antagonized all pressor responses to autonomic agents and central vagus nerve stimu lation in anesthetized rats and dogs, however, oudenone showed no anti-cholinergic, histaminergic, beta-adrenergic and adrenergic neuron blocking properties.Tyrosine hydroxylase, which catalyzes the hydroxylation of tyrosine to form dihy droxyphenylalanine, is the rate limiting step in the catecholamine biosynthesis (1) and many substances have been tested as potential inhibitions of this enzyme (2). Recently, several new inhibitors of tyrosine hydroxylase and dopamine-i3 hydroxylase from microbial origin have been discovered (3-10). Oudenone is one of these microbial inhibitors of tyrosine hydroxylase.From biochemical experiments, oudenone has been reported to inhibit tyrosine hydroxyl ase both in vitro and in vivo and decreases endogenous catecholamine levels (3, 5), however, pharmacological actions of oudenone have yet to be clarified. The purpose of the present work was to investigate the pharmacological actions of oudenone (synthetized according to the procedure by Ohno et al. (4)) in detail and to elucidate the mechanisms whereby these actions were caused by oudenone. MATERIALS AND METHODS Experiments in the anesthetized normotensive ratsMale Wistar rats weighing 280-350 g were anesthetized with urethane (1.5 g/kg s.c.), the trachea cannulated and arterial blood pressure and heart rate were recorded from the right common carotid artery with a pressure transducer (Nihon Kohden, MPU-0.5) con