It has been demonstrated that propranolol has the ability to lower the ocular tension in patients with glaucoma when given by intravenous injection (Phillips, Howitt, and Rowlands, I967; Vale and Phillips, 1970), when applied topically (Bucci, Giraldi, Pecori, Missiroli, and Virno, I968; Vale, Gibbs, and Phillips, 1972), or when given orally (Phillips and others, I967; Cot6 and Drance, I968). However, the topical use of propranolol has a possible disadvantage in that it produces local anaesthesia. (Propranolol also possesses membrane activity which is in part responsible for its action against cardiac arrhythmias. The local anaesthesia and membrane activity are distinct from the ,Breceptor blocking properties.) For this reason the effects of other n-receptor antagonists on ocular tension are being investigated. The one selected for this study was practolol (Eraldin). It is a compound having no local anaesthetic or anti-arrhythmic properties but capable of blocking cardiac 0-adrenergic receptors in doses which have no effect on other 3-receptors (Dunlop and Shanks, I968). Cardiac n-receptors are those designated as 01 by Lands, Arnold, McAuliff, Ludena, and Brown (I967).
Propranolol was introduced as a 0-adrenergic receptor antagonist, having about ten times the potency of pronethalol against isoprenaline (Black, Crowther, Shanks, Smith, and Dornhorst, I964) while being devoid of intrinsic sympathomimetic activity.A preliminary investigation with systemic racemic propranolol intravenously and by mouth showed that it caused a lowering of ocular tension in patients with glaucoma (Phillips, Howitt, and Rowlands, I967). These observations were confirmed by Cote and Drance (i968) using orally administered propranolol in humans, and by Vale and Phillips (I970) using intravenously administered propranolol in humans and rabbits. Following reports that topical propranolol was also effective in reducing tension (Bucci, Giraldi, Missiroli, and Virno, i968), it was decided to reinvestigate the effect of topical propranolol; a previous, unpublished trial with propranolol in humans had given disappointing results, particularly when it was compared with the effects of topical propranolol in the rabbit (Vale, I968). MethodThe investigation was carried out for a period of 4 days on ten patients, six male and four female, aged 47 to 82 years. This group included three patients with bilateral open-angle glaucoma, five with bilateral ocular hypertension, one with unilateral ocular hypertension, and one with chronic closed-angle glaucoma; in the last, a left sector iridectomy and a right iris inclusion had been done.
We have developed inhibitors of glutathione reductase that improve on the inhibition of literature lead compounds by up to three orders of magnitude. Thus, analogues of Safranine 0 and menadione were found to be strong, reversible inhibitors of yeast glutathione reductase. Safranine 0 exhibited partial, uncompetitive inhibition with Ki and a values of 0.5mM and 0.15, respectively. Thionine 0 was a partial (hyperbolic) uncompetitive inhibitor with Ki and 1y values of 0.4 pM and 0.15, respectively. LY83583 and 2-anilino-l.4-naphthoquinone also showed (hyperbolic) partial, uncompetitive inhibition with micromolar Ki values. For Nile Blue A a model for two-site binding with (parabolic) uncompetitive inhibition fitted the data with a Ki value of 1 1 pM and a kinetic cooperativity between the sites of 0.12, increased to 0.46 by preincubation of the enzyme and Nile Blue A in the presence of glutathione disulphide. Analysis of the effects of preincubation on the kinetics and cooperativity indicated the possibility of a slow conformational change in the homodimeric enzyme, the first such indication of kinetic cooperativity in the native enzyme to our knowledge. Further evidence of conformational changes for this enzyme came from studies of the effects of dimethyl sulphoxide which indicated that this co-solvent, which at low concentrations has no apparent effect on initial velocities under normal assay conditions, induced a slow conformational change in the enzyme. Thionine 0, Nile Blue A and LY83583 were redox-cycling substrates producing superoxide ion, detectable by means of cytochrome c reduction, but leading to no loss of glutathione reductase activity, under aerobic or anaerobic conditions. The water-soluble Safranine analogues Methylene Blue, Methylene Green, Nile Blue A and Thionine 0 (5 mg/kg i.p. x 5) were effective antimalarial agents in vivo against P . berghei, but their effect was small and a higher dose (50mg/kg i.p. x 1) was toxic in mice. Comparison was made with human glutathione reductase and its literaturereported interactions with several tricyclic inhibitors as studied by X-ray diffraction. It is possible that the conformational changes detected in the present study from alterations *Corresponding author. Fax: 0161 275 2396. E-mail: Ken.Douglas@man.ac.uk. 327 328 R.M. LUOND el al.in detailed kinetic inhibition mechanisms may shed light on information transfer through the glutathione reductase molecule from the dimer interface ligand pocket to the active-site.
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