Abstract
Metipranolol (Betamann) is a clinically efficacious ocular hypotensive drug and preclinical experiments were undertaken to characterize this beta-adrenoceptor antagonist. In vitro beta1- and beta2-adrenoceptor antagonism was evaluated using the guinea pig atrium and the rat uterus, respectively. The respective pA2 values were 8.3 and 8.4. Topical metipranolol, 0.3% and 0.6%, blocked both the hypotension (beta2-mediated) and the tachycardia (beta1-mediated) elicited in ganglion-blocked, conscious rabbits by isoproterenol, 0.5 μg/kg, i.v. The Ki for displacement of3H-dihydroalprenolol binding to rabbit iris + ciliary body homogenates was 34 nM. The effect of metipranolol, 0.3% and 0.6%, was not particularly striking on the intraocular pressure (IOP) of conscious, normotensive rabbits. However, the elevated IOP of the alpha-chymotrypsinized rabbit eye was significantly decreased (maximum reduction of 5.8 mm Hg) following the instillation of metipranolol, 0.3%. IOP recovery in conscious rabbits following hyperosmotic challenge (i.v. infusion of a 20% NaCl solution) was not decreased by a 1-h pretreatment with a 0.3% solution. In contrast, a significant reduction of 41% was elicited by a 0.6% solution. Hence, the ocular hypotensive effect of metipranolol may result from decreased aqueous humor inflow. Metipranolol, 0.6%, was devoid of effect on rabbit pupil diameter. However, corneal local anesthesia was elicited in the rabbit by both 0.3% and 0.6% solutions of the drug, the effect being more marked with the higher concentration.
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References
Bartsch W, Dietmann K, Leinert H, Sponer G (1977a) Cardiac action of carazolol and methypranol in comparison with other beta-receptor blockers. Arzneimittelforsch 27: 1022–1026
Bartsch W, Sponer G, Dietmann K (1977b) Experiments in animals on the pharmacological effects of metipranolol in comparison with propranolol and pindolol. Arzneimittelforsch 27: 2319–2322
Best M, Rabinovitz AZ, Masket S (1975) Experimental alpha-chymotrypsin glaucoma. Ann Ophthalmol 7: 803–810
Bylund DB, Snyder SH (1976) Beta adrenergic receptor binding in membrane preparations from mammalian brain. Mol Pharmacol 12: 568–580
Cepelik J, Dienstbier E (1982) Effects of adrenergic stimulating and blocking agents on intraocular pressure in the rabbit. Glaucoma 4: 216–224
Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (K i) and the concentration of inhibitor which causes 50 percent inhibition (ICP50) of an enzymatic reaction. Biochem Pharmacol 22: 3099–3108
Demmler N (1983) Versuche der Druckeinstellung mit Metipranolol-Augentropfen bei einigen Glaukomsonderformen in der augenärztlichen Praxis. Klin Monatsbl Augenheilkd 182: 153–155
Heel RC, Brogden RN, Speight TM, Avery GS (1979) Timolol: a review of its therapeutic efficacy in the topical treatment of glaucoma. Drugs 17: 38–55
Langham ME, Lee PM (1957) Action of Diamox and ammonium chloride on formation of aqueous humor. Br J Ophthalmol 41: 65–92
Lewis MJ, Grey AC, Henderson AH (1983) Inotropic beta-blocking potency (pA2) and partial agonist activity of propranolol, practolol, sotalol and acebutolol. Eur J Pharmacol 86: 71–76
Nathanson JA (1980) Adrenergic regulation of intraocular pressure: identification of beta2-adrenergic-stimulated adenylate cyclase in ciliary process epithelium. Proc Natl Acad Sci USA 77: 7420–7424
Neufeld AH, Page ED (1977) In vitro determination of the ability of drugs to bind to adrenergic receptors. Invest Ophthalmol Vis Sci 16: 1118–1124
O'Donnell SR, Wanstall JC (1979) The importance of choice of agonist in studies designed to predict beta2: beta1 adrenoceptor selectivity of antagonists from pA2 values on guinea pig trachea and atria. Naunyn Schmiedebergs Arch Pharmacol 308: 183–190
Page ED, Neufeld AH (1978) Characterization of alpha- and beta-adrenergic receptors in membranes prepared from the rabbit iris before and after development of supersensitivity. Biochem Pharmacol 27: 953–958
Phillips CI, Howitt G, Rowlands DJ (1967) Propranolol as ocular hypotensive agent. Br J Ophthalmol 56: 222–226
Schmitt CJ, Gross DM, Share NN (1984) Beta-adrenergic receptor subtypes in iris-ciliary body of rabbits. Graefes Arch Clin Exp Ophthalmol 221: 167–170
Scriabine A, Torchiana ML, Stavorski JM, Ludden CT, Minsker DH, Stone CA (1973) Some cardiovascular effects of timolol, a new beta-adrenergic blocking agent. Arch Int Pharmacodyn Ther 205: 76–93
Sears D, Sears M (1974) Blood-aqueous barrier and alpha-chymotrypsin glaucoma in rabbits. Am J Ophthalmol 77: 378–383
Van Rossum JM (1963) Cumulative dose-response curves. II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn Ther 143: 299–330
Vareilles P, Lotti VJ (1981) Effect of timolol on aqueous humor dynamics in the rabbit. Ophthalmic Res 13: 72–79
Vareilles P, Silverstone D, Plazonnet B, Le Douarec J-C, Sears ML, Stone CA (1977a) Comparison of the effects of timolol and other adrenergic agents on intraocular pressure in the rabbit. Invest Ophthalmol Vis Sci 16: 987–996
Vareilles P, Conquet Ph, Le Douarec J-C (1977b) A method for the routine intraocular pressure (IOP) measurement in the rabbit: range of IOP variations in this species. Exp Eye Res 24: 369–375
Vareilles P, Schmitt C, Lotti VJ, Le Douarec J-C (1978) Etude expérimentale du timolol: un nouvel hypotenseur oculaire. J Fr Ophthalmol 12: 717–721
Zimmerman TJ, Kaufman HE (1977) Timolol, a beta-adrenergic blocking agent for the treatment of glaucoma. Arch Ophthalmol 95: 601–604
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Sugrue, M.F., Armstrong, J.M., Gautheron, P. et al. A study on the ocular and extraocular pharmacology of metipranolol. Graefe's Arch Clin Exp Ophthalmol 222, 123–127 (1985). https://doi.org/10.1007/BF02173535
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DOI: https://doi.org/10.1007/BF02173535