title: The direct vascular relaxing action of betaxolol, carteolol and timolol in porcine long posterior ciliary artery.
abstract: The vascular relaxing properties of three beta adrenoceptor antagonists, betaxolol, carteolol and timolol, currently used in the treatment of glaucoma, were characterized, compared and contrasted in the porcine long posterior ciliary artery. Isolated arterial ring segments precontracted with increased extracellular KCl (plus 40 mM) or the thromboxane analog, U-46619 (3 x 10(-7) M), were relaxed in a concentration-dependent fashion by betaxolol, carteolol, timolol or nitroprusside. In vessel segments depolarized with increased extracellular KCl, EC50 values indicated that the intrinsic relaxant sensitivity to betaxolol was equal to that of nitroprusside, six-fold greater than that of carteolol, and ten-fold greater than that of timolol. Similarly, the maximum relaxation occurring at equimolar concentrations (10(-4) M) for the beta adrenoceptor antagonists was betaxolol > carteolol = timolol. Qualitatively similar results were noted in ring segments of the rabbit external iliac artery precontracted with increased extracellular KCl (plus 30 mM). Under conditions in which specific receptor-linked events are absent and voltage-gated Ca++ entry is maximized, the Ca++ concentration response relationship in porcine long posterior ciliary artery was shifted to the right in an apparent competitive manner by betaxolol, reflecting a 5.6-fold reduction in the sensitivity to Ca++. Conversely, nitroprusside reduced the Ca++ sensitivity three-fold in a noncompetitive fashion; not only shifting the Ca++ concentration response relationship to the right, but also depressing the maximum by 57%. Porcine long posterior ciliary arterial segments precontracted to a similar degree with U-46619, in which voltage-gated Ca++ entry is only one component of many specific cell signalling transduction mechanisms contributing to the precontraction, exhibited a sensitivity to betaxolol that was six-fold less than to nitroprusside, but two-fold greater than to timolol and 20-fold greater than to carteolol. These results are consistent with an obvious direct vascular relaxing capacity for beta adrenoceptor antagonists that primarily represents a capacity for inhibiting voltage-gated Ca++ entry in vascular smooth muscle. Additionally, the differential potencies of these three beta adrenoceptor antagonists characterized in this study suggests that this property is much more likely to contribute to any potentially beneficial effects of betaxolol than carteolol or timolol.
authors.affiliation: Department of Medical Pharmacology and Toxicology, College of Medicine, Texas A&M University Health Science Center, College Station.
authors.forename: R K
authors.initials: RK
authors.lastname: Hester
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: E J
authors.initials: EJ
authors.lastname: Becker
authors.forename: M
authors.initials: M
authors.lastname: McLaughlin
authors.forename: L
authors.initials: L
authors.lastname: DeSantis
mesh_terms: D000818:Animals; D001158:Arteries; D015784:Betaxolol / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002354:Carteolol / Q000494:pharmacology*; D002924:Ciliary Body / Q000098:blood supply*; D007083:Iliac Artery / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D011817:Rabbits; D013552:Swine; D013999:Timolol / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D009599:Nitroprusside; D013999:Timolol; D002354:Carteolol; D015784:Betaxolol; D002118:Calcium