Vasodilatory mechanism of levobunolol on vascular smooth muscle cells.
Topical application of levobunolol hydrochloride, a beta-adrenergic antagonist used for treatment of glaucoma, is reported to increase ocular blood flow. We studied the mechanism of levobunolol-induced vasodilation in arterial smooth muscle. The effects of levobunolol or other agents on isolated, pre-contracted rabbit ciliary artery were investigated using an isometric tension recording method. The effects of the same agents on intracellular free calcium ([Ca(2+)](i)) in cultured human aortic smooth muscle cells were also studied by fluorophotometry. Levobunolol relaxed ciliary artery rings that were pre-contracted with either high-K solution, 1microM histamine, 10microM phenylephrine, or 100nM endothelin-1. The relaxation induced by levobunolol was concentration-dependent over the range of 10microM to 0.3mM. Inhibition of endothelial nitric oxide synthase or denudation of the endothelium did not affect this relaxation. Histamine-induced contractions were inhibited by the histamine H(1) antagonist pyrilamine. Radioligand binding experiments showed that levobunolol did not bind to the H(1) receptor. Further, histamine induced transient contraction in Ca(2+)-free solution, and levobunolol inhibited this contraction by 74.6+/-11.0%. In cultured smooth muscle cells in the presence of extracellular Ca(2+), levobunolol significantly inhibited the histamine-induced elevation of [Ca(2+)](i). However, it did not inhibit the increase of [Ca(2+)](i) in histamine-stimulated cells incubated in Ca(2+)-free solution. These results indicate that levobunolol may relax rabbit ciliary artery by two different mechanisms. First, the relaxation could be due to the blockade of Ca(2+) entry through non-voltage-dependent Ca(2+) channels. Second, levobunolol may change the Ca(2+) sensitivity of vascular smooth muscle cells.
Dong
Yaru
Y
Department of Ophthalmology, Akita University School of Medicine, 1-1-1 Hondo, Akita, Akita 010-8543, Japan.
Ishikawa
Hitoshi
H
Wu
Yazhen
Y
Yoshitomi
Takeshi
T
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019842:Ciliary Arteries / Q000187:drug effects / Q000502:physiology; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D002040:Levobunolol / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011817:Rabbits; D046509:Tissue Culture Techniques; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D004110:Diltiazem; D002040:Levobunolol; D002118:Calcium