S214
SURVEY OF OPHTHALMOLOGY VOLUME 43 • SUPPLEMENT 1 • JUNE 1999
© 1999 by Elsevier Science Inc. 0039-6257/99/$19.00
All rights reserved. PII S0039-6257(99)00042-9
Systemic and Ocular Vascular Roles of the
Antiglaucoma Agents -Adrenergic Antagonists
and Ca
2+
Entry Blockers
DAO-YI YU, PHD, MD,
1
ER-NING SU, PHD, MD,
1
STEPHEN J. CRINGLE, PHD,
1
VALERIE A. ALDER, PHD,
1
PAULA K. YU, BSc,
1
AND LOUIS DeSANTIS, PHD
2
1
Lions Eye Institute and Centre for Ophthalmology and Visual Science, University of Western Australia, Nedlands, WA,
Australia, and
2
Alcon Laboratories Inc., Fort Worth, TX, USA
Abstract. This review addresses whether the antiglaucoma agents -adrenergic antagonists and Ca
2+
entry blockers cause vasoactive effects in the retinal and other ocular vasculatures, as they do in other
tissues. The potent vasodilating effects of Ca
2+
entry blockers on ocular vessels have recently been dem-
onstrated in in vivo and in vitro studies, implying that the maintenance of ocular vascular tone relies
almost exclusively on extracellular Ca
2+
. Ca
2+
entry blockers may potentially play a role in relaxing the
retinal, long posterior ciliary, and ophthalmociliary arteries to improve the ocular circulation in vascu-
lar diseases in which there is considerable vascular tone present. The -adrenergic antagonists are dis-
cussed with reference to their antihypertensive role, their effect on other vascular beds, and finally what
is known of their effect in the ocular vasculature. The emerging evidence that particular selective -adren-
ergic antagonists, such as betaxolol, are also potent Ca
2+
channel entry blockers in other vascular beds
is presented. Betaxolol has been shown to induce vasodilatation in the retinal and other ocular vascular
beds, although studies have shown that
1
-adrenergic receptors are sparse in these vascular beds. This
implies that an alternative mechanism must be responsible for betaxolol-induced vasodilatation. Evi-
dence is presented that betaxolol vasodilates via its potent Ca
2+
channel entry blocking properties, and
its potency and ability to vasodilate are compared with those of nimodipine and timolol, as well as with
those of other Ca
2+
channel entry blockers. Important areas for future research in this area are dis-
cussed. (Surv Ophthalmol 43 [Suppl 1]:S214–S222, 1999. © 1999 by Elsevier Science Inc. All rights
reserved.)
Key words. -adrenergic antagonists • -adrenergic receptors • calcium channels •
calcium entry blockers • glaucoma • long posterior ciliary artery • retinal artery
Ideally, potential antiglaucoma drugs should not
only lower intraocular pressure (IOP), the major
risk factor for glaucoma, but also improve or have
no direct effect on ocular perfusion.
9,81
Certainly,
drugs that reduce both IOP and ocular blood flow
should not be contenders for antiglaucoma treat-
ment. In recent years, Ca
2+
entry blockers have
been investigated as potential antiglaucoma agents
23
and were compared with -adrenergic antagonists in
current use, such as betaxolol and timolol, for their
effects on the ocular circulation. In this review, the
current understanding of the relative effects of Ca
2+
entry blockers and -adrenergic antagonists on ocu-
lar vessels and their mechanisms of action will be dis-
cussed. Vascular smooth muscle contraction and di-
latation are directly regulated by intracellular Ca
2+
concentration ([Ca
2+
]
i
), which is determined by
Ca
2+
entry into the cell, Ca
2+
release from intracellu-
lar sites, and Ca
2+
removal. Two membrane systems
play key and integrated roles in the regulation of
smooth muscle [Ca
2+
]
i
. These are the cell mem-
brane (plasmalemma), which binds the cell and con-
trols Ca
2+
movements through agonist receptor in-
teraction and membrane depolarization, and the
intracellular organelle, the sarcoplasmic reticulum
membrane where Ca
2+
release, uptake, and move-
ments are controlled by second messengers. This ar-
ticle will focus on Ca
2+
movements through the plas-
malemma. The Ca
2+
channels in endothelial cells,
which are quite different from those in smooth mus-
cle,
16
will not be covered, although the action of
some vasoactive agents that modulate Ca
2+
move-