SURVEY OF OPHTHALMOLOGY VOLUME 29. NUMBER 3. NOVEMBER-DECEMBER 1984

CURRENT RESEARCH EDWARD COTLIER, EDITOR

Physiology and Pharmacology of Aqueous Humor

Inflow

KEITH GREEN, PH.D., DSC.

Departments of Ophthalmology and Physiology, Medical College of Georgia, Augusta, Georgia

Abstract. Recent physiological and pharmacological data pertinent to aqueous humor inflow regulation have been reviewed. New anatomical and electrophysiological data are presented, particularly related to aqueous humor secretion. The action of adrenergic agonists and antago- nists is discussed in relation to changes in intraocular pressure, and the effects of a variety of experimental perturbations is presented. The multiple factors which aKect aqueous humor inflow are discussed in the context of an evaluation of recent pertinent literature. (Surv Opbthalmol 29:208-2 14, 1984)

Key words. adrenergic drugs * aqueous humor inflow l blood ffow l

pharmacology l physiology l secretion

M aintenance of normal intraocular pressure (IOP) depends upon the balance of fluid

exchange at different locations in the eye. Either an increase in the rate of aqueous humor production or a decrease in the rate at which it leaves the eye will cause an increase in IOP. Of

major importance is the fluid exchange across the large surface area of the epithelium of the ciliary

body, which is the site of aqueous humor forma- tion.2g Ultimately, aqueous humor leaves the eye through the trabecular meshwork and uveal path- way.

Anatomy

The ciliary body consists of two cellular epithelial layers, the nonpigmented layer next to the posterior chamber and the underlying pigmented layer. The basal membrane of the nonpigmented cells faces the posterior chamber as a result of embryological in- folding of the optic cup. This basal membrane is covered by an internal-limiting membrane which is

continuous with that of the retina and iris. Tight

junctions connect the lateral surfaces of the nonpig-

mented cells near their apices, constituting part of

the blood-aqueous barrier. The nonpigmented cells, which are considered to be the primary source of aqueous humor, contain many mitochondria and

have numerous invaginations in their basal surfaces which serve to increase their surface area. The pig-

mented cells also have invaginations on their baso- lateral surfaces. Anatomical studies of the entire ciliary epithelium indicate a complex integration of cells, with histological variation in different areas of the ciliary process. The regional differences may have functional physiological significance.

The blood supply to the ciliary body arises from both the major circle of the iris and the anterior ciliary arteries. Venous drainage is mainly via the vortex veins, although some blood leaves via the intrascleral veins into the episcleral veins. Numer- ous arterioles pass along the crest of each ciliary process, and capillaries extend along the leaflets of

208

PHYSIOLOGY AND PHARMACOLOGY OF AQUEOUS HUMOR INFLOW ‘09

each process. The fluid that ultimately becomes

aqueous humor is derived from these blood vessels.

The sympathetic nerve supply of the uveat blood vessels, which ma)’ influence the fixmation of the aqueous humor, is carried by the short ciliar) nrr\‘(‘s. The parasympathetic innervation of the iris anct ciliarv h(~dy arises from the ciliary ganglion.

Physiology

The physiologic mechanisms for aqueous humor

tbrmation include both ultrafiltration and secretion.

Ultrafiltration is the result ofgradients in fluid pres-

sure between the \,arious compartments of the eye

(dialysis under applied !lrrssure), but the individual

contributions to these !xcssure gradients have not yet been measured” and much remains to he deter-

mined about their rote in aqueous humor formation. Although a limited dependence of IOP on systemic

blood !xessure exists, increased IOP reduces aquc-

ous inflow. indicating a responsiveness of aqueous inlltrw to altered h\,drostatic pressure gradients.

The c~mponcnt ofccllular secretion is better under-

stood than the component of ultrafiltration. For es- ample, the concentrations of Na’, Ii’. CF. hicar-

honate. some amino acids, ~g1ucosc. and other

organic, compounds in aqueous humor are main-

tained 1~) specific transport sysrems in the ciliar) epi,tl~li urn. II.;‘“‘.l( illll( Ttic low protein concentration

01‘ atlu~011s humor relative to serum results from

exclusion of large molecules by the blood-aqueous barrier. l’hr presence of such a barrier requires ac-

ti\:e transport systems (sither for moving certain ions

and molecules across the cellular layer into the eye that may bc required by the lens and other intraocu-

lar s(ruc1ures. or lbr removal ofsuhstances from the

aqueous humor; at the same time, the barrier itself is necessary to keep transported material from Irak-

ing back into (he riliary body.

IMerminations haire been made, both in isolated

tissues and in the intact eye, of various characteris-

tics of the permcahitit\., of the blood-aqueous har- rier.” ii ‘I’ “w” These studies have shown that the rabbit ciliar)~ epithelium “’ is more leaky to fluid than

that of the primate,“.” although more recent esti- matcxs decrease this difI?rence.” Electrophysiologi-

cal studies of the isolated ciliary epithelium haire revealed the need for Na + TL”‘.i’.ic’ and HCO,-,“.“’ fol

the maintenance of‘s transepithelial potential differ- enc~ and short-circuit current (indices of ion trans- port or secretion across membranes): the latter paramrtcbrs arc inhibited by ouabain”,“’ and furose- midc. “’ indicating !,oth a dependence on cellular metahotism as well as a role for anion exchange.

‘I‘tic organic- anion transport systems ofthe anterior U\YYL bear a strong relationship to those of’ the kid- ne\. and li\.rr.“.‘~“’ TherP is also considerable resem-

blance of the process of aqueous humor formation to

the formation of cerebrospina! fluid.

The blood-aqueous barrier and cellular perme- ability are both of paramount importance in detcr- mining both normal aqueous humor inflow and drug rllPcts upon it. Many types of intercellular junctions. including gap junctions. have been iden-

tilied between the nonpigmented rpithelial cells of monke) ciliary epithrlium,“‘~“” indicatin,? that the

cells arcjoined in a metabolic syncytium with occur- rences in one cell being capable of‘ rapid transmis-

sion to others. In rabbit ciliary epithelium, both

electrical and histological (i.e., clyc dift’usion) rvi-

dence indicates that the cells of the nonpigmented

and pigmented epithelium are connected not only

brtivren themselves tlut also with each other, with the entire ciliary epichelium acting as a syncytium.”

\‘arious inhibitors of cellular c)zymcs drcreasc aqueous humor inflow 1)). different remounts,“.“.”

!xoviding e\ridcnce for active secretory processes in the citiar)- epith~lium. The Na +. K’ ATPase inhibi-

tors, ouabain” and vanadate,” experimentally rc- duct IO! aficr intravitreat and topical ndministra-

(ion. rcspecti\,cly. Vanadatr ion, an intracellular regulator ofXTPase activity. reduces ratjbir IOP b)

decreasing aqueous humor l&nation and mav pro-

vide a means of‘ reducina IOP in glaucoma,“,i’i at-

though recent results ha\fc shown that topical vana-

dale does not loM.er IOP in ocular hypertensive patients.“’ Xs well as these specific inhibitors. sevcr-

al nonspecific metabolic inhibitors such :ls dinitro-

phenol and cyanide also decrease IOP.” indicating a depcnclcncc ofaqueous inflow on an in(nct cellular

mc~tabotism.

Pharmacology

Specific adrenergic and cholinergic drug recep-

tors ha\fc been identified in the ciliary body and their link to the cellular metabolism of‘cyctic nucleo-

tides (e.g., cyclic AMP) and their response to drugs

has been examined.““~‘” Recent studies”.7’.“” have in-

dicated that drug effects on fluid flow into and out of‘ thr eye are more complex than originally conceived.

and the mechanisms of dru,q action are stilt under- stood only superficially. This is illustrated by the

fijIlowing examples. Drugs which have primarily al- pha-adrcnergic cflects cause an initial rise in rabbit

IOP fi)t!owed by a hypotensi\rc rcsponsc. Drugs with beta-adrenrrgic activity have onI>, an immedi- ate hypotensive elect on IOP. with beta,-agonists being particularly potent.‘” The d-isomers of var- ious adrenergic agonists have been shown to cause a fall in rabbit IOP, accompanied by only limited vascular or cardioactive effects, which suggests that the,), ma). t1ax.e a useful role in ocular therapy,.“’ The repeatcld administration of a beta-adrcncr,qlc drug

210 Surv Ophthalmol 29(3) November-December 1984 GREEN

to rabbit eyes causes lesser effects with successive

doses,“’ a phenomenon similar to the tolerance found in man with beta-adrenergic drugs. This

adaptation to daily topical epinephrine administra- tion in rabbits is suppressed with flurbiprofen, a prostaglandin synthetase inhibitor,” indicating pos-

sible prostaglandin mediation of adaptation.

The density of both alpha- and beta-adrenergic

receptors has been measured in the iris-ciliary body

of the rabbit after various medical or surgical proce- dures,;l.7:3 The density of beta-adrenergic receptors appears to be inversely related to the level of adren-

ergic stimulation. However, the ability to synthesize cyclic AMP (the intracellular mediator of heta-

adrenergic response) does not necessarily parallel

either the changes in receptor density or in IOP. The complexity of the response is indicated by the fact that a single administration of timolol inhibited

the beta-adrenergic mediated synthesis of cyclic adenylic acid (CAMP) by the rabbit iris-ciliary

body; but within three hours, the tissue regained its

ability to produce CAMP when challenged in r&o

with isoproterenol. ‘.“’ This short-lived efrect in rah-

bits is in contrast to the prolonged IOP-lowering

effect of timolol in humans. Also puzzling is the observation that cyclic AMP

le\,els in rabbit aqueous humor increase (a response

normally associated with beta-stimulatory drugs) within one hour after topical epinephrine treatment,

coinciding with an increase in IOP rather than with the pressure-lowering eff‘ect that occurs later.“.‘?.“’

M’hen CAMP alone is given, the IOP decreases. Ti-

molol blocks the initial CAMP increase caused by epinephrine, but the epinephrine-induced fall in

IOP occurs as usual, thereby dissociating the CAMP

changes from the hypotensive effects. An initial at-

tempt to correlate morphology and permeability of iris vessels with beta-adrenergic drug functions has been made with the ratH7.” and monkey eye.‘” Clear- ly, more remains to be learned about the cellular

and chemical basis of the ocular adrenergic re- sponses, particularly since these drugs are among

the ones most commonly used in the treatment of glaucoma.

Supersensitivity or subsensitivity of tissues to commonly used drugs is of clinical interest. Epi- nephrine appears to decrease either the numbers or the availability of adrenergic receptors. A probable

mechanism is that the activation of cellular adenyl cyclase by guanyl regulatory protein is uncoupled, thereby decreasing the activity of the beta-receptors (which modulate the adenyl cyclase-guanyl regula- tory protein interaction) and consequently decreas- in,g the beta-physiologic response.“.‘i7,7”.“’ Adrener- gic supersensitivity to drugs does not affect the ciliary epithelial permeability to fluid, based on the

observation that the permeability of normal ciliary epithelium is increased by adrenergic agonists,“’ whereas no enhancement of adrenergic effects of

permeability is found in the sympathectomized eye (even though the whole eye is supersensitive to low

doses of agonist). “’

A marked decrease in the ocular response to cho-

linergic agonists occurs following the devrelopment

of adrenergic supersensitivity in the cat.-‘” The loss

of inhibitory sympathetic input to the iris sphincter

is thought to leave the cholinergic input unopposed, thereby eventually leading to cholinergic subsensiti-

vity. As a result of continued bombardment of re- ceptors by agonist, the receptors lose sensitivity. It’hen pilocarpine and echothiophate were applied

to owl monkey eyes, it was found that continuous

treatment with echothiophate produced a subsensi- tivity to the miotic effect but not to the hypotensive

effect of pilocarpine.“’ This suggests that two popu-

lations of‘acetylcholine receptors may exist, one in the iris sphincter and a second in the ciliary muscle,

with pilocarpine acting as a muscarinic agonist on

the iris and an antagonist on the ciliary muscle. In

addition, evidence for two classes of acetylcholine

binding sites in iris-ciliary tissues has been obtained

using receptor-ligand assays,“’ which utilize specific

radiolabeled compounds which attach to certain re- ceptors. These findings may have some relationship

to receptor involvement in aqueous inflow.

Prostaglandins and related naturally occurring autacoids are released following ocular insult, and

inflammatory and allergic reactions ha\:e been of interest because they result in an increased abnor-

mal aqueous humor inflow.“’ These ellects are more

prominent in rabbits”-“’ than in primates and hu- mans.“” I ,ow doses ( 10 to 500 ,~g) of topically ap-

plied prostaglandin E_, have also been shown to cause significant falls in IOP in cats and monkeys

without concomitant aqueous flare and miosis. This may provide a new approach to the control of IOP and the management of glaucoma.“’ Iris muscle has

also been shown to incorporate prostaglandin pre-

cursor arachidonic acid into its glycerolipids which

it converts to prosta,glandin derivatives.’ This con- version is stimulated by norepinephrine in a dose-

dependent manner, which indicates a possible link between glycerolipids, prostaglandins, and adrener- gic receptors.’ Prostaglandin biosynthetic pathways have been identified in the iris and other ocular

tissues, with the prostaglandins, thromboxanes, leu- cotrines and prostacyclins identified as metabolites of arachidonic acid.“,“‘.“” The biologically-potent thromboxanes and prostaglandins have contrasting effects on blood vessels and platelets, and possibly other tissues. These substances and their metabo- lites may play an important regulatory role in ocular

PHYSIOLOGY AND PHARMACOLOGY OF AQUEOUS HUMOR INFLOW 211

tissues especially cluring inflammatory reactions.

:4 natural peptide transmitter or mediator is sul)-

stance P. which, after stimulation of ocular sensor) nerves, is released into the eye accompanied by mio- sis and infl~~mmation.” Substance P may he one of the mecliators of‘ immediate ocular responses to

trauma or irritants.” together with other neuropep-

tides \vhich ma). influcncc adrrnergic or cholinergic input to the eye. (:hanges in ciliary body permeahil-

it? are part of‘an inflammatory response, and sevcr-

a1 \xoacti\.e”’ and adrcner,+c dru,gs,‘” including

both hcta,- and beta,-adrcnergic agents,” have been shown to ha1.c direct ell?cts on isolated rabbit ciliar!,

cpithclial Iluid permcat)ilit).. Acetylcholine in-

creases hotlt Ilrtid secretion and passi1.e permeahil- it), of‘ the membrane, as does the pcptide hrady- kitiin. which also ma!. pIa!. a role in inflammator)~

eltix2s in tftc eve. “I

Since puhlic~ttion of‘ the report that marihuatta

smoking lcads to a f41 in IOP in both normal \x)lun- tc’crs ant1 glaucoma paticttts,“’ considerable work

has hccsn done \vith lipid-soluhlc cannahinoids. I)cl- ~~~-‘)-~~~~r;t1t)-~lroc~~tl~t~t~~i~~ol. identilied with the he-

It;t\,ioral ellticts of‘ marihuana. is the cannahinoicl

prcsctit in marihuana in the grcatcst amount. al- thouglt about 60 othrr cxnnahinoids exist which

Illa)’ cAY)k(~ other 1).pic;tl patterns of‘ heha\.ior c,hatigc*. Studies in rahhits ha1.e shown that thcsc catinahittoids cshihit a hpcctrum of‘ activity wilh

regard IO lo\vcriy IOP.” Sotnc cannahinoids have

hY~I1 qi\,vti ititra~~c~tiottsl~“’ or topically to hu- l,l;lt,s, 2 II Ili:II ‘Topically administered THC caused a slight fkll itt IOP in hoth trcatcd and contralateral

c)es itt one study” and cornea1 punctate krratitis

has hccti reported. “.“’ It appears that the small drop in IOP in t)oth e\-es is cartsed hy ‘I‘HC: entering the

systemic circulation Ii-om the eye. These studies.

hoby\ cr. rcportcd no fjll in IOP fbllowing topi- cal administration of‘ clclta-9-tetrahydrtxattnahin- (,I II I:i/II ‘Topical THC:, therrfbrc, does not rcducc iti~raoc~ttlar pressure.

Itt~~~a~xwotts ~tdmitiistratictti of Lvater-extracted

material from marittuana (hll>hl) causes a marked IOP fitlI in rahhits at (.oncctttrations as low as 1

microyam of’ 3:if)hl per animal.“’ Correlated with the hll in IOP is a marked reduction in aqueous

infltnv.” Sitnilar efl‘ects are ibund in the primate, hut

only ,tIicr intra\.itreal iniection ofdrug.” These wa- tcr-s~luhlc compouttds may he \,aluahle tools in dis-

ccrnitt~ the mechanisms of‘aqueous inflow and the undcrIying pharntacologg;!~ o!‘aqueous titrmation and in pro\.iding a hasis fi)r new drug development. i’

fntra\.itrcal or close-arterial administration of c~h~~lcra roxin leads to a pronounced and prolon,grd f;iIl 01’ IOP in rahhils.” (~orrcfatecl with this fBl1 in IOP is a sustained stitnulation ol‘cAhlP synthesis in

the ciliary processes,” which either decreases aque-

ous humor formation” or increases outflow facility.” The temporal consequences of cholera toxin in

terms of‘ the relative changes in cAR/IP and IOP require fitrther investigation. Another a,ynt, fbrsko-

lin, \vhich directly stimulates cellular cAMP has hccn lbund to reduce IOP ol‘rahhits. tnonke)x, and

humans.-” Thesr studies ma); provide a litrther no- tion 01‘ the role of‘ cvclic X,ZlP in the rcytlation 01‘

Iluid inflow into thC eye.

Regional hlood flo\v, which may \velf all?ct aque-

ous humor tixmation h>, altering local pressure gra-

dicnts across ocular memhrancs. has hccn mcas- ured in the rahhit rye at itttc.r\.als after topical

application of‘ drugs, and time-dependent changes have hecn Ibund. Sr\val adrenergic agonists de- creased blood tlow of‘tfle iris and ciliar), processes at

one hour after administration in hotft ttormal and

s!.rnf~attt~‘ctotnizrd e!.cs \vttctt the 1OP \vas un-

changed.“” .4t three hours aficr cpincphrine admitt- istration. fto\vt‘\.er, al a time \vhctt 101 \vas rc-

ducetl. (iliar!. process hlood How \vas normal. and

iridic blood llow had increased, possibly due to tht incxx~asrtl prevailing pcrlitsion pressure. ;\ rcdttc-

lion in blood Ilow to the iris and c-iliar!, processes 01‘

the tnottkcy c!.c up to six hours hzis hc~ctt reported fi)flo\vitig the topical applic2tion 01‘ (-c~1’itir~plit.inc,. ’ Kcwnt studies have shown that to1)ical cyitir~phritie decrcasch retinal blood flow in apltakic rahl)ir eyes.“”

~T‘o1~icall\-;tl,plircl pilocarpine incrvascs blood Ilow

through th(b iris. ciliary proccsscs. at~d cilinr)- mus-

cle ol‘ntonkc~~ cy.x by ahout 150 pcrccnt, suggrstittg that blood flow is mediated throttgh \xsc,ular mus-

carinic cholincru;ic receptors. ’ I ntracratiial srimula-

tiott 01‘ rahhit oculomolor tict7.c cat~scb a reduction

in blood How in the iris and ciliary processes (imply- ing a \,asc)constrictive rltticl). \vhich wits potetitiatcd

hv ittdomcrhacin. a l~rosl;t,~l;ttiditi itthihitor.“” In

s).ml)~ttt”‘ctottlized rahhits. oculomo~or tter\ c stim- ulation caused a IonxlastinE ~2sodilatioti. Stimula-

tion 01‘rahl)it lilih cranial ner\‘c c~ausecl an incxasccl blood Ilow to the iris and c.iliar\, processes. a hreak-

do\vn ot‘thc hloocl-aqueous harrier, and an cle\atc~cl

intraocular pressutx attrihulc’d [(I rc~lcased su i)-

stance P.“’ Thcsc studies rcy~rt~settt scattered clues that blood flow rates afl+ctcd 1)~ tic~urotra~ismittcrs.

ttcttroactive pepticIt’s. and modulators are impor- tant in altbcting aqucwus humor litrtnatioti. pwsutn-

ahI>. h!, altering hyclrostalic prwsurv ~txclirtits

across memhratlcs.

A tiutnl)cr 01‘ cxperimcntal pc~rturhations have

hecn lixrnd to influence rahhit aqueo~~s humor in- flab-. suc.h as sbxtemic afkalosis, that incrcascs, and acidosis. that decreases aqueous li~rmation ratv~“’

\Tasoprvssiti ailects IOP and aquvotts inflow in ral)- bits.“’ hrtt such a connection has nol I)cctl tttadc in

212 Surv Ophthalmol 29( 3) November-December 1984 GREEN

humans.

Evidence has been obtained over the past decades of a central nervous system effect on IOP, but the

localization of such a central regulatory locus has

not been made in humans. It is known that injec- tions of substances into the third ventricle cause

alterations in IOP and, by implication, aqueous in-

flow. Prostaglandins, arachidonic acid, and hypo-

osmotic solutions all increase IOP after injection

into the third ventricle, apparently by increasing aqueous humor inflow.“’ Intraventricular injection

of calcium ions causes a dose-dependent elevation of IOP and a reduction in body temperature; the in-

creased IOP is also the result of increased aqueous inflow.“” It is known that hypothermia decreases”’

and hyperthermia increases aqueous formation,” again implicating a central control mechanism.

Also, general anesthetics such as halothane,“’ barbi-

turates, and ketamine’” affect IOP. Some studies

suggest that optic nerve section influences certain ocular responses such as that caused by osmotic

stress or barbiturates,” but not the effects of hy- perthermia.“’ These observations, if confirmed, could provide important information about the cen-

tral control of aqueous humor formation. It is known that increasing IOP suppresses the

rate of aqueous humor formation, a phenomenon

known as pseudofacility. It remains to be deter-

mined, however, whether or not high IOP affects

blood flow or blood pressure in the ciliary body vasculature, or if the suppression is purely a mem-

brane effect caused by changing the hydrostatic gra-

dients across the ciliary epithelium (the ultrafiltra- tion component of aqueous humor formation). A sustained rise in IOP was accompanied by a gradu-

al loss of the suppression of aqueous inflow such that the value returned toward the pre-elevated IOP lev- els,lh indicating some type of physiological adapta- tion.

In summary, while it is evident that considerable

advances have been made in our knowledge of the physiology and pharmacology of aqueous humor inflow, we currently fall markedly short of compre-

hension of all but the basic phenomena. Improve- ments and innovations in techniques have allowed new areas ofinterest to be identified, and these must be pursued with vigor in order to provide an ade- quate comprehension of the pharmacology of aque- ous humor inflow.

Acknowledgment

Mrs. Sylvia Catravas provided valuable secretarial assis-

tance.

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Supported in part by research grants EY04558 and EY04559 from the National Eye Institute.

Reprint requests should he addressed to Keith Green, Ph.D., I).Sc.. Department of Ophthalmolog)-, Medical College of Georgia. .\I(:(; Box 3059, Augusta, GA 30912.