PPII: SO042-6989(96)OO096-X

Vision Re.~.,Vol.36,No.23,pp.3843-3849,1996Copyright0 1996ElsevierScienceLtd.All rightsreserved

Printedin GreatBritain0042-6989/96$15.00+ 0.00

Bradykinin Receptor Inhibition Affects the Rodb-wave in the Cat ElectroretinogramPHILIPP C. JACOBI,* HARTMUT OSSWALD,~EBERHART ZRENNER+

Received 27 November 1995; in revisedform 19 March 1996

In 10 anaesthetized cats, electroretinographic (ERG) measurements were carried out to furtherelucidate the involvement of bradykinin as a substrate component of the renin-angiotensin systemin retinal neurotransmission. Reducing angiotensin II concentration by angiotensin-convertingenzyme (ACE)inhibition increased sensitivity [0.5 log units) and gain (50%) of the rod b-waveamplitnde. The b-wave implicit time was decreased only at high stimulus intensities (>10–2 cd/m),Blocking bradytdnin receptors specifically decreased rod b-wave implicit time for all intensities,while its amplitude remained unaffected. Bradykinin effects were independent of alterations ofangiotensin II activity. We therefore suggest that bradyldnin influences inner retinal signalprocessing, hereby further supporting the hypothesis of a renin-angiotensin system involvement inretinal neurotransmission. Copyright K) 1996 Elsevier Science Ltd

Bradykinin Electroretinography Renin-angiotensin system Neurotransmission Intensity–response function Angiotensin converting enzyme

INTRODUCTION

Bradykinin (BK) is a nonapeptidewith a wide range ofactionsthat havebeen extensivelyinvestigatedin isolatedorgans, including the retina (Erdos, 1989; Taylor et al.,1989). BK is known to influence vascular permeability,tonus of smooth muscle cells and by activation ofphospholipase-A2,BK has alsobeen shownto be a potentstimulator of prostaglandin and leukotriene synthesis(Griesbacher & Lembeck, 1989; Zusmann, 1987). Bystimulating nociceptive afferent nerve fibres BK en-hances pain and hyperalgesia (Steranka et al., 1987).However, not much is known whether BK—as manyother peripherally active peptides—is also involved inmodulatingneuronalactivity,more specifically in retinalneurotransmission.

BK is inactivated by the angiotensin convertingenzyme (ACE) and thus closely related to the renin–angiotensin system (Fig. 1). Recent studies havesuggested that various components of the renin–angio-tensin system(RAS) are involvedin modulatingneuronalactivity in the central nervoussystem(Severs & Daniels-Severs, 1973; Brecha, 1983; Brecha et al., 1981; Felix,

*Towhom all correspondenceshouldbe addressedat the Departmentof Ophthalmology, University Eye Hospital Cologne, Joseph-Stelzmannstr.9, 50931 Cologne,Germany.

~Departmentof Pharmacology,Universityof Tuebingen,Wilhelmstr.16, 72076Tuebingen,Germany.

~Department of Pathophysiologyof Vision and Neuro-Ophthalmol-ogy,UniversityEye HospitalTuebingen,Schleichstr.12-16,72076Tuebingen,Germany.

1982;Kolb & Nelson, 1983;Lind et al., 1985;Sessle &Henry, 1987; Story & Ziogas, 1987; Watt & Su, 1988;Morgan, 1989;Morgan et al., 1989;Ferrari-Dileo et al.,1988). Moreover, immunocytochemicaland electroreti-nographicaldata provided experimental evidence of theRAS also participating in retinal neuromodulation(Dahlheim et al., 1988; Mallorga et al., 1989; Zrenneret al., 1989;Datum & Zrenner, 1991;Kohleret al., 1992;Jurklies et al., 1993;Jacobi et al., 1992, 1994;Kaelin etal., 1994).A possiblerole of BK in retinalphysiologyhasso far not been investigated.

Recent experiments revealed that inhibition of ACEinduces changes of electroretinographicpotentialsorigi-nating in the inner retina, while outer retina signalsremainunaffected(Jacobiet al., 1992,1994).To a certainextent some of these effects were reversible onangiotensin-11(ANGII) substitution, thus indicating anANGII-mediated influenceon ERG responses (Jacobi etal., 1992, 1994). However, blocking ACE actionsimultaneously changes the metabolism of other pep-tides, including BK (Fig. 1). As ACE catalyses bothsubstrates—it increases the formation of ANGII butinactivatesBK—it seems difficultto assign the observedeffects of ACE inhibitionto a single substrate.

The aim of this study was to further elucidate apossibleANGII influencefrom a BK-mediated effect onthe electroretinogram(ERG)in anaesthesized cats. Forthis reason we applied a specificBK receptor antagonist(Hoeldo)prior to ACE inhibition(Quinapril).An increasein BK concentration following ACE inhibition shouldthen have no neurobiochemicalinfluenceat the receptor

3843

-.—.-.—.

3844 P. C. JACOBI et al.

I inactivepepti~es

+“7

}Angie- — angiotensin I angiotensin II —

tensinogenangiotensin III

FIGURE 1. The angiotensin–reninsystem and the interactionswith other peptides found in the retina of various species. Thecompetitive ACE inhibitor Quinapril reduces the catalysis of the physiologically active octapeptide angiotensin-II and

inactivates bradykininsimultaneously.Hoeldois a specific BK receptor blocker with no intrinsic activity.

site. The pharmacokinetics and -dynamics of ANGII,however, are not influencedby preceding applicationofthe BK receptor blocker. We can, therefore, assume thatdifferences in effects on ERG responses of single ACEinhibition on the one hand, and of ACE inhibition inconjunctionwith BK receptorblockadeon the other maybe due to a BK-mediatedaction. Since bradykinincan beshown to have a specific influence on electroretino-graphic responses, this study provides further evidencefor the involvementof the RAS in retinal neuromodula-tion.

METHODS

Preparations and recordings were carried out asdescribed in detail previously (Jacobi et al., 1994). Allanimals were treated according to the resolution of theEuropean CommunitiesCouncil Directive (1986) on theUse of Animals in Research.Anesthesia was initiatedbyan i.m. injectionof ketamine and thiaminehydrochloride(3:2; 0.15 mg/kg) in 10 adult cats. Animals were thenintubated and carefully monitored for respiration andcirculation parameters. Arterial blood pressure wasmonitored on-lineby means of a femoral artery catheter.A femoral” vein catheter was used’for iv. drug appli-cation. By repeated intravenous injections (0.1 ml) ofpentobarbital (Nembutal 60 mg/ml) the maintainanceofanesthesia was ensured.

The ERG was recorded by means of corneal contactlens electrodes (ERG Jet Electrode) with pupils fullydilated. Subdermalelectrodesplaced at the forehead andthe front leg served as indifferentand ground electrodes,respectively. The luminance of a Ganzfeld-stimulator(LKC, Utas 2000) was attenuated by neutral densityfilters (Kodak Wratten). All measurementswere carriedout in the dark-adapted state and stimulus luminanceranged from b-wave threshold to saturation (l.5*10–2–

2.4 cd+/m2) using a 150 W Xenon flash light (lambda=508 nm; duration: 10 ~sec).

For ACE inhibition Quinapril (Parke-Davis) disolvedin 0.9’%salinewas intravenouslyinjected at a concentra-tion of 4 mg/kg. In five animals the specificbradykininreceptor blocker Hoe140(Hoechst AG) was injected (1mg/k ) 2 hr prior to ACE inhibition. H6e140(D-Arg-

8 .5[Hyp ,Thl ,D-Tic7,0ic8]-bradykinin)is a highly potent,competitiveBK antagonist,specificto BK receptors andwith no intrinsicactivity (Hock et al., 1991;Wirth et al.,1991). Electrophysiologicaldata were recorded severaltimesbefore and after applicationof the drugs.Statisticalanalysis was performed using the non-parametric Wil-coxon test.

RESULTS

Arterial blood pressure

The ACE inhibitorQuinaprilregularlycauseda drop inmean arterial blood pressure (MAP), irrespective of thepresence of Hoe140.The relative reduction in MAP wasgreatest (42 ~ 17mmHg) at 90 min after the injectionand lasted for another 30-60 min. Hoe140,on the otherhand, did not lead to MAP changes.

Scotopic b-wave

The effects of the ACE inhibitor Quinapril and thespeci”ficBK receptor blocker Hoe140on the scotopic b-wave amplitude are demonstrated in Fig. 2. Theamplitudes of the b-waves were plotted against thelogarithm of integral luminance of the stimulus, pre-sented for 17)psec at a fixed stimulus interval of 5 secafter dark adaptation for at least 90 min. The intensity–response functions (V—logI) obtained before drugapplication (solid circles) follows a typical sigmoidalcourse.An increase of irradiancebeyond 2 or 3 log unitsabovethe b-wave threshold,producesa dmp in amplitude

BRADYKININAFFECTSTHE ERG B-WAVE 3845

(+ 800

600

400

vma~:

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400

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+controlT

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-———— +– – – – – – – – – –T

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104 103 10-2 10-1 1 10

integral luminance (cd*s/m2)

+co.trol

+H””140

-&--H0el4o + Quinapril A

-——— 4—2

104 104 10-2 10-’ 1 10

integral luminance(cd*s/m2)

FIGURE 2. (a) Effects of the ACE inhibitor Quinapril (soIid diamonds)on the b-wave amplitude of the scotopic intensity–response function. Quinapril was injected at a dose of 4 mg/kg. Responses presented here were recorded 90 min after theinjection of Quinapril.ACE inhibitionincreases sensitivity(0.5 log units) and gain (50Y~)of all resPonses.Q@wildoesnotalter the typical sigmoidalcourse and the dip between the two rising phases of the control (solid circles) recordedbefore ACEinhibition (n= 5; mean f SEM). (b) The application of Hoelw does not affect the b-wave amplitude. Subsequent ACEinhibition results in the same amount of increase in b-wave sensitivity and gain as seen without prior BK blockade, thusindicatingan ANGII-mediatedeffect. Hoeldowas injected at a doseof 1mg/kg.Responsespresentedherewere recorded90 min

(Hoe140)and 160min (Hoel,o and Qqinapril)afterthedmg injections (n=5; mean * SEM).

—

3846 P. C. JACOBI et al.

between two rising phases. The second rising phase isconsidered to be generated by cones (Arden et al., 1960;van Lith, 1966)whereas the dip between them is thoughtto be a result of interactions within the rod pathway(Olsen et al., 1986).Quinaprilresults in an increaseof theb-wave amplitude.The V –logI functionalso shiftsto theleft and becomes steeper [diamonds in Fig. 2(a)]. Botheffects indicate an overall increase in sensitivity(0.5 logunits) and gain (5070). Changes in amplitude weresignificant (P < 0.05). These results are indicative ofan ANGII involvementin affecting the scotopicb-waveamplitude.However,the broad substratespecificityof theACE raises the question of an involvement of variousother ACE substrates. As ACE inhibition not onlyreduces the ANGII activity but also increases the BKconcentration via reduced BK inactivation, in a secondseries of experiments we injected the BK receptorblocker HoelAOprior to ACE inhibition [Fig. 2(b)].Hoelqo is a competitive receptor blocker with a highaffinity to BK receptors. The systemic halftime valueexceeds4 hr (Wirth et al., 1991).The injectionof Hoe140itself does not affect the scotopic b-wave amplitude[diamonds in Fig. 2(b)]. However, subsequent ACEinhibition leads to an increase in amplitude comparablewith thoseexperimentswhere no BK receptorblockerhasbeen applied [solid triangles in Fig. 2(b)]. Consequently,effects of ACE inhibition on the ERG amplitude underthese circumstancesare likely to be mediated solely viathe RAS without involvementof BK.

The implicit time of the scotopicb-wave showsa quitedifferentbehaviour (Fig. 3). ACE inhibitionshortenstheimplicit time as one could expect from the amplituderisein Fig. 2. Responseselicited 2.5 log units above thresholdare reduced by Quinapril by approximately 119%[soliddiamonds in Fig. 3(a)]. The difference is statisticallysignificant (P < 0.05). Responses obtained at lowerstimulus irradiances are not affected significantly. Incontrast to the b-wave amplitude, the implicit time isaltered by Hoe140application. The implicit time of thewhole V—logI function is reduced significantly (P <0.05) by Hoe140[diamonds in Fig. 3(b)]. SubsequentACE inhibition does not result in further changes [solidtriangles in Fig. 3(b)]. In summary, the BK receptorblockade does not affect the scotopicb-wave amplitude,nor does it change the Quinapril induced effect on the b-wave amplitude.However, there is a marked influenceofHoe140on the implicit time, strongly suggesting a BKinvolvement in the time domain of ERG b-wavegeneration.

Scotopic a-wave

At a stimulusluminanceof 2.4 cd/m2,influenceson thescotopic a-wave were also evaluated. Before drugapplication mean ( + SD) amplitude and implicit timewere 175 i 23 pV and 13 + 1.3msec, respectively.Thecourse of the a-wave remains unaltered throughout theentire experiment. The,a-wave reflecting activity of theouter retina is not affected by ACE inhibition, BKreceptorblockadeor by the combinationof Quinapriland

Hoelqo application. This observation might point to aspecific influence of the pharmacological alterations onthe different layers of the retina.

Hertz jlicker

In order to obtain a cone responsewithout exposuretoextensive light adaptation, a 30 Hz red flicker wasrecorded. Prior to drug administration, amplitude andimplicit time are 14.6,aV(-J 4.7 pV SD) and 59.3 msec(+ 12.4 msec SD), respectively. The 30 Hz flickeramplitude and latency were not affected by ACEinhibition,BK receptor blockade or by the combinationof Quinapriland Hoe140application.The data from the 30Hz red flicker response indicate that the cone pathway isnot as involved in a hypothetical RAS-mediatedneuromodulatoryprocessin the retina as the rod pathway.

DISCUSSION

The present results support the evidence that theobserved effects of intravenously applied bradykinininhibitor Hoe140and subsequentACE inhibitionQuina-pril on the cat electroretinogram represent actions ofmodulation within the angiotensin–bradykininmetabo-lism on retinal neurotransmission. We previously re-ported that ANGII is present in the neuroretina,affectingamplitude and implicit time of electroretinographicresponses (Zrenner et al., 1989; Jacobi et al., 1994). Inthe present study we have extended those findings byrecording ERG responses under specific BK receptorblockade,supportingthe notionof a RAS involvementinretinal neurotransmission.Both BK, as well as ANGII,are substratesof ACE—thekey enzymeof the RAS-andhave been reported to occur in various ocular tissues ofhuman, feline, bovine and cat (Ferrari-Dileoet al., 1988;Kaelin et al., 1994). Undoubtedly, there is evidence(Igemoto & Yamamoto, 1978; Igic & Kojovic, 1980)indicating that an ocular renin–angiotensinsystem mayexist. However, the precise localization of the compo-nents of the RAS and the sites for synthesisand activitystill remain unclear, especially concerning neuroretinalactivity (Ferrari-Dileo et al., 1987, 1988; Danser et al.,1989;Strittmatteret al., 1989;Deinum et al., 1990).

In a previousstudy, inhibitionof ACE by Quinapril inanaesthesized cats resulted in distinct changes of ERGresponsesoriginatingin the inner retina, which were to acertain extent reversible on ANGII supplementationandnotexplainedby its effectson the vascularsystem(Jacobiet al., 1994;Demant et al., 1982;Niemeyeret al., 1982).Signals originating in the outer retina (PIII) remainedunaffected (Jacobi et al., 1994). This strongly pointstowards a modulatory effect of ANGII on retinalneurotransmission. Since ACE converts a number ofsubstrates it is conceivable that other substrates such asBK may also be present in the neuroretina, therebycharacterizingACE rather than other substratesas beingof importance in the course of modulating retinalprocessing.

The present results support this hypothesis. Theapplication of a specific BK blocker (Hoe140)does not

BRADYIUNINAFFECTSTHE ERG B-WAVE 3847

(a)

60

50

40

30

(b)

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.“70-

160-

50-

40-

L30-, 1 1 I 1 1

104 10-3 10-2 10-’ 1 10

integral luminance (cd*a/m);’

FIGURE 3. (a) Effects of the ACE inhibitor Quinapril (solid diamonds) on the b-wave implicit time of the correspondingscotopicintensity–responsefunction.’In the control,increasingstimulusluminanceleads to the expecteddecreaseof the b-waveimplicit time (solidcircles). ACE inhibitionresults in a furtherreduqtionof’theitiplicit time for responsesrecordedat stimulusluminance =10- 2cd/m2.(b)The applicationof Hoe140significantlyreduces the b-wave’implicittime at all stimulus intensitiesbetween 12and 20%.’SubsequentQuinaprilinjectiondoes not leadto further changes.These results are stronglyindicativeof a

BK-mediatedeffect on the scotopic b-wave implicit time. ,,:, ! ;::,.. :,,.

3848 P. C. JACOBI et al.

affect the a-wave but has some effect on the b-wave.Depolarizing bipolar cells possibly are the neuronalorigins of this response and, therefore, ought to beconsidered as a probable site of action. However, effectson the b-wave implicit time could also be interpreted asamacrine cell-mediated. Subpopulations of amacrinecells increase the time course of rod signals (Nelson,1982). Again there is immuncytochemical evidence tosupport these assumptions,since specificANGII bindingsites have been revealed in a subpopulationof amacrinecells in chicken (Datum & Zrenner, 1991).

An influenceof bradykininon the depolarizingbipolarcells has to be considered in conjunction with Miillercells, sinceboth contributeto the formationof the b-wave(Miller & Dowling, 1987). The Mi,illercell/K+-hypoth-esis of b-wave generation implies that the light-evokedincrease in extracellular [K+] in the outer and innerplexiform layers results in an influx of [K+]into Mullercells,which in turn resultsin a radial currentflowthroughthe cells that can be picked up by corneal electrodes(Miller & Dowling, 1987; Kuffler, 1967; Faber, 1969).The [K+]increase in the outer plexiform layer is mainlygenerated by the depolarizingbipolar cells and predomi-nates in generatingthe response(Faber, 1969;Dick et al.,1985; Stockton & Slaughter, 1989). Thus, the b-wavemay reflect indirectly the activity of the depolarizingbipolar cells and the observed alterations could beexplained by some kind of neuronal influence of theRAS on these cells.

However, since IK+]-metabolismin the Miiller cell ismost probably responsiblefor the b-wave modulationofMi.tilercell function itself, alterationsshould show up inthe ERG (Kuffler, 1967). Neuropharmacologicalactionson Mi.illercells would alter neurotransmission in theretina as well, but in a more global manner since glialcells rather than individualneurons are involved.A glialcell-mediated mechanism on the extracellularpotassiumlevel, thereforecould play a role in the BK effect as well.

The probability of the observed ERG alterationssimplybeing due to variationsin systemicbloodpressureis very low. Demant et al. (1982) convincinglyshowedthat variations in the systemic arterial blood pressurehave no effect on the b-wave of the cat electroretinogram.Autoregulation of retinal circulation has therefore beenpostulated (Niemeyer et al., 1982). We confirmedtheseresults by reducing the mean arterial blood pressure(MAP) by means of dihydralazine injections (Jacobi etal., 1994); ERG responses remained stable even whenlowering the MAP to 60 mmHg. This notion of a MAP-independent influence is further supported by theobservation that the a-wave—representing activity inthe outer retina—is not affected by changes in BK orANGII activity, while responses generated in innerretinal layers (b-wave) are influenced.,Finally, it shouldbe mentioned, that in spite of the presumed autoregula-tion, a local ocular circulation-retinal or choroidal inparticular-could theoreticallybe affectedby the appliedneuropeptides, which would occur undetected by ourexperiments.

In summary, the results presented here support ahypothesisof RAS involvementin retinalneurotransmis-sion that is not linked to its systemicvasoactive effects,since: (1) inner retina (b-wave) and not outer retinaresponses (a-wave) are affected; (2) subsequent topreviously reported ANGII effects we can now reporton experiments with a BK-mediated influence onmammalian ERG with no effects on systemic bloodpressure;(3) the amplitude-increasingeffect of Quinaprilis not alteredby previousBK receptorblockade;(4) theseresults are in accordancewith immunohistochemicalandin vitro electroretinographicstudies that point to innerneuroretina involvement.Whatever the possible cellularoriginmightbe, these in vivo experimentsfurther supportevidenceof the renin–angiotensinsystembeing involvedin retinal neuromodulation, which shows up in theGanzfeld ERG.

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