Exp. Eye Res. (1979) 28, 199-209

Effects of Tertiary Amine Local Anesthetics on Ion Transport in the Isolated Bullfrog Cornea HOWARD

F. SCHOEN AND OSCAR

A. C!ANINA

Departments of Ophthalmology and Physiology, Moun.t Sinai School of Medicine of the City V+ziversity of &VewYork, New York, M. I’. 100.29. F.S.=1. (Received27 July 1978, Xew York) Corneas were mounted in Ussing-type chambers and their short-circuit current (KC) and resistance measured. Of eight local anesthetics tested, four (benoxinate, etidocaine, lidocaine. and mepivacaine) stimulated the WC w h en added to the epithelial bathing solution at concentrations of from 0.02 to 1 mM. The stimulation, which usually lasted for 40-60 min, was seen only when the Ringer’s solution contained Cl. At higher concent’rations or after longer incubations, these local anesthetics inhibited the WC. Four other local anesthetics, dibucaine, tetracaine, proxymetacaine (proparacaine), and procaine, only inhibited the Cl-dependent SCC when added to the epithelial bathing solution. with ID,,‘s (after 60 min) of about 0.04, 0.3, 2 and 10 mnr, respectively. Stimulation of the RCC was always accompanied by a reduction in the transcorneal electrical resistance. Inhibition of the SCC was accompanied by an increase, decrease, or no change in resistance. In some cases where the SCC was inhibited, the resistance fell to very low levels, but this effect, was often part.ially reversed ahen the drug was washed out of the chamber. It is suggested that local anest.hetics inhibit the SK by directly altering the chloride permeability of cornea1 epithelial ~11s. The explanation for the stimulatory effect is less clear. but could be due to an eleoatio:l of intracellular Ca levels or to hormone-like effects of the drugs. Key tuords: short-circuit current; electrical resistance: cornea1 permeability; cornea1 epithelium ; chloride transport ; sodium transport.

1. Introduction The study of the effects of tertiary amine local anesthetics on cornea1 epithelial ion transport would appear to be worthwhile for several reasons.Local anesthetics afiect ion transport in such diverse systemsas nerve cells (Ritchie, 1971)and frog skin (Skou and Zerahn, 1959) and the question arises as to what their effects might be on the ion transport properties of the cornea1 epithelium. Repeated topical application of localanestheticsto the invivocorneadamagestheepithelium (Behrendt, 1956; Epstein and Paton, 1968) and there could be a relationship between this phenomenon and the effects of local anesthetics on the electrical properties of the in vitro cornea. Finally, local anesthetics appear to interact with Ca in several systems (Douglas and Kanno, 1967; Feinstein, Fiekers and Fraser, 1976; Feinstein and Paimre, 1969; Poste. Papahadjopoulos, Jacobson and Vail, 1975; Ritchie, 1971; Rubin, Feinstein, Jaanus and Paimre, 1967; Seeman, 1972) and although there is some dispute as to the role of Ca in the response of nerve cells to local anesthetics (Hille, 1977; Narahashi, Frazier and Takeno, 1976) the observation that the Ca ionophore A23187 influences active Cl transport in the cornea (Candia, Montoreano and Podos, 1977) is suggestive. We therefore have attempted to define the nature of the responsesof cornea1 ion transport to local anesthetics and have searchedfor preliminary evidence for a role of (‘a in some or all of the responses. 001448:35/79/020199-+I1

SOl.OO/O

10 199

1979 Academic

Press

Inc. (Lontlon)

Limited

2. Methods Electrid

measurements

Corneas were excised from bullfrogs (Rullu catesbeinna) weighing approximately 61)O g and each cornea was mounted as a membrane in a modified Ussing chamber by a tmthotl previously described (Candia, 1972). Th e t rans-cornea1 electrical potential was monitcmd through agar-0.457; NaCl-filled polyethylene bridges connected to saturated KC--ca,lomel half-cells. External current was passed across the membrane via similar bridges. The membrane was continuously short circuited and the short-circuit current @CC) recorded by a Heath model EU-20 recorder modified as an automatic voltage clamp. Resistance was determined by periodically measuring the current necessary to depolarize the nl~mbranc a few millivolts from the short-circuited condition. ChlorideJEux

measureme~~t.~

Corneas were short-circuited in the Ussing chambers and 2-3 &!i of 36C1 were added to one side of the chamber (labeled side). When the SCC had stabilized, 3-ml samples were taken from the 5 ml of solution on the unlabeled side every 20 min and replaced with fresh solution. After 60 min, the drug was added to the epithelial bathing solution and sampling was continued for another 80 min. One 5 ~1 sample was taken from the labeled side and diluted with 3 ml of unlabeled Ringer in order to determine the specific activity of that side. The radioactivity of the unlabeled side was always less than 0.1% of that of the labeled side. The results are presented as the average of three control periods and the average of the last three periods following addition of the drug. Samples were mixed with a modified Bray’s solution and counted in a scintillation spectrometer. Solutions

and

incubation

conditions

Unless otherwise noted, experiments were done at room temperature (23-24”) in a Trisbuffered Ringer’s solution which contained, in mM: Na+, 103; K+, 2.5; Ca2+, 1.0; Mg2+, 1.2; Cl-, 105.5; SO:-, 1.2; gluconate-, 2.0; glucose, 26; Tris-SO, buffer, 2. The solutions were bubbled with air and the pH, measured with a glass electrode, was 8.3-8.4. For experiments in Cl-free medium, SO, salts were substituted for Cl salts, and the osmolarity was adjusted with sucrose to that of the Cl-containing solutions. It was found in pilot experiments that the drugs were more active when added to the epithelial bathing solution. Therefore, except where noted otherwise, the various drugs tested were added to the epithelial solution. The local anesthetics were obtained as HCl salts, which have a,n acid reaction. Additions of up to 1 mM did not lower the pH of the Ringer by more than 0.2 pH units. For higher anesthetic concentrations, the pH of the drug solution was adjusted to 8.3 with NaOH prior to addition to the chamber. The local anesthetics used in this study were: benoxinate (Aldrich Chemical Company, Milwaukee, Wis.); dibucaine and procaine (Pfaltz and Bauer, Stamford, Conn.); etidocaine Products, Worcester, Mass.); and the lidocaine analog, &X314, (A st ra Pharmaceutical lidocaine (Elkins-Sinn, Inc., Cherry Hill, N. J.) ; mepivacaine (Sterling Winthrop Research Institute, Rensselaer, N.Y.); proxymetacaine (E. R. Squibb and Sons, Inc., Princeton, N.J.); and tetracaine (Sigma Chemical Company, St. Louis, MO.). The Ca ionophore A23187 (Eli Lilly and Co., Indianapolis, Ind.) was added in 50 ~1 of ethanol to the epithelial bathing solution to a final concentration of 10~~. In control experiments this volume of ethanol had no effect on SCC or electrical resistance. Amphotericin B (E. R. Squibb) was added to the epithelial bathing solution to a final concentration of 10 pM.

EFFECTS

OF

LOCAL

ANESTHETLCY

ON

(!ORNEA

201

3. Results Stimulatory

effects on chloride-dependent SCC

Of the local anesthetics tested, four (henoxinate, etidocaine, lidocaine and mepivacaine) had stimulatory effects on the SCC. It has been shown that 90-950;;, of this current represents active Cl transport (Candia and Askew, 1968; Zadunaisky, 1966). Within 30 set of adding the drug to the epithelial bathing solution there was typicall) a small, brief decline in the SCC, followed by a rapid rise, followed by a more gradual decline. A typical response to mepivacaine is shown in Fig. 1. The dose-responsca relationships for the stimulatory effects are shown in Fig. 2. Mepivacaine was t.he rnclc;t stimulafory. followed by lidocaine.

Minutes

Prc. 1. EfTect of 0.71 mw-mepivacaine containing Ringer.

after

drug

on short-circuit

addition

current

of a cwncx

bathed

in

chloride-

c

200

II.0

C

I

I 0-I

Drug concentration

FIQ. 2. Stimulation of chloride-dependent A, etidocaine; 0, benoxinate. statistically significant (P < 0.05).

n , lidocaine;

short-circuit Stimulation

(mu 1

current by local anesthetics. 0, mepivacaine; to 150% of control or larger was in all cases

202

l--I

20 Minutes

E B z

0

after

20

40 drug addltlon

-.-1--.

60

40

: 60

120

100 b)

e z m 5C

C

-50 Minutes

afler

drug

addition

FIG. 4. (a) Effect of dibucaine on ahort-circuit current of corneas bathed in chloride-containing a, 0.04 mns; b, 0.1 mM; C, 0.2 mM. In curve b, drug was washed out of the chamber at arrow. is from one experiment. (b) Effect of tetracaine on short-circuit current of corneas bathed containing Ringer. a, 0.067 mix; b, 0.17 mM; c, 0.33 miw; d, 0.67 mM.

Ringer. Each curve in chloride-

EFFECTS

OF

LOCAL

ANESTHETIC’S

ON

CORNEA

3U

The quaternary analog of lidocaine, QX314. had no effect on the electrical parameters when added to the epithelial bathing solution at concentrations as high as 7 11lM. However, when added to the endothelial bathing solution, 7 mM QX314 caused a 33”,, stimulation of the SCC. The effects of these drugs on C1 fluxes were not measured because of the relativeJ,v short, duration of the stimulatory phase. However, all these anesthetics failed to havn any effect on electrical parameters of corneas bathed in Cl-free solut.ions, indicatjirrg that the stimulation of the SCC was Cl dependent. At, higher concentrations and/or at longer incubations. all of these drugs show~~l inhibitor,v effects as well (see below). The inhibitory effect overwhelmed the st8imrtlatc jr\. effect of benosinate (Fig. 3) to t,he extent t,hat at O-5 tnM the latt.er effect was >si(tlll(‘tinletw barely d&ect’ahle as a plateau in the decline of the WC’.

Drug concentrotlon

(mM)

The four local anesthetics not mentioned in the previous section showed no intlic:atiorl of an,v stiruulatory action on the Cl-dependent SC(‘. The inhibitory responsesto added drug were almost8immediate, the decline in the SW beginning IO.-30 set after t~he clrug was added. Typical responsesto dibucaine and tetracaine are shown in Fig. -2. In general. the effects on the SCCwere not reversed lvhen the drug-containing bathing solutiorls were replaced with drug-free bathing solutions. After very short incubatiotjs with dibucaine (the only drug tested in this manner) the SCC!was partially r~store~l upon drug removal, as indicated in Fig. 4(a). As shown in Fig. 5, dihucaine was the most potent inhibitor tested, with an IDB,, of about 0.040 ~IIVI. Benoxinate and tetracaine had approximately equal LLjs,‘s of >bl)outa 0.25 I11M. The other local anesthetics had ID,,‘s of greater than 1 rn~. As mentioned above, the stimulatory local anesthetics were also inhibitory at longer incubation times or at higher concentrations than those required for stimulation. Eflects orbtranscorneal electrical resistancein XaCl Ringer All the stimulatory local anesthetics caused a reduction in transcorneal electrical resistance during the stimulatory phase. The reduction in resistance was always less than the increase in the SCC, however, so that the open circuit p.d. rose also.

21 I4

H. F. SCHOEN

AND

0. A. (‘ANl,l~\

Inhibitory effects on the SW were accompanied by either an increase. a tl(>(:reibsra. or no change in resistance (Table I). Upon prolonged incubation (longer than 60 min) with the higher concentrations of tetracaine and dibucaine, the resistance often fell tcl very low levels. This low resistance was usually still higher than that oftleepit.holializc~ti corneas (Candia, 1972) and it sometimes rose considerably upon washinp out of thtb drug.

Effect of loud anesthetics ON,transcorrzeal electrical ~resistmnce Time

0~10 0.25 0~50

(6)

0.040 0.10 0.20

(7)

0,016

(2)

0.16 0.50 14

(6)

Lidocaine

0.074 0.71 4.1

(4) (5) (W

Mepivacaine

0.071

(2)

Dibucainc

0.71 3.6 7.1

2;;

(4) (2)

(5) (4) (4)

I4 10

(4) (4)

Proxymetacaine

I.0 10

(5) (4)

042l 0.067 0.17 0.33 0.6i

(2)

(5) (4) (6) (5)

* Per cent of control, mean & S.E. 7 Significant at the level of 5% or less by paired

Inhibitory

drug atlditiou

1:;

Procaine

Tetracaine

after

t-t,est,.

effect on chloridejuxes

Dibucaine was the most potent inhibitory levels caused a fairly mode of action of dibucaine was the unidirectional Cl fluxes. The

of the anesthetics tested and, at less than completely stable increase in the transcorneal resistance. The investigated more fully by measuring the effect on results are shown in Table II.

EFFECTS

OF

LOCAL

ANESTHETIC’S

ON

CORNEA

205

It can be seen that the forward (aqueous side to tear side) Cl fluxes declined from an average of 0.59 to 0.24 pEq/h r . cm2, a decline of 0.35 pEq/hr . cm2. The average SCC of these experiments decreased from 0.44 to 0.07 pEq/hr * cm2, a change of Ok pEq/hr * cm2. Thus, the decline in the SCC is fully accounted for by the decline in forward Cl fluxes. This is confirmed by the fact that there was a very small, although statistically significant. effect on the backward (tear to aqueous) fluxes. TABLE

[I

Efect of 0.1 mM dibumim

‘,I = 5 Forwartl

flux

SW .n =z

0.59*0.05

0.24 * 0.02

0.44+0.05

0~07*042

-n.37f0.03*

().$jg)f)p*

0.34+0.05 0~28+0~03

0~30*0~04 0.04 ~042

--0~04*0~01* --w24*042*

6

Racltwsrd

flus

SCY ’

* Significant

Interactions

OH C1Jlrrw.s

at the

level

of 26:/,

or less

by pired

t-test.

usitlzcalcium

The (la ionophore A23187 has been shown to stimulate Cl transport in the bullfrog cornea. 10pM causing an approximate doubling of the SCC in Cl-containing Ringer (Candia et al.. 1977). A23187 had no effect on the SCC when added to a dibucaineinhibited cornea with zero SCC.Where there was still a residual SCC,A23187 approximately doubled this to a level that was still far below the control SCC. When mepivacaine was added at the peak of the Ca ionophore response,it never causedany further stimulation, but rather caused someinhibition of the SCC. When (la ionophore was added at the peak of the mepivacaine response,the results were variable; usually, but not always, there was a further stimulation. After the mepivacaine-stimulated SCC had returned to a steady state level, addition of (‘a ionophore sometimesgave a stimulatory responsesimilar to that seenin corneas not pretreated with the local anesthetics (Candia et al.. 197T) although sometimesth.e stimulation was much lessthan normal. High concentration of Ca (11 nlM) appeared to protect the cornea from the inhibitory effect of dibucaine, but only slightly. Effects on sodiwv~~ transport

in chloride-free Ringer

When the bullfrog cornea is incubated in Cl-free Ringer, the SCCdeclines to a very low level. This SCC reflects the low rate of net Na transport (Candia and Askew. 1968). Tetracaine (a Cl transport inhibitor) either had no effect on this low SCC, or caused a slight reduction in the already low SCC to closer to zero. Mepivacaine (a Cl transport stimulant) had no effect on this SCX’. The small SCC in Cl-free Ringer can be greatly increased by adding 10~~ amphotericin B to the epithelial bathing solution (Candia: Bentley and Cook, 1974). The effect of 0.71 mM mepivacaine on such Na-transporting corneas was variable.

‘OR

H. F. SC’HOEN

AS11

0. A. C:AiYDlA

Out of nine corneas. the drug caused a mean stimulation of the Na-tiel~endcnt~ 8(~‘(’ of 480/h in six corneas, but, no stimulation at all in the remaining three corneas. l’etracaine and dihucaine were lesspotent inhibitors of this stimulated Na S(‘(’ thall of the Cl-originated S(!C in NaC’l Ringer. Although some inhibition was m m at. t,he lower concentrations, greater than a0 r ?;, inhibition occurred onlv st those cc)nceIltrations that, also caused a large reduction in electrical resistance. 4. Discussion Inhibition.

of uctive chloride

transport

Most of the well-characterized biological effects of local anesthetics appear to be due to an inhibition of passiveion transport (Seeman,1972). In the caseof blockage of nerve impulse transmission, the effect seemsto be due to direct action of the anesthetics on Na and K permeahility (Hille, 1977; Narahashi, Frazier and Takeno, 1976; Shanes. Freygang, Grundfest and Amatniek, 1959) while in other systems the observed biological effect appears to be secondary to the inhibition of membrane permeabilit,v to Ca (Douglas and Kanno, 1967; Feinstein and Paimre, 1969; Rubin et al., 1967).

Comparison

of relative

potencies

Block Bennett et al. (1942)

Procaine iMepivacaine Lidocaino Tetracaine Dibucaine

1

167-200

of nerve Skou (1954)

(procaine

=

1) of

action potential Rosenberg and Ehrenpreis (1961)

1

1

350- 575 765-1530

135

local anesthetics

Truant and Takman (1965)

1 2.1 34 31 SC 54

ID for WC &” ’ in bullfrog cornea

1 34 t5.6 37 “50

The active Cl transport of the bullfrog cornea1epithelium is one of many systems that appear to be stimulated hy increasesin intracellular Ca concentration (Candia et, al., 1977). Thus, it would seem reasonable to propose that the inhibition of active Cl transport by local anesthetics described in this paper is due to a blockage of intracellular Ca movement. However, the failure of the Ca ionophore A23187 to effectivelr reverse the inhibition argues against this explanation. Two other possibleexplanations of the inhibitory effect exist. One is a direct effect of the local anesthetics on the passive pathway of Cl movement in series with the active Cl pumping mechanism. The other is an inhibition of the pump mechanism itself. Inhibitory effects of local anesthetics on Na,K-ATPase have been reported (Bond and Hudgins, 1976,1977; Seeman,1972).However, the dosesreportedly required for enzyme inhibition are considerably higher than those required for nerve block whereasthe inhibitory effect on active Cl transport occurs at concentrations similar to those required for nerve block (Skou, 1954; Truant and Takman, 1965). Moreover,, ouabain, which inhibits Cl transport in the cornea, produces an increase in the hack-

EFFECTS

OF

LOCAL

ANESTHETICS

OK

CORNEA

207

ward Cl fluxes (Candia, 1972) whereas dibucaine produces a small reduction. Thus it seems most likely that in the cornea the local anesthetics inhibit active Cl transport through a reduction of Cl permeability. While the potency of any local anesthetic on nerve impulse transmission varies considerably depending on the method of defining nerve block, the nature of the biological material, and the pH, a reasonably consistent pattern of relative potency can be discerned. Some relevant data are summarized in Table III, along with the relative potencies determined for 50% inhibition of the SCC in frog cornea estimated from Fig. 5. It is evident that there is a correspondence between the effect on nerves and the effect on SCC in frog cornea, which suggests that the inhibitory effects of the local anesthetics on the Cl-dependent SCC of the cornea have some relation to the inhibitory effects on the cation-dependent functions of nerve. Stimdation

of active chloride

transport

Although Cl transport was not measureddirectly in these experiments, the stimulation of the SCCcaused by benoxinate, etidocaine, lidocaine. mepivacaine, and QX314 is assumedto be due to a stimulation of net Cl transport since no effect on the SCY was seenin Cl-free Ringer in the absenceof amphotericin B. The dual effect seenin R. catesbeianacornea with someof the tested local anesthetics is rentiniscent of that reported in R. esculmtclskin by Skou and Zerahn (1959), who observed that procaine could both stimulate and inhibit net Na transport, depending on concentration and on which side of the skin the drug was applied. Their data strongly suggestedthat the receptor for the etimulatory effect was located on the surface of the skin epithelium while the site of the inhibitory action was at a deeper layer. In the cornea, an action at the tear surface of the cornea1epithelium seemsto be ruled out by the failure of QX314 to stimulate except when added to the endothelial side bathing solution. Two possibleexplanations may be proposed for the stimulatory effect. One is that the stimulatory local anesthetics displace Ca from membranes thereby raising the intracellular concentration of Ca and indirectly stimulating active Cl transport. An increase in intracellular Ca concentration is the explanation proposed for the stimulatory effect on the SCC of the Ca ionophore (Candia et al., 1977). The Ca-displacing effects of local anesthetics occur at concentrations that are sometimes considerably below the concentrations required for nerve block (Feldman and Weinhold, 1977: Seeman, 1972), as do the SCC-stimulating effects we observed in the cornea. The other possibility is that the tertiary amine local anesthetics may mimic the action of some natural stimulatory hormone (or block the action of an inhibitory hormone) on the cornea1 epithelium. In this regard it is suggestive that the local anesthetics in their cationic forms bear someresemblancein structure to acetylcholine (Ritchie, 1971). Acetylcholine is present in large amounts in the cornea1epithelium (Barber, 1974). Inhibitiorb of active Na transport In the amphotericin-treated cornea, Na enters the epithelial cells via an artificiallycreated passive pathway and is actively transported out of the cells by a Na, K-ATPase-related pump (Candia et al., 1974). The inhibition of this Na transport by local anesthetics could be due to an action on either the passive portion or the active portion of this pathway. Local anesthetics have been shown to disrupt artificial

208

H.

F. SC’HOES

AS

II

0.

A. (‘AS

1)1X

membranes such that the effectiveness of antibiotic ionophores in increasing 1tten1hrane permeability is reduced (Papahadjopoulos, 1972). As noted above, local U,IIUSthetics have also been shown t#oinhibit Na.K-ATPase, hat at higher eoncentrat ic,lls than those causing nerve block. C70mparison

of tetracaine

experiments

witl~

those

,in Ilbe

rctbbit cornea1

epitheliwt~

Mention should be made about the seemingly coptradictory results obtained l)y Burstein and Klyce (1977) with tetracaine on the isolated short-circuited rabbit cornea. These authors found that tetraeaine stimulated the SC’C. except at doses greater than 0.33 111M. Furthermore, it reduced the open circuit pd. In our results with the frog cornea, those local anesthetics that stimulated the SU’ also stimulated the p.tl., although to a lesser extent. Moreover, tetracaine \vats never titimulatory. While the difference from our results could he due to the presence of 20 tn>I-Tris (which has somestructural similarity to local anesthetics) in their Ringer as opposed to only 2 rnnf in ours, it seemsmore likely that the difference in effect of tetraoaine reflects a speciesdifference between frog and rabbit in the functional organization of the cornea1epitheliom. ACKNOWLEDGMENTS

The authors thank Astra Pharmaceutical Products, Sterling Winthrop Research Institute, E. R. Squibb and Sons,and Eli Lilly and Co. for their generousgifts of someof the drugs usedin this study. The researchwas supported by NIH Grants EY 0016~and EY 01867.Howard F. Schoenisa Postdoctoral Traineesupportedby NIH Grant EY 0’7014. A preliminary account of this work was presentedat the Spring, 1977, meeting of the Association for Researchin Vision and Ophthalmology. REFERENCES Barber, G. W. (1974). Physiological chemistry of the eye. Arch. Ophthalmol. 91, 141-59. Behrendt, T. (1956). Experimental study of cornea1 lesions produced by topical anesthesia. Am. J. Ophthalmol. 41,99-105. Bennett, A. L., Wagner, 5. C. and McIntyre, A. R. (1942). The determination of local anestheticpotency by observation of nerve action-potentials. J. Pharmacol. h’xp. Ther. 75, 125-36. Bond, G. H. and Hudgins, P. M. (1976). Inhibition of ATPase activity in human red cell membranes by tetracaine. Biochem. Pharmacol. 25, 267-70. Bond, G. H. and Hudgins, P. M. (1977). Irreversible inactivation of human red cell ATPase activity by tetracaine. Biochem. Phurmacol. 26, 2241-5. Burstein, N. L. and Klyce, S. D. (1977). Electrophysiologic and morphologic effects of ophthalmic preparations on rabbit cornea epithelium. Invest. Ophthalmol. Vis. Sei. 16, 899-911. Candia, 0. A. (1972). Ouabain and sodium effects on chloride fluxes across the isolated bullfrog cornea. Am. J. Physiol. 223, 1053-7. Candia, 0. A. and Askew, W. A. (1968). Active sodium transport in the isolat.ed bullfrog cornea. Biochim. Biophys. Acta 163, 262-5. Candia, 0. A., Bentley, P. J. and Cook, P. I. (1974). Stimulation by amphotericin B of active Sa transport across amphibian cornea. Am. J. Physiol. 226, 143844. Candia, 0. A., Montoreano, R. and Podos, S. M. (1977). Am. J. Physiol.: Renal Fluid Electrolyte PhysioE. 2, 94-101. Douglas, W. W. and Kanno, T. (1967). The effect of amethocaine on acetylcholine-induced depolarization and catecholamine secretion in the adrenal chromaffin cell. Br. J. Phapmncol. Chemother. 30, 612-19. Epstein, D. L. and Paton, D. (1968). Keratitis from misuse of cornea1 anesthetics. New England J. Med. 279, 396-9.

EFFECTS

OF

LOCAL

ANESTHETICS

ON

CORNEA

“o!+

Peinstein, M. B., Fiekers, J. and Fraser, C. (1976). An analysis of the mechanism of local anest’het’ir inhibition of platelet aggregation and secretion. J. Pharmacol. Exp. Ther. 197,215-28. Peinstein, M. B. and Paimre, M. (1969). Pharmacological action of local anesthetic8 on excitationcontraction coupling in striated and smooth muscle. Fed. Proc. 28, 1643-8. Feldman, D. A. and Weinhold, P. A. (1977). Calcium binding properties of rat heart plasma membrane and inhibition by structural analopues of n.r,-propranolol. Biochem. Phormncol 26.2283-Y. Hille. B. (1977). Local anesthetics: Hydrophilic and hydrophobic pathways for t,he drug-receptor rea&on. J. &n. Physiol. 69,497-515. Narahashi, T.. Frazier. D. T. and Takeno, K. (1976). Effects of calcium on the local anesthetic suppression of ionic conductances in squid axon membranes. J. PharmnaoZ. Exp. Th,w. 197, 426-38. Papahadjopoulos. D. (1972). Studies on the mechanism of act,ion of local anesthetics with phospholipid model membranes. Biochim. Biophys. Acta 265, 169-86. Paste, G., Papahadjopoulos, D., Jacobson, K. and Vail, W. J. (1975). Effect8 of local anesthetics on membrane properties III. Enhancement of susceptibility of mammalian cells to agglutinat ion by plant lectins. Biochim. Biophys. Acta 394,520-39. Ititchie. J. M. (1971). The mechanism of action of local anesthetic agents. In International hh?/dopedin of Pharmacology and Therapeutics (Ed. Lechat, P.). Section 8. Local Anesthetics. Vol. 1. pp. 131-66. Pergamon Press, Oxford. Rosenberg. P. and Ehrenpreis, 6. (1961). Reversible block of axonal conduction by curare after treatment’ with cobra venom. Biochem. Pharmncol. 8, 192-206. Rubin, It. P., Feinst,ein, M. B., Jaanus, S. D. and Paimre, M. (1967). Inhibition of catecholamine secretion and caalcium exchange in perfused cat adrenal glands hp tet,racaine and magnesium. J. Pharmncol. Exp. Ther. 155, 463-71. Seeman, I’. (197%). The membrane actions of anesthet,irs and tranquilizers. Phtwnncol. Rev. 24, Xx-65.5. Shams. 4. 31.. Freygang, W. H., Grundfest, H. and Amatniek, E. (1959). Anesthetic and (Xalc%tt action in the voltage clamped squid giant axon. J. Gen. Physiol. 42, 793-802. Skou. J. C. (1954). Local anaesthetics I. The blocking potencies of some local anaesthetics and of butyl alcohol determined on peripheral nerves. ilcta Phurmncol. Tosicol. 10, 281-91. Skou. J. C. and Zerahn, K. (1959). Investigations on the effert of some local anaesthetics and other amines on the active transport of sodium through the isolated short-circuited frog skin. Ijiochim. Biophys. Beta 35, 324-33. Truant, A. P. and Takman, B. (1965). Local anesthetics. In llrill’s Pharnuology in Medicinr, 3rd ed. (Ed. DiPalma, J. R.). Pp. 133-56. McGraw-Hill, New York. Sidney and London. Zadunaisky, J. A. (1966). Active transport of chloride in frog cornea. Am.. J. Physiol. 211,506-12.

Effects of tertiary amine local anesthetics on ion transport in the isolated bullfrog cornea.

Exp. Eye Res. (1979) 28, 199-209 Effects of Tertiary Amine Local Anesthetics on Ion Transport in the Isolated Bullfrog Cornea HOWARD F. SCHOEN AND O...
769KB Sizes 0 Downloads 0 Views