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Year : 1971  |  Volume : 19  |  Issue : 4  |  Page : 145-154

Aspirin inhibits oculo-tensin and prevents rise of eye tension

From, the Oxford University Departments of Pharmacology and Physiology; the National Institute for Medical Research, Mill Hill, London, U.K; & the Sola. Hakim Medical Research Centre, 249 Dr. D. Naoroji Rd., Bombay, India

Correspondence Address:
Sohrab A.E Hakim
From, the Oxford University Departments of Pharmacology and Physiology; the National Institute for Medical Research, Mill Hill, London, U.K; & the Sola. Hakim Medical Research Centre, 249 Dr. D. Naoroji Rd., Bombay, India

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How to cite this article:
Hakim SA. Aspirin inhibits oculo-tensin and prevents rise of eye tension. Indian J Ophthalmol 1971;19:145-54

How to cite this URL:
Hakim SA. Aspirin inhibits oculo-tensin and prevents rise of eye tension. Indian J Ophthalmol [serial online] 1971 [cited 2020 May 28];19:145-54. Available from: http://www.ijo.in/text.asp?1971/19/4/145/34974

  Preliminary Communication II Top

In the Preliminary Communi­cation I, the author showed that injection of 0.1 mg sanguinarine into the third ventricle of the brain of cats produced a rise of eye tension averaging 13.6 mm Hg., and sustained for nearly two hours. During these two hours, a ciliary-iris hormone is present in the aqueous. This hormone can be continually washed out by perfusing the anterior chamber with saline through a special needle. The saline wash, containing the hor­mone, when dripped onto the eye of another (recipient) cat, raises its eye tension. The hormone was named "oculo-tensin", and considered to be most probably identical with prostaglandin F2a. (Hakim [20]).

Cat Oculo-tensin Raises Human and Monkey Eye Tension

To approximate the effects of cat's oculo-tensin to the problem of human eye tension, the saline washing from donor cat's eyes, after injecting sanguinarine, was dripped onto one eye of recipient rhesus monkeys or human volun­teers. This raised eye tension both in monkeys and man.

Prostaglandins and Aspirin

The prostaglandins were dis­covered 36 years ago as active seminal substances (von Euler 9). Their subsequent separation, de­tection in many parts of the body and marked activity soon placed them amongst the leading pro­blems in physiological, pharmaco­logical and clinical research throughout the world (Pickles 26; Bergstrom and Samuelison [7] ; von Eulecs and Eliasson [10] ; Horton [21] ; Ramwell [26] ; Karim [2] ).

Professor J. H. Burn, who has initiated and guided the author's pharmacological re­searches on argemone oil and sanguinarine at Oxford since 1951 (Hakim[13],[14]), reviewing the

above preliminary communica­tion, suggested that since aspirin was known to neutralise the effects of prostaglandins, experi­ments should be made to deter­mine if aspirin could inhibit san­guinarine from liberating prosta­glandins into the eye, and thereby prevent its eye tension raising action (Burn, [8] ). This remarkable suggestion has been fully confirm­ed by the experiments reported in this communication, which strongly support the author's view that oculo-tensin is identi­cal with prostaglandin F2a, and is the master-key to the mechanism of both normal and pathological eye tension. The following 200 experiments on cats, show how eye tension was raised by sangui­narine or codeine, and also how this can be prevented or abolish­ed by aspirin.

Rise of Eye Tension with Sanguinarine

Cats were anaesthetized with pentobarbitone sodium i.p., and the eye tension recorded four times in both eyes at intervals of 15 minutes with a Schiotz's tono­meter (+ 5.5g) to determine its basic level. The most frequent reading was between 14.6 and 17.3 mm Hg, but ranged from 20.6 to 7.1 mm Hg. In cats, the tonometric values are very close to the manometric levels. In this communication, the emphasis is not on the absolute value, but in the change in eye tension. The tension was then raised by in­jecting sanguinarine either into the brain, as in the Preliminary Communication I, or by intra­venous injection. For brain in­jection, sanguinarine chloride was diluted in iso-electric brain saline and 20 mg in 0.1 ml inject­ed five times through the cannula leading into the third ventricle (Feldberg and Sherwood[11],Hakim[15],[16], [19] ), at intervals of 15 min., in 20 cats. The average rise of tension was 7.8 mm Hg. (max 11 mm, min 5 mm), the maximum reached in 120 min, and the level returning to basic in 200 min. [Figure - 1], In all experiments on cannulated cats, the animals were tested a few days previously by injecting sanguinarine through the cannula, to be certain of the tension response. The opening of the cannula into the third ven­tricle was verified by injecting a dye through it, post mortem, and sectioning the brain.

Prof. Burn advised that san­guinarine should also be tried intravenously, to confirm the similarity of its action by both routes. In 10 cats, sanguinarine chloride 10 mg in 100 ml saline was slowly injected into the saphenous vein. This produced a rise of eye tension averaging 5.3 mm Hg (max 9.8 mm, min 5.1. mm), the maximum reached in 75 min and the basic level resumed in 200 min. [Figure - 1]. shows the rise produced by both routes. Although 100 times more sanguinarine was given by the intravenous route. the rise in eye tension was higher and more prolonged by brain in­jection. This further supported the author's earlier experiments Hakim [16],[19] ) that the hypothal­mic areas adjoining the lateral walls of the third ventricle, are the target areas stimulated by sanguinarine and monitor the rise of eye tension.

Aspirin Lowers Eye Tension:

Cats were anaesthetized and given aspirin by one of three routes. (i) Aspirin 400 mg/kg was suspended in water and introduc­ed into the stomach through a stomach tube in 10 cats, (ii) aspi­rin was dissolved in iso-electric brain saline and 1 mg in 0.1 ml injected into the brain of 10 cats, and (iii) aspirin was suspended in saline, 25 mg/ml, with a little gum acacia and instilled every minute as eye drops in 5 cats.

Aspirin produced a fall in eye ten­sion [Figure - 2]. Aspirin by stomach produced an average fall of 6.7 mm Hg. in 105 min, returning to normal in 175 min. By brain in­jection, the fall was 5 mm, reach­ing a maximum in 60 min and nor­mal in 150 min. Aspirin had to be continually given as eye drops for 120 min to sustain a fall of 4.8 mm, which rapidly returned to normal in 40 min. The maximum lowering effect was by stomach, but the large dose did not justify comparison with the brain route. The eye drop technique requires buffering, as aspirin irritates the cornea. The effects are seen in [Figure - 2].

The hypotony produced by aspi­rin suggests that the normal eye is constantly producing a basic quantum of prostaglandin, which is essential for maintaining a nor­mal degree of constrictive tone in the aqueous outflow channels, and whereby sufficient back-pressure maintains the basic tension in the anterior chamber of the eye.

Aspirin followed by Sanguinarine:

Aspirin was given first by stomach tube to 5 cats and by brain injection to 5 cats. After 60 min, sanguinarine was given by brain injection to 6 of these cats and by intravenous injec­tion to 4. The predominant effect was a fall in eye tension, the average by both routes was 8.2 mm Hg., (max 12 and min 4.3 mm), the maximum fall occurring in about 50 min., and returning to normal in 150 min.

Sanguinarine Followed by Aspirin:

In another group of cats, san­guinarine was injected first in 20 cats by brain and in 10 intra­venously. The tension rose, and was recorded every 15 min for one hour. Thereafter, aspirin was given by stomach to 20 of these cats, and by brain to 10. By either route, aspirin prevented the tension from rising further and rapidly produced a fall in ten­sion well below the original basic level. Greater hypotony was produced by aspirin given by stomach. [Figure - 3] illustrates the effects of this experiment, and clearly illustrates aspirin antagonising the effects of sanguina­rine. For comparison, a curve of the sanguinarine effect, without aspirin, is included.

Aspirin Effects due to Inhibition of Oculo-tension:

Three groups of experiment were done to demonstrate that the antagonism of sanguinarine by aspirin, was in reality the anta­gonism of oculo-tensin by aspirin. These were possible by the double-cat technique (Hakim [20] ).

Aspirin Prevents Formation of Oculo-tensin:

Aspirin was given to 10 donor cats by brain and 5 by stomach. After one hour, sanguinarine was injected in ten of these by brain and in 5 intravenously. There was a fall in tension, averaging 6.2 mm Hg in these donor cats, pro­bably because aspirin had pre­vented the formation of oculo­tensin. The saline wash from one eye of each donor cat was drip­ped during the entire experiment on one eye of a recipient cat. There was no rise of tension in the eyes of any of the recipient cats, since the washings from the donors did not contain oculo­tensin.

Aspirin Stops further formation of Oculo-tensin:

Sanguinarine was injected into 10 cats i.v. and in 15 by brain. The tension was allowed to rise for 60 min. Thereafter, aspirin was given to each of these cats, either by mouth or by brain in­jection. The raised tension preci­pitiously fell to normal and con­tinued to fall below normal. It was assumed that the formation of oculo-tensin was halted. By leading the eye wash from each of these donor cats to 25 untreat­ed recipient cats, the latter show­ed a small parallel rise, during the time the tension was rising in the donor cats, due to oculo­tensin from donor to recipient. Again when the tension fell in the donor cats, it also fell in the recipient cats, as no further oculo-tensin was transmitted. The experiment is illustrated in [Figure - 4].

Aspirin Neutralises Oculo-tensin Already Formed.

Sanguinarine was injected in 10 donor cats i.v., and in 10 by brain. The tension rose and fell in the usual manner. During the experiments, the eye wash from each donor cat was dripped on one eye of 20 recipient cats, all of which had received an injection of aspirin in the brain. The reci­pient cats, because they had re­ceived aspirin, did not respond by the normal rise of tension from the oculo-tensin, but showed hypotony. The formed oculo­tensin from the donor cats was neutralised by aspirin given to recipient cats. This is illustrated in [Figure - 5].

Codeine, Sanguinarine and Aspirin on Eye Tension:

Sanguinarine, the glaucoma­genetic alkaloid in argemone seed oil, is also the commonest alkaloid in probably all 700 spe­cies of prolific poppy-fumaria weeds (Hakim [17]). It is directly available to man through medi­cinal herbs and some poppy seeds, and indirectly through milk, flesh and eggs of animals that have grazed on poppy pas­tures (Hakim[8]). This author found sanguinarine in the opium plant and a related alkaloid in opium. Codeine, like sanguina­rine is also an iso-quinoline alka­loid associated with opium and other poppies, and important be­cause of its frequent human con­sumption. It raised eye tension by brain injection (Hakim[19]).

Codeine phosphate was pre­pared like sanguinarine, and 1 mg injected into the brain of 21 cats. This produced a rise of eye ten­sion upto 8.5 mm Hg., reaching maximum in 60 min and return­ing to normal in 120 min. In another five cats, codeine and aspirin were both injected into the brain. Aspirin prevented the rise of eye tension. Three donor cats were injected codeine into the brain, and the eye wash from each dripped upon one eye of three untreated recipient cats. Eye tension was raised in both donor and recipient cats, confirm­ing the release of oculo-tension by codeine, as with sanguinarine. Ten times more codeine was re­quired to raise eye tension than sanguinarine. It is interesting to compare the graphs of raised eye tension produced in rabbits by intravenous injections of sangui­narine or codeine hydrochloride by Leib Scherf[24] and recorded by electronic aparatus. The ele­vation and duration of raised ten­sion was far higher with 4 mg sanguinarine than with 30 mg codeine.

Opium Smoke Inhalation Raises Monkey Eye Tension:

A group of monkeys was made to inhale smoke from 50 mg opium. The opium was dissolved in water, dried on sand and heat­ed in a test tube. A stream of air blew the smoke through poly­thene tubes into the nostril of the monkeys. Within 5 to 10 minutes, there was a small fall in eye tension. This was followed by a prolonged rise. This also occur­ed in a human volunteer.

Pharmacology o f Eye Tension:

Ambache extracted from rab­bit irises a pharmacologically active chemical called "irin", and showed that it was released into the aqueous by mechanical sti­mulation of the iris, and that it produced rise of eye tension and dilatation of the pupil. Irin is a mixture of prostaglandins E 2 and F 2 a. Both these prostaglan­dins have been found in the cat's iris (Ambache[1],[2],[3],[4]).

Different prostaglandins have totally different physiological effects (Bergstrom, Carlson and Weeks[6]). Waitzmann and King[30] found that prostaglandins E l and E 2 injected intravenously in cats, raised their eye tension and lowered their blood pressure, but, when injected into the eye, pro­duced miosis and insignificant rise of eye tension. In rabbits, E l and E2 injected into the eye, produced miosis and marked rise of eye tension, whilst even a thousand-fold dose of F l a, pro­duced miosis but no rise of eye tension.

In order to substantiate that oculo-tension is a prostaglandin, and that it is prostaglandin F 2 a many experiments are being con­ducted in this laboratory. Sheep irises contain prostaglandin F 2 a (Anggard and Samuelsson [5]). Fresh sheep irises are ground with saline (1/5th iris/ml) and filtered. Half of this crude ex­tract is acidified with HCL to pH 3, extracted with ether, and the ether evaporated. The trace residue taken up in pharmacolo­gical saline, produced marked contraction of a special duodenum preparation used in this labora­tory. The remainder of the crude iris extract is incubated for 30 minutes with aspirin 0.1-..2 mg/ ml. It is then extracted with ether and tested as above. Aspi­rin, 0.1 mg/ml reduced the con­traction by 50% whilst 0.2 mg/ml produced total inactivation. This method for extracting, puri­fying and testing crude iris ex­tracts is practically specific for prostaglandins (Ambache[1],[2],[3],[4]); Gilmore, Vane and Wyllie [12] ) . Further details will be published later.

Prostaglandins and the Uterus:

Observation on the active con­traction of the human uterus by contact with human semen in 1930 (Kurzrok and Lieb 23) re­sulted in the discovery of the prostaglandins. Today, prosta­glandins are being clinically used for therapeutic abortions (Karim [22] ). It is interesting that abortions have often been record­ed in human Argemone oil poison­ing, probably by the release of prostaglandins by the sanguina­rine in argemone oil. Experi­mental confirmation from this laboratory will be published else­where.

Aspirin Now Found to Inhibit Synthesis o f Prostaglandins in Many Tissues:

After the above experiments were completed, the author was glad to receive three recent con­firmatory publications by Vane [27],[28],[29] and his colleagues in London, on the inhibition of prostaglandins in the guinea-pig lung, dog spleen and human blood platelets, by aspirin, indometha­cin, etc. These valuable experi­ments showed that prostaglandin release can be often equated with its synthesis and that aspirin and indomethacin quantitatively in­hibited the synthesis of prostaglandins E 2 and F2 a. These authors suggest that the action of aspirin, indomethacin and other similar drugs as antipyretics, analgesics, anti-inflamatory and anti-rheumatic agents are due to the inhibition of prostaglandins. These experiments indirectly yet completely support the findings reported in this communication and the identity of oculo-tensin with prostaglandin.

I wish to thank Professor J. H. Burn, FRS for his guidance on the pharmacology of sanguinarine since 1951 and for his invaluable suggestion on aspirin counteract­ing sanguinarine. This work has been possible through the guid­ance from the Nobel Laureates Sir Robert Robinson PRS and the late Sir Henry Dale PRS; Sir Stewart Duke-Elder FRS, Dr. W. Feldberg FRS, the late Sir Edward Mellanby FRS, Dr. Lady May Mellanby Sc.D., and many others.

  References Top

AMBACHE, N. Properties of Irin, a physiological constituent of the Rabbit's Iris. J. Physiol., Lond., 135, 114-132, 1957.  Back to cited text no. 1
AMBACHE, N. Further studies in the preparation, purification and nature of Irin. J. Physiol., Lond., 146, 255-294, 1959.  Back to cited text no. 2
AMBACHE N. KAVANAGH, L. & WHITING, J. Effect of Mechanical Stimulation on Rabbit's eyes: re­lease of active substance in ante­rior chamber perfusates, J. Physiol. Lond., 176, 378-403, 1965.  Back to cited text no. 3
AMBACHE, N., BRUMMER, H. C., ROSE J., & WHITING, J. Thin­ layer chromatography of spasmo­genic unsaturated hydroxy-acids from various tissues. J. Physiol., Lond., 185, 77-78 P. 1966.  Back to cited text no. 4
ANGGARD, E. & SAMUELSSON, B., Smooth muscle stimulating lipids in sheep Iris. The identifica­tion of Prostaglandin F2a. Bio­chem. Pharmac. 13, 281-283. 1964.  Back to cited text no. 5
BERGSTROM, S. CARLSON, L. & WEEKS, J. The Prostaglandins: a family of biologically active lipids. Pharm. Rev. 20, 1-48, 1968.  Back to cited text no. 6
BERGSTROM, S. & SAMUELSSON, B. Editors. Prostaglandins. Second Nobel Symposium. Almqvist & Wilksell, Stockholm. 1967.  Back to cited text no. 7
BURN, J. H. Guidance and per­sonal communications. 1951-1971.  Back to cited text no. 8
von EULER, U. A depressor sub­stance in the vesicular gland. J. Physiol.. London, 84, 21 P. 1935.  Back to cited text no. 9
von EULER, U. & ELIASSON, R. Prostaglandins. Acad. Press. New York. 1968.  Back to cited text no. 10
FELDBERG, W. & SHERWOOD, S. A permanent Cannula for In­traventricular Injections in cats. J. Physiol., London., 20, 3P. 1953.  Back to cited text no. 11
GILMORE, N., VANE, J. & WYL­LIE, J. Prostaglandins released by the Spleen. Nature. 218, 1135. 1965.  Back to cited text no. 12
HAKIM, S. The Biological Action of Argemone Oil. D. Phil. Thesis. University of Oxford. 1953.  Back to cited text no. 13
HAKIM, S. Argemone Oil, Sangui­narine & Epidemic Dropsy Glau­coma. Brit. J. Ophthal. 38, 103-216. 1954.  Back to cited text no. 14
HAKIM, S. Extraction & Detection of Poppy Alkaloids. J. Physiol., Lond., 138, 8 P. 1957 a.  Back to cited text no. 15
HAKIM, S. Poppy Alkaloids & Glaucoma. J, Physiol., Lond., 138 41 P. 1957 b.  Back to cited text no. 16
HAKIM, S. MIJOVIC, V. & WAL­KER J. Distribution of certain Poppy-Fumaria Alkaloids & a Possible Link with the Incidence of Glaucoma. Nature, 189 , 198-201. 1961 a.  Back to cited text no. 17
HAKIM, S. MIJOVIC, V. & WAL­KER J. Experimental Transmission of Sanguinarine in Milk. Detec­tion of a Metabolic Product. Nature, 189, 201-204. 1961 b.  Back to cited text no. 18
HAKIM, S. Sanguinarine & Hypo­thalamic Glaucoma. J. All-India Ophthal. Soc. 10, 83-102, 1962.  Back to cited text no. 19
HAKIM, S. Ciliary-Iria Hormone Regulates Eye Tension. J. All­ India Ophthal. Soc. 18 , 143-149. 1970.  Back to cited text no. 20
HORTON, E. Hypotheses on physiological role of prostaglan­dins. Physiol. Rev. 49, 127-161. 1969  Back to cited text no. 21
KARIM, S. Effects of PGs E 2 & F 2 a on uterine activity and cardio­vascular system, J. Obstet. Gynaec. Br. Commonw. 77, 200-210, 1971.  Back to cited text no. 22
KURZROK, R. & LIEB, C. The Action of Semen on the Human Uterus. Proc. Soc. Exp. Biol, Med, 26, 268-272, 1930.  Back to cited text no. 23
LIEB, W. & SCHERF, H. Papa­veraceae Alkaloide and Augendruk (Poppy Alkaloids and Eye Ten­sion. German). Klin. Mbl. Augen­lik. 128, 686-705 1956.  Back to cited text no. 24
PICKLES, V. Prostaglandins. Biol. Rev. 42, 614-652. 1967.  Back to cited text no. 25
RAMWELL, P. PG Symposium, Worcester Found. Exp. Biol. Inter­science. 1968.  Back to cited text no. 26
SMITH, J. & WILLIS A. Aspirin Selectively Inhibits Prostaglandin Production in Human Platelets. Nature New Biology 231, 235-237. 1971.  Back to cited text no. 27
VANE, J. Inhibition of Prostaglan­din Synthesis as a Mechanism of Action of Aspirin-like Drugs. Nature New Biology 231 232-236, 1971.  Back to cited text no. 28
VANE, J., FERREIRA S. & MON­CADA, S. Indomethacin & Aspirin Abolish Prostaglandin Release from the Spleen. Nature New Biology 231, 237-239. 1971.  Back to cited text no. 29
WAITZMAN, M. & KING, C. Prostaglandin Influences on Intra­ocular Pressure & Pupil Size. Am. J. Physiol. 212, 329-334. 1967.  Back to cited text no. 30


  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]


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