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Year : 1970  |  Volume : 18  |  Issue : 4  |  Page : 143-149

Ciliary-iris hormone regulates eye tension

From the Oxford University Department of Physiology and Pharmacology, the National Institute for Medical Research, Mill Hill, London, U.K; the Sola Hakim Medical Research Centre, 249 Dr. Naoroji Road, Bombay 1, India

Correspondence Address:
Sohrab A.E Hakim
From the Oxford University Department of Physiology and Pharmacology, the National Institute for Medical Research, Mill Hill, London, U.K; the Sola Hakim Medical Research Centre, 249 Dr. Naoroji Road, Bombay 1, India

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How to cite this article:
Hakim SA. Ciliary-iris hormone regulates eye tension. Indian J Ophthalmol 1970;18:143-9

How to cite this URL:
Hakim SA. Ciliary-iris hormone regulates eye tension. Indian J Ophthalmol [serial online] 1970 [cited 2023 Dec 8];18:143-9. Available from: https://journals.lww.com/ijo/pages/default.aspx/text.asp?1970/18/4/143/35629

  Preliminary Communication Top

Glaucoma is the most serious problem in ophthalmology. Fundamental know­ledge is lacking concerning its basic cause, pathological mechanism, or radi­cal treatment (von Graefe[13]; Duke­Elder [8],[9] Sugar[37]. Unravelling the basic physiology of that most elementary, yet hitherto unknown mechanism which regulates and raises eye tension, is of crucial value. Experimental re­search with Argemone oil and Sangui­narine has now made it possible to demonstrate a physiological regulatory mechanism which definitely monitors normal, and probably pathological eye tension.

Argemone oil poisoning is a well­established cause of symptomless non­inflammatory human glaucoma occur­ring in tropical countries, usually, but not invariably associated with epidemic dropsy, and resulting from ingestion of edible oils deliberately adulterated with the oil from seeds of the Argemone Poppy. Argemone inexicana Linn., in­troduced from the West Indies into the Eastern tropics (Maynard[31]; Mukherji[32]; Chopra [4] ; Kirwan[24],[25]; Duke-Elder[7],[9] ; Sugar[37]; Somerset[36]; Maegraith [29] ; Manson-Bahr[30]; Watt[39]; Hakim[15],[20])

Sanguinarine, the active alkaloid in Argemone Poppy oil, produces dropsy, raised eye tension, destructive changes in the retina and optic nerve in rhesus monkeys and other experimental animals (Hakim[22]). Sanguinarine is not restricted to the Argemone Poppy, but is almost certainly present in all the boo species of Poppy-Fumaria herbs which grow as prolific weeds in most parts of the world (Hakim[18]; Santavy[35]). Animals grazing on these weeds can absorb and transmit Sanguinarine to man through milk, flesh, liver and eggs (Hakim[16],[17]; Kaplan[23]).

The present discovery of a physio­logical, rather than mechanical basis for regulating eye tension has been pos­sible only because of the author's prior findings of methods for experimentally raising eye tension at will, without even touching the eye-ball or interfer ing by mechanical or obliterative tech­niques, with either the production, or the return of aqueous from the eye.

An acute rise of eye tension can be produced by either subcutaneous or in­travenous injection of Sanguinarine in rabbits, cats and monkeys (Hakim[7],[20],[22]). The rise of eye tension by intravenous injection of Sanguinarine in rabbits was corroborated by the use of a manometric electronic recording system by Leib and Seherf [27] .

Sallmann and Lowenstein[34] and Gloster and Greaves[12] showed that elec­trical stimulation of hypothalamic areas on the sides of the third ventricle of the brain of cats, can produce a rise of eye tension, independently of blood pres­sure. This led the author to inject a minute quantity of Sanguinarine through a cannula fixed in the skull of cats leading into either the lateral or third ventricle. The very first injection of a hundredth of the intravenous dose of Sanguinarine directly into the target eye tension raising area of the brain, raised the eye tension (Hakim[17]).

Subsequent experiments on zoo cats, both with and without general anaes­thesia, were presented as the Conference Lecture at the All-India Ophthalmolo­gical Conference in 1962 (Hakim[20]). The experimental technique was also demonstrated at the 19th International Congress of Ophthalmology, New Delhi, 1962.

The classical experiments of Loewi[28] and Bain[3] on two isolated beating frog hearts perfused in series with balanced saline, demonstrated that electrical sti­mulation of the vagus nerve of the donor heart liberated a chemical (ace­tylcholine) into the perfusing saline, which slowed both the donor and reci­pient hearts [Figure - 1]a.

Since either electrical (Sallmann and Lowensfein [34] ; Ginster and Greaves[12]), or chemical (Hakim [16],[17],[20],[22] ) stimula­tion at the hypothalamus, raises, by re­mote mote control, the ocular tension in the eyes; the experiments of Loewi [28] and Bain [3] suggested to this author the pos­sibility that a neuro-hormone might be similarly liberated at the termination of the nerves connecting brain and eyes, and that this neuro-hormone, liberated into the aqueous, was raising the eye tension.

Sir Henry Dale applied his vast dis­coveries in experimental physiology to ophthalmology (Dale[5]). As the author's research supervisor, he encouraged him to constantly review ophthalmology in the light of basic physiology. The con­cept of an ocular neuro-hormone which regulates eye tension was enunciated in 1962 (Hakim[20]) and demonstrated in the author's laboratory to visiting ophthalmologists, but the final proofs have only lately been obtained.

  Method Top

To prove the existence of a theoreti­cal neuro-hormone allegedly liberated into the aqueous and which raises eye tension, it is necessary (i) to raise eye tension without manipulating the eye, (ii) to continually remove the aque­ous for testing, (iii) to detect the hor­mone in the aqueous by chemical and pharmacological tests, and (iv) to show that the hormone in the aqueous raises eye tension when transferred to the eye of another animal.

One cat (donor) is fitted with a cannula (Feldberg and Sherwood[11]) leading into the third ventricle of the brain. After a few days the cat is anaesthesised by Pentobarbitone sodium and a special needle devised in this laboratory [Figure - 1]c is inserted through the cornea, into the anterior chamber and again out through the cornea. The central portion of the needle lies inside the anterior chamber. The needle is fixed rigidly by the two punctures in the cornea and is posi­tioned well away from, and in front of, the iris. The needle being fixed to the cornea, any head or eye movements of the cat, cannot alter its distance from the iris.

The tunnel of the needle is per­manently blocked in its centre and two holes are drilled through the side of the shaft, 3 mm. distant from each other and on either side of the central block. One end of the needle is connected with a fine tube to a reservoir of balanced saline kept at a suitable height. The saline flows through the tube into the needle, enters the anterior chamber from one side hole, mixes with the aqueous. re-enters the needle from the other side hole and drips outside of the eye from the other end of the needle. A fine tube is then connected to the outflow end of the needle and the saline is allowed to run out of the anterior chamber for an hour, to wash out the plasmoid aqueous formed as a result of the trauma of inserting the needle.

Thereafter, another cat (recipient) is anaesthetised and tied in the usual sitting position on a tilted stand. The outflow tube from the donor cat is ad­justed so that drops of outflow from the donor eye continuously fall on the corneal surface of one eye of the reci­pient cat. The other (control) eye of the recipient cat is similarly bathed with drops of saline coming directly from the common reservoir [Figure - 1]b. The eye tension and the size of the pupil is re­corded every 15 minutes with a Schiotz's tonometer (+ 5.5 g.) in the un-needled eye of the donor cat and in both eyes of the recipient cat.

  Results Top

During one or more hours, no notice­able change was observed in the basic eye tension or pupil size of the donor or recipient eyes in 20 different experi­ments. Thereafter, 20 ug Sanguinarine chloride in o.1 ml. of a special iso-elec­tric brain saline (Hakim[21]) was injected through the cannula into the third ventrible. The injections were repeated five times every 15 minutes.

Soon after the second or third injec­tion, a progressive rise of tension and dilatation of the pupil not reacting to light, was recorded in the un-needled eye of the donor cat. The mean in­crease of eye tension in these 20 experi­ments was 13.6 mm. Hg., the maximum increase was 19 mm. Hg., the minimum increase was 7 mm. Hg. The raised tension was maintained for 60 min. and returned to normal in 45 min.

Simultaneously, the tension in the eye of the recipient cat which was be­ing washed with hormone-containing saline from the eye of the donor cat, showed a progressive rise of eye ten­sion and dilatation of the pupil. The mean increase was 20.5 mm. Hg., the maximum increase was 45 mm. Hg., and the minimum increase was 11 mm. Hg.

After about 60 mins., the eye tension gradually declined in the donor cat and similarly in the recipient cat eye re­ceiving the donor's eye wash. Through­out the experiment, the control eye of the recipient cat, receiving drops of saline from the common reservoir, showed practically no change in eye tension or pupil size.

In other experiments the eye tension of the donor cat was raised by inject­ing 5-10 mg. Sanguinarine chloride in saline by intravenous drip. The same effects were observed in the eyes of donor and recipient cats.

It was evident that saline itself or saline washing the anterior chamber, did not raise eye tension when dropped on the eye of a recipient cat, but dur­ing the period when eye tension was raised by Sanguinarine in the donor cat, some active substance was liberated into the aqueous, which could be washed out by saline, and falling on another remote eye, could raise its eye tension.

  The Hormone Top

The chemical solubilities and pharmacological properties of the eye-tension raising hormone closely resemble those of Prostaglandin F2α-, = (9a. 11a, 15 (S)-trihydroxy 5-cis, 13-transprosta­dienoic acid); and Cat Irin. It is sug­gested that this hormone be called "oculo-tensin". The best and most suggestive testing system for oculo-ten­sin is by drops falling on the intact eye, raising the eye tension. The drops, when containing the hormone, also increase the rate of beat of isolated four-day-old embryonic chick hearts and contract the isolated rat uterus. Pharmacological ex­periments on this hormone will be pub­lished later.

Rabbit Inn is known to be present in extracts of the iris, and it is liberated into the aqueous by mechanically stroking the iris. It locally dilates the pupil and raises eye tension (Ambache[2]). In this laboratory, saline extract of sheep, bull, or cat irises was dropped from a reservoir onto eyes of cats or rabbits, and raised their eye tension.

Prostaglandin F2 is α known to pro­duce a prolonged constriction of veins, even more than of arteries (von Euler [10] ; Ducharme[6]) and rabbit Irin is more active in the absence of blood (Ambache[1]). The ideal situation for the action of oculo-tensin is therefore available in the eye. Oculo-tensin. when liberated into the aqueous, drains through Schlemm's canal (in primates) and into the sub-conjunctival aqueous veins in all species, the veins usually containing only traces of aqueous pro­tein. If these are constricted, the drain­age of aqueous is impeded, back-pres­sure builds up, and eye tension rises in proportion to the amount of oculo­tensin in the aqueous. The experimental absorption of oculo-tensin from eye drops through the conjunctiva, is understandable, since prostaglandins are even absorbed through the vagina (Ramwell[33])

Pros taglandins are known to be re­leased in the brain and at nerve termi­nals (RamweII[33]). Rhythmic diurnal activity of many physiological processes are believed to be monitored from the hypothalamus and influenced by emotion. Both the normal diurnal varia­tion of eye tension and the anomalous rises triggered by emotion, might be explained by phasic variations of the electrical activity in the hypothalamus, releasing oculo-tensin in the eye. This concept of monitoring eye tension from the brain would be substantially sup­ported by both sets of experiments on the electrical and chemical stimuation of the hypothalamus, described above.

Prostaglandins are rapidly inactivated in the lungs and liver by the enzyme u 5-hydroxyprostaglandin dehydrogenase (Vane[38]). This enzyme was pre­pared by extracting sheep lung in phosphate buffer, and dripped on one eye of a cannulated cat, the other eye was dripped with buffer only. There­after, Sanguinarine was injected as usual through the cannula into the cat's brain. The tension in the eye re­ceiving plain buffer increased as usual. The tension in the other eye dripped with lung extract, did not rise at all, due to the enzyme, which had inacti­vated oculo-tensin. This experiment suggests the fascinating possibility of lowering pathological eye tension by a natural physiological antagonist, pre­scribed as eye drops.

Valuable information on prostagland­ins and irin is available in numerous papers by von Euler[10], Ambache [1],[2] , Vane[38],Ramwe11[33] and others. In spite of their extensive research, no practical or physiologically functional use of the prostaglandins was known (RamweII [33] ). Oculo-tensin is a prostaglandin, brought for the first .time into the domain of physiological function and practical use.

  Acknowledgement Top

I wish to record my gratitude to the inspiring memory and matchless achi­evements of Albrecht von Graefe (1828-1870), who passed away one hundred years ago, Sir Stewart Duke­Elder, regards von Graefe as "undoubt­edly the greatest ophthalmologist who ever existed" (Duke-Elder, S., 1969.)

  References Top

Ambache, N.: Further studies in the preparation, purification and nature of Irin. J. Physiol. 146, 255-294. 1959.  Back to cited text no. 1
Ambache, N., Kavanagh, L. and Whi­ting, G.; Effect of mechanical stimu­lation of Rabbits' Eyes. Release of active substances in antorior chamber perfusates. J. Physiol. 176, 378-408. 1965.  Back to cited text no. 2
Bain, W.: A Method of demonstrating humoral transmission of effects of Cardiac Vagus stimulation in Frog. Quart. J. Exper. Physiol. 22,: 269-274. 1932.  Back to cited text no. 3
Chopra, R. and De N.: Epidemic in Manbhum and Purulia Ind. J. med. Res. 25; 101. 1937.  Back to cited text no. 4
Dale, H.: The Eye as a Physiological Reagent. (The Bowman Lecture). Trans. ophthal. Soc. U.K. 71; 117. 1951.  Back to cited text no. 5
Ducharme, D. W., Weeks, J. and Montgomery, R.: Studies in the Mechanism of the Hypertensive effect of Prostaglandin F2 cc J. Pharmacol, Exp. Therap. 160; 1-10. 1968.  Back to cited text no. 6
Duke-Elder, S.: Sanguinarine. Text-Book of Ophthalmology. 6; 6852-6855. 1954.  Back to cited text no. 7
Duke-Elder, S.: The Actiology of Simple Glaucoma. (The Bowman Lecture) Trans. ophthal. Soc. U.K. 77; 205-228. 1957.  Back to cited text no. 8
Duke-Elder, S.: Glaucoma Secondary to Epidemic Dropsy. System of Ophthalmo­logy. 9; 684-687. von Graefe ibid. 9; 379, 614. 1969.  Back to cited text no. 9
Von Euler, U.: Weitere Untersuchungen uber Prostaglandin, die Physiologisch aktiv Substenz gewisser Genitaldrusen. (Further experiments on Prostaglandin. the physiologically active substance in certain genital glands (in German). Skand. Arch. Physiol. 81; 65-80. 1939.  Back to cited text no. 10
Feldberg, W. and Sherwood, S.: A permanent cannula for intraventricular injections in cats. J. Physiol. 20; 3P. 1953.  Back to cited text no. 11
Gloster, J. and Greaves, D.: Effect of Diencephalic Stimulation upon Intra­ocular Pressure. Brit. J. Ophthal. 41; 513--532. 1957.  Back to cited text no. 12
Von Graefe, A.: Vorlaufige Notiz uber das Wesen des Glaucomas. (Latest Notes on the Glaucomas (in German). von Graefe's Arch. fur Ophthal. 1; 375. 1854.  Back to cited text no. 13
Hakim, S.: The Biological Action of Argemone Oil. D. Phil. Thesis, Univer­sity of Oxford. 1953.  Back to cited text no. 14
Hakim, S.: Argemone Oil, Sanguinarine, and Epidemic-Dropsy Glaucoma. Brit. J. Ophthal. 38; 193-216. 1954.  Back to cited text no. 15
Hakim, S.: Extraction and Detection of Poppy Alkaloids. J. Physiol. 138; 8p. 1957a.  Back to cited text no. 16
Hakim, S.: Poppy Alkaloids and Glaucoma. J. Physiol. 138; 41P. 1957b.  Back to cited text no. 17
Hakim, S., Valerie Mijovic and Walker J.; Distribution of Certain Poppy ­Fumaria Alkaloids and a Possible Link with the Incidence of Glaucoma. Nature 189; 193-201. 1961a.  Back to cited text no. 18
Hakim, S., Valerie Mijovic and Walker­J.: Experimental Transmission of Sanguinarine in Milk: Detection of a Metabolic Product. Nature 189; 201-204. 1961b.  Back to cited text no. 19
Hakim, S.: Sanguinarine and Hypo­thalamic Glaucoma. J. All-India Ophthal. Soc. 10; 83-102. 1962.  Back to cited text no. 20
Hakim, S.: Sanguinarine-A Carcinogenic Contaminant in Indian Edible Oils. Indian J. Cancer 5; 183-197. 1968.  Back to cited text no. 21
Hakim, S.: Death, Cardio-myopathy, Symptomless Glaucoma and Cancer from Edible Oils containing Argemone. Maharashtra Med. J. 17; 109-130. 1970.  Back to cited text no. 22
Kaplan, M., Abdussalam, M. and Bijlenga, G.: Diseases Transmitted Through Milk. World Health Orga­nisation: Monograph Series No. 48. p. 63. 1962.  Back to cited text no. 23
Kirwan, E.: Glaucoma in Epidemic Dropsy. Arch. Ophthal. 12; 1. 1934.  Back to cited text no. 24
Kirwan, E.: Ocular Complications in Epidemic Dropsy. Ind. med. Gaz. 70; 485. 1935.  Back to cited text no. 25
Kirwan, E.: Aetiology of Chronic Primary Glaucoma. Brit. J. Ophthal. 20; 321. 1936.  Back to cited text no. 26
Lieb, W. and Scherf, H.: Papaveraceae­Alkaloide and Augendruk (Poppy Alkaloids and Eye Tension. German). Klin. Mbl. Augenhk. 128; 686-705. 1956.  Back to cited text no. 27
Loewi, O.: Ubertragbarkeit der Herzne­rvenwirkung. (Transmissibility of a substance produced by stimulating heart nerves. German). Pfluger's Arch. 189; 239, 193, 201. 1921. and 203; 408, 1924. and 214; 687. 689. 1962.  Back to cited text no. 28
Maegraith, B.: Epidemic Dropsy. In Price's Textbook of the Practice of Medicine. 310-312. ELBS Ed. Oxford U.P. 1966.  Back to cited text no. 29
Manson-Bahr, P.: Epidemic Dropsy. Glaucoma in Epidemic Dropsy. In Tropical Diseases. ELBS Ed. 745-748. 793. 1967.  Back to cited text no. 30
Maynard, F.: Preliminary Note on Increased Intraocular Tension met with in Cases of Epidemic Dropsy. Ind. Med. Gaz. 44; 373. 1909.  Back to cited text no. 31
Mukerjee,: Epidemic Dropsy Glaucoma Proc. Far Eastern Congress. 7; 272. 1927.  Back to cited text no. 32
Ramwell, P., Shaw, J., Clarke, G. Grostic, M., Kaiser, D. and Pike, J.: In Progress In The Chemistry of Fats and other Lipids. 9; ii, 231-273. 1968.  Back to cited text no. 33
Von Sallmann, L. and Lowenstein, O. Responses of Intraocular Pressure to Electrical Stimulation in the Dience­phalon. American J. Ophthal. 39; Supp. 11-29. 1955.  Back to cited text no. 34
Santavy, F.: Papaveraceae Alkaloids. In Manske's The Alkaloids. 12; 333-454. 1970.  Back to cited text no. 35
Somerset, E.: Glaucoma in Epidemic Dropsy. In Ophthalmology in the Tropics. 155. 1962.  Back to cited text no. 36
Sugar, S.: Secondary Glaucoma Asso­ciated with Epidemic Dropsy. In The Glaucomas. 354-355. 109-139. 1957.  Back to cited text no. 37
Vane, J., Priscilla Piper and Wyllie, J.: Inactivation of Prostaglandins by the Lungs. Nature 225; 600-604. 1970.  Back to cited text no. 38
Watt, J. and Breyer-Brandwijk, M.: Argemone mexicana L. In Medicinal and Poisonous Plants of Southern and Eastern Africa. p. 815-828. 1962.  Back to cited text no. 39


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