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| ARTICLE |
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| Year : 1970 | Volume
: 18
| Issue : 4 | Page : 143-149 |
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Ciliary-iris hormone regulates eye tension
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
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
 Source of Support: None, Conflict of Interest: None  | Check |
How to cite this article:
Hakim SA. Ciliary-iris hormone regulates eye tension. Indian J Ophthalmol 1970;18:143-9 |
| Preliminary Communication | |  |
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 | | |
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 | | |
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 | | |
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 | | |
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.)
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