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Acetazolamide and Ocular Tension⋆
PROVOCATIVE TESTS IN GLAUCOMA closure glaucoma, provocative tests are necessary to make a diagnosis of angle-closure glaucoma. 3. Mechanisms of the dark-room and mydriasis tests are discussed with emphasis on gonioscopic control. 4. Precautions should be taken to prevent undesirable effects of the mydriasis test. 5. Differential diagnosis between angleclosure glaucoma and chronic simple glauco-
241
ma is particularly important in an eye with a narrow angle. 6. Co-existence of angle-closure glaucoma and chronic simple glaucoma should be suspected in an eye with a narrow angle in which there are both a strongly positive dark-room test with closure of the angle and a strongly positive water-drinking test with the angle remaining narrow but open. 585 West End Avenue (10024).
REFERENCES
1. Smith, R. : Gonioscopic studies in congestive glaucoma. Brit. J. Ophth., 38:136-143 (Mar.) 1954. 2. Shaffer, R. N., and Chandler, P. A.: In Newell, F. (ed.): Glaucoma: Transaction of the First Conference. New York, Josiah Macy, Jr., Foundation, 1955, pp. 26-27. 3. Becker, B., and Shaffer, R. N. : Diagnosis and Therapv of the Glaucomas, St. Louis, Mosby, 1961, p. 145. 4. Gorin, G. : Shortening of the angle of the anterior chamber In angle-closure glaucoma. Am. J. Ophth., 49:141, 1960. 5. Smith, R. : The incidence of primary glaucomas. Tr. Ophth. Soc. U. Kingdom, 78 :245-259, 1958. 6. Posner, A. : Angle-closure glaucoma : Its incidence in relation to chronic simple glaucoma. EENT Monthly, 43:84 (Sept.) 1964.
ACETAZOLAMIDE AND OCULAR
TENSION*
N O T E S CONCERNING T H E M E C H A N I S M OF ACTION ROBERT P .
T H O M A S , M.D.,
AND M E R L E W .
RILF.Y,
PH.D.
With the technical assistance of John S. Newton and Cleveland Jones Augusta, Georgia INTRODUCTION
Acetazolamide ( D i a m o x ) is a carbonic anhydrase inhibitor introduced as an ocular hypotensive agent by Becker in 1954 1 and widely utilized since, both in clinical medicine and as a tool for investigating aqueous humor dynamics. Along with other agents of this group, it is an effective diuretic. T h e drug also affects other secretory activity, in* From the Division of Ophthalmology, Department of Surgery, Medical College of Georgia. This investigation was supported by Public Health Service research grant No. NB 04218-03 from the National Institute of Neurological Diseases and Blindness and by the Medical Research Foundation of Georgia.
eluding that of the gastric, pancreatic and parotid glands. T h e ocular hypotensive effect of Diamox appears to be due to a reduction in aqueous formation. 2 A considerable body of evidence has accumulated to support the concept that the d r u g interferes with the t r a n s fer of ions into the eye by inhibiting the carbonic anhydrase present in the ciliary body. There are several objections to this hypothesis, however. T h e drug has no effect on the intraocular pressure when administered locally 3 even though its concentration in the eye is sufficient to inhibit the carbonic anhydrase in the iris and ciliary body. 4 It is also of interest that, on systemic administration,
242
ROBERT P. THOMAS AND MERLE W. RILEY
the gradient of hydrogen and bicarbonate ions between the aqueous and the plasma is not significantly altered. 5 (See Davson: T H E EYE,
Vol. I and Duke-Elder:
SYSTEM OF
OPHTHALMOLOGY, Vol. V I I , for a more complete discussion of this question.) An alternate hypothesis concerning the action of Diamox holds that the local ocular hypotensive effect of the drug is mediated by changes in the blood. T h e nature of these proposed changes has not been well defined nor does there appear to be much experimental data to support this latter concept. T h e following series of experiments was designed to explore this latter possibility. M E T H O D S AND M A T E R I A L
Medium-sized mongrel dogs weighing between 8-10 kg and adult albino rabbits weighing between 2-4 kg were utilized in the experiments. Intravenous secobarbital sodium was used for general anesthesia. The same certified Schiotz tonometer was utilized for all tension measurements. All tensions are expressed in scale readings ( S R ) . Blood pressure was monitored during acute experiments by means of a femoral, or where appropriate, aortic catheter connected to a manometer. T h e standard dose of Diamox given intravenously was 250 mg in rabbits and 500 mg in dogs. All animals were screened prior to the experiments in the following routine fashion : T h e animal was anesthesized with intravenous secobarbital sodium and the ocular tension followed at 10-minute intervals for 30 minutes. A n y animal fluctuating one S R or more from preanesthetic ocular tensions at the end of 30 minutes, was discarded from the experiment. T h e animal was then given the standard dose of Diamox intravenously and the ocular tension was checked at 10-minute intervals for one hour. Animals which reacted less than two S R from baseline tension were discarded from the experiment. A n attempt was made to obtain animals which had a fall in the ocular ten-
sion of four S R or more following Diamox. There was an interval of 48 hours or more between reactions to Diamox in any one animal. E X P E R I M E N T 1. E F F E C T OF AORTIC BLOCKADE
If the ocular hypotension effect of Diamox is brought about by means of some change in the blood, it appears possible that some other gland or organ system is involved in this change. This experiment was designed to test the hypothesis that some abdominal organ or gland is involved in the ocular action of Diamox. PROCEDURE
Suitable reactive dogs were utilized. T h e abdominal aorta was exposed through a midline abdominal incision and occluded just as it emerged from beneath the diaphragm with a Kelly clamp or a ligature. The blood pressure was monitored by means of a catheter inserted into the aorta just above the occlusion. T h e occlusion of the aorta usually resulted in an elevation in the blood pressure and a slight rise in the intraocular pressure. This was allowed to stabilize for a period of 30 minutes before the Diamox was given. Following stabilization, the standard dose of Diamox was given and the intraocular pressure followed in the usual fashion. RESULTS
AND DISCUSSION
The results are presented in graph form in Figure 1. A s noted, the ocular hypotensive effect of Diamox was partially blocked by aortic occlusion but in no case was complete blockade achieved. There is no doubt that aortic blockade in the manner described induces manifold changes in the milieu interne, both physical and chemical which might account for the buffering of the ocular hypotensive effect of Diamox. O n the other hand, the experiment is consistent with the hypothesis that some of the abdom-
ACETAZOLAMIDE AND OCULAR TENSION
inal viscera are concerned with the ocular effects of Diamox. In this context, the lack of complete blockade could be due to collateral circulation with adequate venous return. Several attempts were made to block both the aorta and the inferior vena cava but the vascular hypotension encountered made interpretation difficult. On one occasion, complete blockade of the ocular hypotonia apparently resulted.
243
Pre op reaction Po»t op reaction
EXPERIMENT 2. ORGAN AND GLAND ABLATION
Since the foregoing experiment apparently indicated that aortic blockade of the abdominal contents in some manner reduces the ocular hypotensive action of Diamox, this experiment was designed to explore the possibility that some specific organ or gland was involved. PROCEDURE
Suitable reactive dogs were anesthetized and various organs removed or isolated through a midline abdominal incision. The After Aortic cross clomping Before Aortic cross damping
g
20
30 TIME (in minutes) Fig. 2 (Thomas and Riley). Effect of adrenalectomy on ocular reaction to Diamox. Median S.R. in eight dogs, 16 eyes.
following procedures were done: nephrectomy (three dogs), pancreatectomy (three dogs), vascular isolation of the liver (one dog) and adrenalectomy (eight dogs). Following the operative procedure, the animals were given the standard intravenous dose of Diamox. RESULTS AND DISCUSSION
10
20 30 40 TIME in minutes
60
Fig. 1 (Thomas and Riley). Effect of aortic cross clamping on ocular reaction to Diamox. Median S.R. in three dogs, six eyes.
Of the dogs with the various procedures done, only the adrenalectomized animals appeared to react less well to Diamox. These animals were reacted immediately postoperatively (fig. 2). In each instance there appeared to be a reduction of the ocular hypotensive effect of Diamox following adrenalectomy. This experiment was interpreted to implicate the adrenal gland in the ocular hypotensive effects of Diamox but the absence of complete blockade in any animal was somewhat disconcerting. The experiment leaves unanswered whether the target cell was contained in the adrenal cortex or medulla. The latter would appear to be more
244
ROBERT P. THOMAS AND MERLE W. R1LEY No Bretylium Bretylium 4mg. I.V.
tem. The drug used was bretylium, an agent which inhibits the effects of postganglionic sympathetic stimulation 8 and blocks the release of norepinephrine when sympathetic nerves are stimulated. 0 T h e drug inhibits the uptake of norepinephrine by the various stores and can release norepinephrine from the stores. 10 The drug also can apparently induce supersensitivity of the adrenergic effector cells 30 minutes following administration. 1 1 PROCEDURE
Rabbits were utilized throughout the experiment. Bretylium was given both topically in various concentrations and intravenously in the standard dose of 4.0 mg. After a 30-minute wait, the animals were reacted to Diamox in the usual fashion. RESULTS
10 20 30 40 TIME in minutes
60
Fig. 3 (Thomas and Riley). Effect of bretylium tosylate (4.0 mg intravenously) on ocular reaction to Diamox. Median S.R. in four rabbits.
likely since epinephrine has a Diamoxlike effect on the eye. Conversely, certain steroids are said to make rabbits react to Diamox more readily. 6 In this context, it is of interest that changes in the adrenal gland have been reported following the chronic administration of Diamox to rabbits and guinea pigs. 7 The observation that adrenalectomy diminished the action of Diamox rather than completely blocking it might be explained by assuming that Diamox in some manner released stores of catecholamines outside of the adrenal gland itself. E X P E R I M E N T 3. E F F E C T OF PHARMACOLOGIC ADRENERGIC NERVE BLOCKADE
In view of the close relationship between the adrenal medulla and the sympathetic nervous system, it was of interest to see if the ocular hypotensive effect of Diamox was dependent on the sympathetic nervous sys-
AND DISCUSSION
N o significant difference in the ocular hypotonia induced by Diamox was apparent following the topical administration of bretylium in concentrations ranging from 0.0005% to 5 % . However, on systemic administration, the drug apparently markedly increased the ocular hypotensive effect of Diamox. To confirm this interesting observation, four nonreactor rabbits were given bretylium 4 mg I V , and after a 30-minute wait were reacted to Diamox in the usual fashion. The results are presented in Figure 3 and clearly indicate the marked increase of the ocular hypotensive action of Diamox following systemic administration of bretylium. This experiment was interpreted to mean that the sympathetic nerves, per se, are not essential for the ocular effects of Diamox. The exaggerated ocular hypotonia from Dia m o x following systemic administration of bretylium may be related to the supersensitivity phenomenon encountered with this drug. T h e same effect could not be achieved following topical administration, so it would appear more likely to be related to the sys-
ACETAZOLAMIDE AND OCULAR TENSION temic effects of the drug. T h e drug inhibits the uptake of norepinephrine by the various stores and can release norepinephrine from the stores. While the precise mechanism remains speculative, this experiment lends additional evidence that the ocular effect of Diamox is related to the adrenergic system.
Right eye (D.C.I. used) Left eye (no D.C.I, used)
E X P E R I M E N T 4. A L P H A AND BETA ADRENERGIC
245
BLOCKING AGENTS
A most useful concept, introduced by Ahlquist 1 2 is that the adrenergic receptors are of two different types, alpha and beta. T h e effects of norepinephrine are primarily alpha while those of isoproterenol are primarily beta. In the present series of experiments, if the ocular hypotensive action of Diamox is related to the release of catecholamines or similar agents which in turn activates the appropriate adrenergic receptor in the eye, the action of Diamox should be diminished by blocking the appropriate adrenergic receptor. PROCEDURE
Suitable reactive rabbits were anesthetized and the adrenergic blocking agents applied topically to one eye, one drop at three minute intervals three times. After a 30-minute wait the animal was treated with Diamox in the usual manner. T h e drugs used were phenoxybenzamine (Dibenzyli n e ) , and alpha adrenergic blocking agent, and dichlorisoproterenol ( D C I ) , a beta adrenergic blocking agent. Various concentrations were used. R E S U L T S A N D DISCUSSION
Dibenzyline, in concentrations up to 5 % , appeared to have no effect on the ocular action of Diamox. W h e n the dibenzyline powder was instilled into the conjunctival sac, some blockade effect was achieved but at this concentration the drug may no longer be acting strictly as an alpha adrenergic blocking agent. Conversely, D C I in concentrations of 1 % regularly blocked or marked-
IP
10
20 30 40 TIME in minutes
50
60
Fig. 4 (Thomas and Riley). Comparison of topical DCI on ocular hypotensive action of Diamox. Median S.R. in 10 rabbits. ly diminished the ocular hypotensive effect of Diamox (fig. 4 ) . I t thus appears possible that the beta adrenergic receptor mediates the ocular hypotensive effect of Diamox. I t is of interest that isoproterenol, which is a beta adrenergic agent, produces a reduction in aqueous formation when applied locally to the eye, 13 an action similar to Diamox. This is in contrast to norepinephrine, an alpha adrenergic agent, which apparently reduces intraocular pressure by increasing the outflow facility. COMMENT
T h e described experiments lend some support to the hypothesis that Diamox achieves its local ocular hypotensive effect at least in part by means of a blood-borne mediator related to the adrenal gland, most likely the adrenal medulla. T h e sympathetic nerves do not appear to be essential for such an effect. T h e experiments with the adrenergic blocking agent, D C I , would indicate that a beta adrenergic effect is involved in the suppression of aqueous formation by
246
ROBERT P. THOMAS AND MERLE W. RILEY
Diamox. It is of interest, in this context, that isoproterenol, a beta adrenergic stimulator, results in a suppression of aqueous
change as knowledge in this general area increases. CONCLUSIONS
formation when applied locally. This hypothesis would explain satisfactorily the lack of effect when Diamox is applied topically and would relate fairly well with the well-known effects of epinephrine on the ocular tension. Conversely, this interpretation of the described experiments rests largely on the validity of certain assumptions, chiefly regarding the actions of the various drugs involved and the effects of various surgical manipulations. These considerations obviously make any interpretation subject to
Adrenalectomy in dogs appears to dim i n i s h t h e o c u ] a r h y p o t e n s i v e action of DiL
a m o x
nerve blocki n i s t e r e d intravenously appears to increase the ocular hypotensive e ff e c t 0 f Diamox 3 Dichlorisoproterenol, a beta adrenergic b l o c k i n g a g e n t > w h e n a p p l i e d t o p ; c a l l y i n 1% reduces the solution> blocks or markedly o c u k r h y p o t e n s i v e e f f e c t of Diamox. 2
ing
Bretyliunl)
agent)
Eugene
w h e n
an
adrenergic
adm
TaJmadge
Memorial
Hospital.
REFERENCES
1. Becker, B. : Decrease in intraocular pressure in man by a carbonic anhydrase inhibitor, Diamox. Am. J. Ophth, 37:13, 1954. 2. : Mechanism of the fall in intraocular pressure induced by the carbonic anhydrase inhibitor Diamox. Am. J. Ophth., 39:177, 1955. 3. Grant, W. M., and Trotter, R. R. : Diamox in treatment of glaucoma. Arch. Ophth., 51:735, 1954. 4. Green, H., Bocher, C. A., Calnan, A. F., and Leopold, I. H. : Carbonic anhydrase and the maintenance of intraocular pressure in the rabbit eye. Arch. Ophth., 53 :463, 1955. 5. Green, H., Bocher, C. A., and Leopold, I. H. : Carbonic anhydrase and the elaboration of bicarbonate ion in the rabbit. Arch. Ophth., 53 :472, 1955. 6. Kinsey, V. E., Camacho, E., Cavanaugh, G. A., Constant, M., and McGinty, D. A. : Dependence of I.O.P.—lowering effect of acetazolamide on salt. Arch. Ophth., 53 :680, 1955. 7. Talamas, J. L., Sanz, E. G., and Benito-Arranz, S. : The effect o£ Neptazane and Diamox on the hypothalamic-pituitary-adrenal axis. Am. J. Ophth., 53:107, 1962. 8. Boura, A. L. A., and Green, A. F. : The actions of Bretylium : Adrenergic neurone blocking and other effects. Brit. J. Pharmacol., 14 :536, 1959. 9. Day, M. D., Roud, M. J., Hetting, G., Axelrod, Jr., and Potrick, R. W. : Actions of bretylium and guanethidene on the uptake and release of noradrenaline. Brit. J. Pharmacol., 18:161, 1962. 10. Cutting, W. C, Dreisbach, R. H., and Elliott, H. W. : Ann. Rev. Pharmacol., 1963, p. 80. 11. Emmelin, N. : Supersensitivity following "pharmacological denervation." Pharmacol. Rev., 13:17, 1961. 12. Ahlquist, R. P. : A study of the adrenotropic receptors. Am. J. Physiol., 153:586, 1948. 13. Eakins, K. E. : The effect of intravitreous injections of norepinephrine, epinephrine and isoproterenol on the intraocular pressure and aqueous humor dynamics of rabbits' eyes. J. Pharmacol, exp. Ther., 140 :79, 1963.
241
ma is particularly important in an eye with a narrow angle. 6. Co-existence of angle-closure glaucoma and chronic simple glaucoma should be suspected in an eye with a narrow angle in which there are both a strongly positive dark-room test with closure of the angle and a strongly positive water-drinking test with the angle remaining narrow but open. 585 West End Avenue (10024).
REFERENCES
1. Smith, R. : Gonioscopic studies in congestive glaucoma. Brit. J. Ophth., 38:136-143 (Mar.) 1954. 2. Shaffer, R. N., and Chandler, P. A.: In Newell, F. (ed.): Glaucoma: Transaction of the First Conference. New York, Josiah Macy, Jr., Foundation, 1955, pp. 26-27. 3. Becker, B., and Shaffer, R. N. : Diagnosis and Therapv of the Glaucomas, St. Louis, Mosby, 1961, p. 145. 4. Gorin, G. : Shortening of the angle of the anterior chamber In angle-closure glaucoma. Am. J. Ophth., 49:141, 1960. 5. Smith, R. : The incidence of primary glaucomas. Tr. Ophth. Soc. U. Kingdom, 78 :245-259, 1958. 6. Posner, A. : Angle-closure glaucoma : Its incidence in relation to chronic simple glaucoma. EENT Monthly, 43:84 (Sept.) 1964.
ACETAZOLAMIDE AND OCULAR
TENSION*
N O T E S CONCERNING T H E M E C H A N I S M OF ACTION ROBERT P .
T H O M A S , M.D.,
AND M E R L E W .
RILF.Y,
PH.D.
With the technical assistance of John S. Newton and Cleveland Jones Augusta, Georgia INTRODUCTION
Acetazolamide ( D i a m o x ) is a carbonic anhydrase inhibitor introduced as an ocular hypotensive agent by Becker in 1954 1 and widely utilized since, both in clinical medicine and as a tool for investigating aqueous humor dynamics. Along with other agents of this group, it is an effective diuretic. T h e drug also affects other secretory activity, in* From the Division of Ophthalmology, Department of Surgery, Medical College of Georgia. This investigation was supported by Public Health Service research grant No. NB 04218-03 from the National Institute of Neurological Diseases and Blindness and by the Medical Research Foundation of Georgia.
eluding that of the gastric, pancreatic and parotid glands. T h e ocular hypotensive effect of Diamox appears to be due to a reduction in aqueous formation. 2 A considerable body of evidence has accumulated to support the concept that the d r u g interferes with the t r a n s fer of ions into the eye by inhibiting the carbonic anhydrase present in the ciliary body. There are several objections to this hypothesis, however. T h e drug has no effect on the intraocular pressure when administered locally 3 even though its concentration in the eye is sufficient to inhibit the carbonic anhydrase in the iris and ciliary body. 4 It is also of interest that, on systemic administration,
242
ROBERT P. THOMAS AND MERLE W. RILEY
the gradient of hydrogen and bicarbonate ions between the aqueous and the plasma is not significantly altered. 5 (See Davson: T H E EYE,
Vol. I and Duke-Elder:
SYSTEM OF
OPHTHALMOLOGY, Vol. V I I , for a more complete discussion of this question.) An alternate hypothesis concerning the action of Diamox holds that the local ocular hypotensive effect of the drug is mediated by changes in the blood. T h e nature of these proposed changes has not been well defined nor does there appear to be much experimental data to support this latter concept. T h e following series of experiments was designed to explore this latter possibility. M E T H O D S AND M A T E R I A L
Medium-sized mongrel dogs weighing between 8-10 kg and adult albino rabbits weighing between 2-4 kg were utilized in the experiments. Intravenous secobarbital sodium was used for general anesthesia. The same certified Schiotz tonometer was utilized for all tension measurements. All tensions are expressed in scale readings ( S R ) . Blood pressure was monitored during acute experiments by means of a femoral, or where appropriate, aortic catheter connected to a manometer. T h e standard dose of Diamox given intravenously was 250 mg in rabbits and 500 mg in dogs. All animals were screened prior to the experiments in the following routine fashion : T h e animal was anesthesized with intravenous secobarbital sodium and the ocular tension followed at 10-minute intervals for 30 minutes. A n y animal fluctuating one S R or more from preanesthetic ocular tensions at the end of 30 minutes, was discarded from the experiment. T h e animal was then given the standard dose of Diamox intravenously and the ocular tension was checked at 10-minute intervals for one hour. Animals which reacted less than two S R from baseline tension were discarded from the experiment. A n attempt was made to obtain animals which had a fall in the ocular ten-
sion of four S R or more following Diamox. There was an interval of 48 hours or more between reactions to Diamox in any one animal. E X P E R I M E N T 1. E F F E C T OF AORTIC BLOCKADE
If the ocular hypotension effect of Diamox is brought about by means of some change in the blood, it appears possible that some other gland or organ system is involved in this change. This experiment was designed to test the hypothesis that some abdominal organ or gland is involved in the ocular action of Diamox. PROCEDURE
Suitable reactive dogs were utilized. T h e abdominal aorta was exposed through a midline abdominal incision and occluded just as it emerged from beneath the diaphragm with a Kelly clamp or a ligature. The blood pressure was monitored by means of a catheter inserted into the aorta just above the occlusion. T h e occlusion of the aorta usually resulted in an elevation in the blood pressure and a slight rise in the intraocular pressure. This was allowed to stabilize for a period of 30 minutes before the Diamox was given. Following stabilization, the standard dose of Diamox was given and the intraocular pressure followed in the usual fashion. RESULTS
AND DISCUSSION
The results are presented in graph form in Figure 1. A s noted, the ocular hypotensive effect of Diamox was partially blocked by aortic occlusion but in no case was complete blockade achieved. There is no doubt that aortic blockade in the manner described induces manifold changes in the milieu interne, both physical and chemical which might account for the buffering of the ocular hypotensive effect of Diamox. O n the other hand, the experiment is consistent with the hypothesis that some of the abdom-
ACETAZOLAMIDE AND OCULAR TENSION
inal viscera are concerned with the ocular effects of Diamox. In this context, the lack of complete blockade could be due to collateral circulation with adequate venous return. Several attempts were made to block both the aorta and the inferior vena cava but the vascular hypotension encountered made interpretation difficult. On one occasion, complete blockade of the ocular hypotonia apparently resulted.
243
Pre op reaction Po»t op reaction
EXPERIMENT 2. ORGAN AND GLAND ABLATION
Since the foregoing experiment apparently indicated that aortic blockade of the abdominal contents in some manner reduces the ocular hypotensive action of Diamox, this experiment was designed to explore the possibility that some specific organ or gland was involved. PROCEDURE
Suitable reactive dogs were anesthetized and various organs removed or isolated through a midline abdominal incision. The After Aortic cross clomping Before Aortic cross damping
g
20
30 TIME (in minutes) Fig. 2 (Thomas and Riley). Effect of adrenalectomy on ocular reaction to Diamox. Median S.R. in eight dogs, 16 eyes.
following procedures were done: nephrectomy (three dogs), pancreatectomy (three dogs), vascular isolation of the liver (one dog) and adrenalectomy (eight dogs). Following the operative procedure, the animals were given the standard intravenous dose of Diamox. RESULTS AND DISCUSSION
10
20 30 40 TIME in minutes
60
Fig. 1 (Thomas and Riley). Effect of aortic cross clamping on ocular reaction to Diamox. Median S.R. in three dogs, six eyes.
Of the dogs with the various procedures done, only the adrenalectomized animals appeared to react less well to Diamox. These animals were reacted immediately postoperatively (fig. 2). In each instance there appeared to be a reduction of the ocular hypotensive effect of Diamox following adrenalectomy. This experiment was interpreted to implicate the adrenal gland in the ocular hypotensive effects of Diamox but the absence of complete blockade in any animal was somewhat disconcerting. The experiment leaves unanswered whether the target cell was contained in the adrenal cortex or medulla. The latter would appear to be more
244
ROBERT P. THOMAS AND MERLE W. R1LEY No Bretylium Bretylium 4mg. I.V.
tem. The drug used was bretylium, an agent which inhibits the effects of postganglionic sympathetic stimulation 8 and blocks the release of norepinephrine when sympathetic nerves are stimulated. 0 T h e drug inhibits the uptake of norepinephrine by the various stores and can release norepinephrine from the stores. 10 The drug also can apparently induce supersensitivity of the adrenergic effector cells 30 minutes following administration. 1 1 PROCEDURE
Rabbits were utilized throughout the experiment. Bretylium was given both topically in various concentrations and intravenously in the standard dose of 4.0 mg. After a 30-minute wait, the animals were reacted to Diamox in the usual fashion. RESULTS
10 20 30 40 TIME in minutes
60
Fig. 3 (Thomas and Riley). Effect of bretylium tosylate (4.0 mg intravenously) on ocular reaction to Diamox. Median S.R. in four rabbits.
likely since epinephrine has a Diamoxlike effect on the eye. Conversely, certain steroids are said to make rabbits react to Diamox more readily. 6 In this context, it is of interest that changes in the adrenal gland have been reported following the chronic administration of Diamox to rabbits and guinea pigs. 7 The observation that adrenalectomy diminished the action of Diamox rather than completely blocking it might be explained by assuming that Diamox in some manner released stores of catecholamines outside of the adrenal gland itself. E X P E R I M E N T 3. E F F E C T OF PHARMACOLOGIC ADRENERGIC NERVE BLOCKADE
In view of the close relationship between the adrenal medulla and the sympathetic nervous system, it was of interest to see if the ocular hypotensive effect of Diamox was dependent on the sympathetic nervous sys-
AND DISCUSSION
N o significant difference in the ocular hypotonia induced by Diamox was apparent following the topical administration of bretylium in concentrations ranging from 0.0005% to 5 % . However, on systemic administration, the drug apparently markedly increased the ocular hypotensive effect of Diamox. To confirm this interesting observation, four nonreactor rabbits were given bretylium 4 mg I V , and after a 30-minute wait were reacted to Diamox in the usual fashion. The results are presented in Figure 3 and clearly indicate the marked increase of the ocular hypotensive action of Diamox following systemic administration of bretylium. This experiment was interpreted to mean that the sympathetic nerves, per se, are not essential for the ocular effects of Diamox. The exaggerated ocular hypotonia from Dia m o x following systemic administration of bretylium may be related to the supersensitivity phenomenon encountered with this drug. T h e same effect could not be achieved following topical administration, so it would appear more likely to be related to the sys-
ACETAZOLAMIDE AND OCULAR TENSION temic effects of the drug. T h e drug inhibits the uptake of norepinephrine by the various stores and can release norepinephrine from the stores. While the precise mechanism remains speculative, this experiment lends additional evidence that the ocular effect of Diamox is related to the adrenergic system.
Right eye (D.C.I. used) Left eye (no D.C.I, used)
E X P E R I M E N T 4. A L P H A AND BETA ADRENERGIC
245
BLOCKING AGENTS
A most useful concept, introduced by Ahlquist 1 2 is that the adrenergic receptors are of two different types, alpha and beta. T h e effects of norepinephrine are primarily alpha while those of isoproterenol are primarily beta. In the present series of experiments, if the ocular hypotensive action of Diamox is related to the release of catecholamines or similar agents which in turn activates the appropriate adrenergic receptor in the eye, the action of Diamox should be diminished by blocking the appropriate adrenergic receptor. PROCEDURE
Suitable reactive rabbits were anesthetized and the adrenergic blocking agents applied topically to one eye, one drop at three minute intervals three times. After a 30-minute wait the animal was treated with Diamox in the usual manner. T h e drugs used were phenoxybenzamine (Dibenzyli n e ) , and alpha adrenergic blocking agent, and dichlorisoproterenol ( D C I ) , a beta adrenergic blocking agent. Various concentrations were used. R E S U L T S A N D DISCUSSION
Dibenzyline, in concentrations up to 5 % , appeared to have no effect on the ocular action of Diamox. W h e n the dibenzyline powder was instilled into the conjunctival sac, some blockade effect was achieved but at this concentration the drug may no longer be acting strictly as an alpha adrenergic blocking agent. Conversely, D C I in concentrations of 1 % regularly blocked or marked-
IP
10
20 30 40 TIME in minutes
50
60
Fig. 4 (Thomas and Riley). Comparison of topical DCI on ocular hypotensive action of Diamox. Median S.R. in 10 rabbits. ly diminished the ocular hypotensive effect of Diamox (fig. 4 ) . I t thus appears possible that the beta adrenergic receptor mediates the ocular hypotensive effect of Diamox. I t is of interest that isoproterenol, which is a beta adrenergic agent, produces a reduction in aqueous formation when applied locally to the eye, 13 an action similar to Diamox. This is in contrast to norepinephrine, an alpha adrenergic agent, which apparently reduces intraocular pressure by increasing the outflow facility. COMMENT
T h e described experiments lend some support to the hypothesis that Diamox achieves its local ocular hypotensive effect at least in part by means of a blood-borne mediator related to the adrenal gland, most likely the adrenal medulla. T h e sympathetic nerves do not appear to be essential for such an effect. T h e experiments with the adrenergic blocking agent, D C I , would indicate that a beta adrenergic effect is involved in the suppression of aqueous formation by
246
ROBERT P. THOMAS AND MERLE W. RILEY
Diamox. It is of interest, in this context, that isoproterenol, a beta adrenergic stimulator, results in a suppression of aqueous
change as knowledge in this general area increases. CONCLUSIONS
formation when applied locally. This hypothesis would explain satisfactorily the lack of effect when Diamox is applied topically and would relate fairly well with the well-known effects of epinephrine on the ocular tension. Conversely, this interpretation of the described experiments rests largely on the validity of certain assumptions, chiefly regarding the actions of the various drugs involved and the effects of various surgical manipulations. These considerations obviously make any interpretation subject to
Adrenalectomy in dogs appears to dim i n i s h t h e o c u ] a r h y p o t e n s i v e action of DiL
a m o x
nerve blocki n i s t e r e d intravenously appears to increase the ocular hypotensive e ff e c t 0 f Diamox 3 Dichlorisoproterenol, a beta adrenergic b l o c k i n g a g e n t > w h e n a p p l i e d t o p ; c a l l y i n 1% reduces the solution> blocks or markedly o c u k r h y p o t e n s i v e e f f e c t of Diamox. 2
ing
Bretyliunl)
agent)
Eugene
w h e n
an
adrenergic
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REFERENCES
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