- Email: [email protected]
Organic Nitrate Therapy in Glaucoma
ORGANIC NITRATE THERAPY IN GLAUCOMA ANGELIKA
J. S. WIZEMANN, M.D.,
AND
VOLKER WIZEMANN, M.D.
Giessen, Gennany
In 1915 Wessely' observed that amyl nitrite causes an increase of intraocular pressure (lOP) in cats. Since then the use of organic nitrates has been considered to be contraindicted in glaucoma. Although the studies on amyl nitrite showed controversial results concerning the effect of that substance on IOP2-8 no case of nitroglycerin causing glaucoma had been reported'r" and some authors warned of the use of organic nitrates in the presence of glaucoma. 15,16 Because coronary heart disease as well as glaucoma occur more frequently in the elderly the application of organic nitrates is of interest clinically. Specific doses of nitroglycerin given intravenously by perfusion technique and high doses of isosorbide dinitrate administered orally were used. We describe herein the effect of organic nitrates on lOP.
tonometer. All measurements in each patient were made by one person. Arterial blood pressure was recorded every 30 minutes. The following three studies were performed: (1) Dose response: by means of a perfusion system, nitroglycerin was given intravenously in doses of9. 7 to 194 IJ.g/minute. Intraocular pressure was measured every five minutes. A doseresponse curve was obtained by changing the infusion speed. Beginning with the lowest dose of nitroglycerin, the dose was increased when a plateau of lOP was reached (usually after 20 to 30 minutes). (2) By administering 97 IJ.g of nitroglycerin per minute, changes in lOP were recorded in five- to 20-minute intervals. (3) Ten volunteers and 44 patients took 40 mg of isosorbide dinitrate orally at 8 o'clock in the morning. Intraocular pressure was measured at 30- to 60-minute SUBJECTS AND METHODS intervals thereafter. Three categories of patients were seIn three additional patients with lected for this study: (1) Ten volunteers open-angle glaucoma, antiglaucomatous with normal lOP, open angles, and no local therapy was interrupted and 2 X 40 history of glaucoma; (2) 25 patients with mg of isosorbide dinitrate was given open angles and borderline or increased orally for three weeks after a two-day lOP without cupping of the disk, in interval. Arterial blood pressure was whom antiglaucomatous treatment had measured at 30-minute intervals when not yet been started; (3) 20 patients with nitroglycerin was infused. In patients narrow angles and borderline or in- undergoing an isosorbide dinitrate theracreased pressure without glaucomatous py, arterial blood pressure was recorded cupping, not under treatment when test- three times a day. In ten patients taked. Intraocular pressures were deter- ing 80 mg of isosorbide dinitrate per day mined with a Goldmann applanation for at least two weeks, blood levels of methemoglobin were determined by using the spectrophotometric method of From Justus Liebig-Universitiit, 63 Giessen, FRG, Evelyn and Malloy." Universitiits-Augenklinik, Friedrichstrasse (Dr. A. Wizemann), and Medizinische Universitiitsklinik, RESULTS Klinikstrasse (Dr. V. Wizemann). d Reprint requests to Angelika J. S. Wizemann, Nitroglycerin administere intraveM.D., Univ.-Augenklinik, D-63 Giessen, Germany. nously led to a dose-dependent decrease 106
AMERICAN JOURNAL OF OPHTHALMOLOGY
90:106-109, 1980
ORGANIC NITRATE THERAPY IN GLAUCOMA
VOL. 90, NO.1 % inhibition (lOP)
11pg Imin. nitroglyc«'in
%/OP
n=5
107
100
'0
I
..
30
".q, I
110
20
10
10
60
nitroglYCHin
50
200 (Jig/min)
40
~---r---r------.--.,....--
o
50
100
ISO
Fig. 1 (Wizemann and Wizemann). Dose response relation between intravenously administered nitroglycerin and lOP.
n.r_-.ngl. gt.ueom. n_ 9
.. _~.. _ .. __ ...A
~o..00 0 •• ,_ ........ _-_ ... o
0
•
30
20 10
in lOP. At a dose of 9.7 ug/minute, lOP was decreased by 9%. Doubling of the dose resulted in an inhibition of lOP by 19%; 50 J.Lg/minute of nitroglycerin inhibited by 24%. The maximum effect occurred at a dose of 100 ug/mtnute. A further increase in dosage of nitroglycerin did not exceed the maximum effect (Fig. 1). When nitroglycerin was infused with a constant dose of 97 J.Lg/minute, a decrease of lOP was recorded in patients with healthy eyes and patients with open and narrow angles. Patients with open angles responded with a maximum decrease in lOP of 50% after 30 minutes of infusion. The effect was constant during the infusion time of 120 minutes. In patients with narrow angles the action of nitroglycerin on lOP was less pronounced and during infusion there was a tendency of an increasing lOP (Fig. 2). Persons with normal lOP and no history of glaucoma showed a similar inhibition pattern under nitroglycerin infusion. A comparable result was obtained when 40 mg of isosorbide dinitrate (Sequels) was given orally twice daily. A decrease of lOP was detected in all 25 patients with open-angle glaucoma after 30 minutes. A 40% decrease in lOP lasted for five to six hours (Fig. 3). During the next
o
30
60
120 min.
90
Fig. 2 (Wizemann and Wizemann). Effect of97ILg of nitroglycerin per minute on lOP.
hours lOP increased slowly. The ten patients with normal lOPs and the 20 patients with narrow-angle glaucoma responded with a decrease in lOP of 25%. In three patients who responded poorly to topical treatment the therapy was interrupted for two days. When isosorbide dinitrate (2 x 40 rug/day) was given, lOP returned to normal (Fig. 4). Approximately 20% of the patients who took isosorbide dinitrate orally complained of headaches. When the therapy was continued, headaches disappeared o narrow - .flgi. glaucoma A.
normM
• ..n -angl.
".IOP
~I.uco,".
100
eo 60
'0 20
o
2
3
5
6
7
~
h
Fig. 3 (Wizemann and Wizemann), Reaction of lOP after 40 mg of isosorbide dinitrate (Sequels) administered orally.
108
AMERICAN JOURNAL OF OPHTHALMOLOGY
JUlX, 1980
lOP
finmHg] Is-CarbachOl 1% 3x
G1aucothil 0.1°/,. 2x
Fig. 4 (Wizemann and Wizemann). Intraocular pressure of a patient with open-angle glaucoma after isosorbide dinitrate monotherapy.
10
,
150170
145180
AA ["""Hg]
810 1216 20 6
8101216206
140180
t
8101216206
except in one patient who was omitted from the study. Systemic blood pressure was least influenced by the doses used when orally administered. Supermaximal doses of 194 ug/minute of nitroglycerin intravenously decreased mean arterial blood pressure by 10 to 20 mm/Hg. When the infusion was withdrawn, blood pressure returned to normal within one hour in all cases. In 16 patients taking isosorbide dinitrate orally for more than six months, no signs of cardiovascular or neurologic disorders could be detected. An escape phenomenon concerning the decreasing effect on lOP has not been seen yet. Methemoglobin concentrations in blood averaged 0.9% of total hemoglobin (range 0 to 2.7%). In no case could a pathologic value of more than 3.0% methemoglobin be measured.
140180
t
8101216206
therapy of angina pectoris and congestive heart failure. In recent years organic nitrates have been used in the therapy of acute myocardial infarction. 19 The cellular action of organic nitrates is still unknown. Nitroglycerin inhibits the calcium influx in potassium depolarized coronary smooth muscle." Because there is a specificity of this action to coronary vessels it seems unlikely that side effects of nitrates, as on the blush areas of the skin, the meningeal and intracranial vessels/' and the observed effect of the lOP can be explained by calcium antagonism. The decrease of lOP after intravenous or oral administration of nitrates did not correlate with the pattern of systemic blood pressure, thus indicating that systemic hemodynamic changes do not influence the effect on lOP. The dose of DISCUSSION nitrates used in our experiments exceeds Organic nitrates such as nitroglycerin those of previous studies. We believe or isosorbide dinitrate have a direct that the ineffectiveness of nitrates on lOP relaxing action on the smooth muscles of described by others7,1G-14 is the result of the blood vessels, mainly the large arter- the comparable low dose administered. With the exception of minor headies and the venous capacity system.P This leads to a venous pooling and a aches no side-effects occurred. It seems decrease of myocardial preload. Conse- unlikely that nitrate-induced methemoquently, those drugs are used in the globin is responsible for the headaches,
ORGANIC NITRATE THERAPY IN GLAUCOMA
VOL. 90, NO.1
because this symptom disappeared when the therapy was continued. In approximately 200 patients who had acute myocardial infarction, and who were treated by intravenous organic nitrates in 1979, no neurologic disorders have been seen by us. Because organic nitrates increase cardiac output in congestive heart failure, cerebral symptoms often improved. Because about one third of all elderly men suffer from coronary heart disease, organic nitrates can exert only beneficial cardiac side-effects, except in patients with mean arterial pressures below 80 mm/Hg. Our preliminary study shows a potential new indication for a drug that has been used for other purposes for more than 100 years. SUMMARY
We determined the effect of organic nitrates on normal volunteers and patients with open-angle and narrow-angle glaucoma. Nitroglycerin lowered intraocular pressure in all patients when administered by the perfusion technique. Isosorbide dinitrate given orally (2 x 40 mg per day) has a potent decreasing effect on intraocular pressure, which cannot be explained by the influence on arterial blood pressure. REFERENCES 1. Wessely, K.: Weitere Beitriige zur Lehre vom Augendruck, Arch. Augenheilkd. 78:247, 1915. 2. Kochmann, M., and Romer, P.: Experimentelle Beitriige zum pathologischen Fliissigkeitswechsel des Auges. Albrecht von Graefes Arch. Klin. Exp. Ophthalmol. 88:528, 1914. 3. Ogawa, M.: Gegenseitige Beziehungen des intraokularen, des arteriellen und des vendsen Druekes bei der Einwirkung verschiedener Pharmaka. Folia Pharmacol. Jpn. 5:15, 263, 1927. 4. Oliveres-Pallares, A.: Erfahrungen iiber den Wechsel des Augendruekes durch verschiedene Gefiissmittel. Arch. Oftal, Hisp. Am. 30:443, 1930.
109
5. Endo F.: Uber den EinHuss der Eintriiufelung verschiedener Medikamente in den Conjunctivalsack auf das Blutkreislaufsystem, insbesondere den Capillardruck der Macula lutea der Retina. Acta Soc. Ophthalmol. Jpn. 39:47, 545, 1935. 6. Christini, G., and Pagliarani, N.: Amyl nitrite test in primary glaucoma. Br. J. Ophthalmol. 33:741, 1953. 7. Grant, W. M.: Physiological and pharmacological influences upon intraocular pressure. Pharmacol. Rev. 7:143, 1955. 8. Kollner, H.: Ober den Augendruck beim Glaucoma simplex und seine Beziehungen zum Kreislauf. Arch. Augenheilkd. 93:135, 1918. 9. Bothman, L., and Cohen, S. J.: Studies in intraocular pressure. Arch. Ophthalmol. 56:110, 1927. 10. Zahn, K.: The effect of nitroglycerin on the retinal circulation. Cesk. Oftalmol. 13:146, 1957. 11. Whitworth, C. G., and Grant, W. M.: Use of nitrate and nitrite vasodilators by glaucomatous patients. Arch. Ophthalmol. 71:492, 1964. 12. Leydhecker, W.,Waller, W., and Krieglastein, G.: Die Wirkung getaerssweitemder Medikamente auf den intraokularen Druck. Klin. Menatsbl. Augenheilkd. 164:293, 1974. 13. Brodehl, D., and Steinbach, P.-D.: Wie wirkt Nitroglycerin auf den intraocularen Druck? Klin. Monastsbl. Augenheilkd. 166:784, 1975. 14. Steinbach, P. D., and Bell, H.: Wirkung gefiisserweitemder Substanzen auf Augeninnendruck und Blutdrock. Albrecht von Graefes Arch. Klin. Exp. Ophthalmol. 202:213, 1977. 15. Havener, W. H.: Ocular Pharmacology, 2nd ed. St. Louis, C. V. Mosby, 1970, p. 460. 16. Smith, M. B.: Handbook of Ocular Toxicity. Acton, Publishing Sciences Group, Inc., 1976, p. 453. 17. Evelyn, K. A., and Malloy, H. T.: Microdetermination of oxyhemoglobin, methemoglobin, and sulfhemoglobin in single sample of blood. J. BioI. Chern. 126:655, 1938. 18. Wilkins, R. W., Haynes, F. W., and Weiss, S.: The role of the venous system in circulatory collapse induced by sodium nitrite. J. Clin. Invest. 16:85, 1937. 19. Chatterjee, K., and Parmley, W.W.: The role of vasodilatator therapy in heart failure. Prog. Cardiovasc. Dis. 19:301, 1977. 20. Crun, G., and Fleckenstein, A.: Die elektromechanische Entkoppelung der glatten Gefli8muskulatur als Grundprinzip der Coronardilation durch (4-(2-Nitrophenyl)-2,6-dimethyl-1, 4-dihydropyridin-3, 5-dicarbonsaure-dimethylester (Bay a 1040 Nifedipine). Arzneimittel-Forsch. 22:334, 1972. 21. Bogaert, M. G.: Organic nitrates in angina pectoris. Arch. Int. Pharmacodyn. Ther. 196:25, 1972.
J. S. WIZEMANN, M.D.,
AND
VOLKER WIZEMANN, M.D.
Giessen, Gennany
In 1915 Wessely' observed that amyl nitrite causes an increase of intraocular pressure (lOP) in cats. Since then the use of organic nitrates has been considered to be contraindicted in glaucoma. Although the studies on amyl nitrite showed controversial results concerning the effect of that substance on IOP2-8 no case of nitroglycerin causing glaucoma had been reported'r" and some authors warned of the use of organic nitrates in the presence of glaucoma. 15,16 Because coronary heart disease as well as glaucoma occur more frequently in the elderly the application of organic nitrates is of interest clinically. Specific doses of nitroglycerin given intravenously by perfusion technique and high doses of isosorbide dinitrate administered orally were used. We describe herein the effect of organic nitrates on lOP.
tonometer. All measurements in each patient were made by one person. Arterial blood pressure was recorded every 30 minutes. The following three studies were performed: (1) Dose response: by means of a perfusion system, nitroglycerin was given intravenously in doses of9. 7 to 194 IJ.g/minute. Intraocular pressure was measured every five minutes. A doseresponse curve was obtained by changing the infusion speed. Beginning with the lowest dose of nitroglycerin, the dose was increased when a plateau of lOP was reached (usually after 20 to 30 minutes). (2) By administering 97 IJ.g of nitroglycerin per minute, changes in lOP were recorded in five- to 20-minute intervals. (3) Ten volunteers and 44 patients took 40 mg of isosorbide dinitrate orally at 8 o'clock in the morning. Intraocular pressure was measured at 30- to 60-minute SUBJECTS AND METHODS intervals thereafter. Three categories of patients were seIn three additional patients with lected for this study: (1) Ten volunteers open-angle glaucoma, antiglaucomatous with normal lOP, open angles, and no local therapy was interrupted and 2 X 40 history of glaucoma; (2) 25 patients with mg of isosorbide dinitrate was given open angles and borderline or increased orally for three weeks after a two-day lOP without cupping of the disk, in interval. Arterial blood pressure was whom antiglaucomatous treatment had measured at 30-minute intervals when not yet been started; (3) 20 patients with nitroglycerin was infused. In patients narrow angles and borderline or in- undergoing an isosorbide dinitrate theracreased pressure without glaucomatous py, arterial blood pressure was recorded cupping, not under treatment when test- three times a day. In ten patients taked. Intraocular pressures were deter- ing 80 mg of isosorbide dinitrate per day mined with a Goldmann applanation for at least two weeks, blood levels of methemoglobin were determined by using the spectrophotometric method of From Justus Liebig-Universitiit, 63 Giessen, FRG, Evelyn and Malloy." Universitiits-Augenklinik, Friedrichstrasse (Dr. A. Wizemann), and Medizinische Universitiitsklinik, RESULTS Klinikstrasse (Dr. V. Wizemann). d Reprint requests to Angelika J. S. Wizemann, Nitroglycerin administere intraveM.D., Univ.-Augenklinik, D-63 Giessen, Germany. nously led to a dose-dependent decrease 106
AMERICAN JOURNAL OF OPHTHALMOLOGY
90:106-109, 1980
ORGANIC NITRATE THERAPY IN GLAUCOMA
VOL. 90, NO.1 % inhibition (lOP)
11pg Imin. nitroglyc«'in
%/OP
n=5
107
100
'0
I
..
30
".q, I
110
20
10
10
60
nitroglYCHin
50
200 (Jig/min)
40
~---r---r------.--.,....--
o
50
100
ISO
Fig. 1 (Wizemann and Wizemann). Dose response relation between intravenously administered nitroglycerin and lOP.
n.r_-.ngl. gt.ueom. n_ 9
.. _~.. _ .. __ ...A
~o..00 0 •• ,_ ........ _-_ ... o
0
•
30
20 10
in lOP. At a dose of 9.7 ug/minute, lOP was decreased by 9%. Doubling of the dose resulted in an inhibition of lOP by 19%; 50 J.Lg/minute of nitroglycerin inhibited by 24%. The maximum effect occurred at a dose of 100 ug/mtnute. A further increase in dosage of nitroglycerin did not exceed the maximum effect (Fig. 1). When nitroglycerin was infused with a constant dose of 97 J.Lg/minute, a decrease of lOP was recorded in patients with healthy eyes and patients with open and narrow angles. Patients with open angles responded with a maximum decrease in lOP of 50% after 30 minutes of infusion. The effect was constant during the infusion time of 120 minutes. In patients with narrow angles the action of nitroglycerin on lOP was less pronounced and during infusion there was a tendency of an increasing lOP (Fig. 2). Persons with normal lOP and no history of glaucoma showed a similar inhibition pattern under nitroglycerin infusion. A comparable result was obtained when 40 mg of isosorbide dinitrate (Sequels) was given orally twice daily. A decrease of lOP was detected in all 25 patients with open-angle glaucoma after 30 minutes. A 40% decrease in lOP lasted for five to six hours (Fig. 3). During the next
o
30
60
120 min.
90
Fig. 2 (Wizemann and Wizemann). Effect of97ILg of nitroglycerin per minute on lOP.
hours lOP increased slowly. The ten patients with normal lOPs and the 20 patients with narrow-angle glaucoma responded with a decrease in lOP of 25%. In three patients who responded poorly to topical treatment the therapy was interrupted for two days. When isosorbide dinitrate (2 x 40 rug/day) was given, lOP returned to normal (Fig. 4). Approximately 20% of the patients who took isosorbide dinitrate orally complained of headaches. When the therapy was continued, headaches disappeared o narrow - .flgi. glaucoma A.
normM
• ..n -angl.
".IOP
~I.uco,".
100
eo 60
'0 20
o
2
3
5
6
7
~
h
Fig. 3 (Wizemann and Wizemann), Reaction of lOP after 40 mg of isosorbide dinitrate (Sequels) administered orally.
108
AMERICAN JOURNAL OF OPHTHALMOLOGY
JUlX, 1980
lOP
finmHg] Is-CarbachOl 1% 3x
G1aucothil 0.1°/,. 2x
Fig. 4 (Wizemann and Wizemann). Intraocular pressure of a patient with open-angle glaucoma after isosorbide dinitrate monotherapy.
10
,
150170
145180
AA ["""Hg]
810 1216 20 6
8101216206
140180
t
8101216206
except in one patient who was omitted from the study. Systemic blood pressure was least influenced by the doses used when orally administered. Supermaximal doses of 194 ug/minute of nitroglycerin intravenously decreased mean arterial blood pressure by 10 to 20 mm/Hg. When the infusion was withdrawn, blood pressure returned to normal within one hour in all cases. In 16 patients taking isosorbide dinitrate orally for more than six months, no signs of cardiovascular or neurologic disorders could be detected. An escape phenomenon concerning the decreasing effect on lOP has not been seen yet. Methemoglobin concentrations in blood averaged 0.9% of total hemoglobin (range 0 to 2.7%). In no case could a pathologic value of more than 3.0% methemoglobin be measured.
140180
t
8101216206
therapy of angina pectoris and congestive heart failure. In recent years organic nitrates have been used in the therapy of acute myocardial infarction. 19 The cellular action of organic nitrates is still unknown. Nitroglycerin inhibits the calcium influx in potassium depolarized coronary smooth muscle." Because there is a specificity of this action to coronary vessels it seems unlikely that side effects of nitrates, as on the blush areas of the skin, the meningeal and intracranial vessels/' and the observed effect of the lOP can be explained by calcium antagonism. The decrease of lOP after intravenous or oral administration of nitrates did not correlate with the pattern of systemic blood pressure, thus indicating that systemic hemodynamic changes do not influence the effect on lOP. The dose of DISCUSSION nitrates used in our experiments exceeds Organic nitrates such as nitroglycerin those of previous studies. We believe or isosorbide dinitrate have a direct that the ineffectiveness of nitrates on lOP relaxing action on the smooth muscles of described by others7,1G-14 is the result of the blood vessels, mainly the large arter- the comparable low dose administered. With the exception of minor headies and the venous capacity system.P This leads to a venous pooling and a aches no side-effects occurred. It seems decrease of myocardial preload. Conse- unlikely that nitrate-induced methemoquently, those drugs are used in the globin is responsible for the headaches,
ORGANIC NITRATE THERAPY IN GLAUCOMA
VOL. 90, NO.1
because this symptom disappeared when the therapy was continued. In approximately 200 patients who had acute myocardial infarction, and who were treated by intravenous organic nitrates in 1979, no neurologic disorders have been seen by us. Because organic nitrates increase cardiac output in congestive heart failure, cerebral symptoms often improved. Because about one third of all elderly men suffer from coronary heart disease, organic nitrates can exert only beneficial cardiac side-effects, except in patients with mean arterial pressures below 80 mm/Hg. Our preliminary study shows a potential new indication for a drug that has been used for other purposes for more than 100 years. SUMMARY
We determined the effect of organic nitrates on normal volunteers and patients with open-angle and narrow-angle glaucoma. Nitroglycerin lowered intraocular pressure in all patients when administered by the perfusion technique. Isosorbide dinitrate given orally (2 x 40 mg per day) has a potent decreasing effect on intraocular pressure, which cannot be explained by the influence on arterial blood pressure. REFERENCES 1. Wessely, K.: Weitere Beitriige zur Lehre vom Augendruck, Arch. Augenheilkd. 78:247, 1915. 2. Kochmann, M., and Romer, P.: Experimentelle Beitriige zum pathologischen Fliissigkeitswechsel des Auges. Albrecht von Graefes Arch. Klin. Exp. Ophthalmol. 88:528, 1914. 3. Ogawa, M.: Gegenseitige Beziehungen des intraokularen, des arteriellen und des vendsen Druekes bei der Einwirkung verschiedener Pharmaka. Folia Pharmacol. Jpn. 5:15, 263, 1927. 4. Oliveres-Pallares, A.: Erfahrungen iiber den Wechsel des Augendruekes durch verschiedene Gefiissmittel. Arch. Oftal, Hisp. Am. 30:443, 1930.
109
5. Endo F.: Uber den EinHuss der Eintriiufelung verschiedener Medikamente in den Conjunctivalsack auf das Blutkreislaufsystem, insbesondere den Capillardruck der Macula lutea der Retina. Acta Soc. Ophthalmol. Jpn. 39:47, 545, 1935. 6. Christini, G., and Pagliarani, N.: Amyl nitrite test in primary glaucoma. Br. J. Ophthalmol. 33:741, 1953. 7. Grant, W. M.: Physiological and pharmacological influences upon intraocular pressure. Pharmacol. Rev. 7:143, 1955. 8. Kollner, H.: Ober den Augendruck beim Glaucoma simplex und seine Beziehungen zum Kreislauf. Arch. Augenheilkd. 93:135, 1918. 9. Bothman, L., and Cohen, S. J.: Studies in intraocular pressure. Arch. Ophthalmol. 56:110, 1927. 10. Zahn, K.: The effect of nitroglycerin on the retinal circulation. Cesk. Oftalmol. 13:146, 1957. 11. Whitworth, C. G., and Grant, W. M.: Use of nitrate and nitrite vasodilators by glaucomatous patients. Arch. Ophthalmol. 71:492, 1964. 12. Leydhecker, W.,Waller, W., and Krieglastein, G.: Die Wirkung getaerssweitemder Medikamente auf den intraokularen Druck. Klin. Menatsbl. Augenheilkd. 164:293, 1974. 13. Brodehl, D., and Steinbach, P.-D.: Wie wirkt Nitroglycerin auf den intraocularen Druck? Klin. Monastsbl. Augenheilkd. 166:784, 1975. 14. Steinbach, P. D., and Bell, H.: Wirkung gefiisserweitemder Substanzen auf Augeninnendruck und Blutdrock. Albrecht von Graefes Arch. Klin. Exp. Ophthalmol. 202:213, 1977. 15. Havener, W. H.: Ocular Pharmacology, 2nd ed. St. Louis, C. V. Mosby, 1970, p. 460. 16. Smith, M. B.: Handbook of Ocular Toxicity. Acton, Publishing Sciences Group, Inc., 1976, p. 453. 17. Evelyn, K. A., and Malloy, H. T.: Microdetermination of oxyhemoglobin, methemoglobin, and sulfhemoglobin in single sample of blood. J. BioI. Chern. 126:655, 1938. 18. Wilkins, R. W., Haynes, F. W., and Weiss, S.: The role of the venous system in circulatory collapse induced by sodium nitrite. J. Clin. Invest. 16:85, 1937. 19. Chatterjee, K., and Parmley, W.W.: The role of vasodilatator therapy in heart failure. Prog. Cardiovasc. Dis. 19:301, 1977. 20. Crun, G., and Fleckenstein, A.: Die elektromechanische Entkoppelung der glatten Gefli8muskulatur als Grundprinzip der Coronardilation durch (4-(2-Nitrophenyl)-2,6-dimethyl-1, 4-dihydropyridin-3, 5-dicarbonsaure-dimethylester (Bay a 1040 Nifedipine). Arzneimittel-Forsch. 22:334, 1972. 21. Bogaert, M. G.: Organic nitrates in angina pectoris. Arch. Int. Pharmacodyn. Ther. 196:25, 1972.