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Effects of sublingual nitrate in patients receiving sustained therapy of isosorbide dinitrate for coronary artery disease
Effects of Sublingual Nitrate in Patients Receiving Sustained Therapy of lsosorbide Dinitrate for Coronary Artery Disease Hidetoshi Naito, MD, Yasuo Matsuda, MD, Kohtaro Shiomi, MD, Tadao Yorozu, MD, Toshiaki Maeda, MD, Hirofumi Lee, MD, Kohzaburo Seki, MD, and Hiroya Nakashima, MD
To examine the effects of subtingual isosorbide dinitrate (ISDN) in patients receiving sustained ISDN therapy, 24 patients with coronary artery disease were divided into 2 groups. Group C comprised 12 patients without sustained ISDN therapy and group N induded 12 patients with sustained ISDN therapy. Defore and during administration of subiinguai ISDN in both groups, aortic systdic pressure, teft ventricuiar end-diastotic pressure and coronary artery diameter were examined at cardiac catheterization. During subtinguai ISDN, the aortic systogcpressuredecreasedby2Of6%(136f26 to 112 f 27 mm Hg, p
From the Division of Cardiology, Saiseikai Yamaguchi General Hospital, and the Department of Internal Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan. Address for reprints: Hidetoshi Naito, MD, Division of Internal Medicine, Saiseikai Yamaguchi General Hospital, 11 Midori, Yamaguchi, Yamaguchi 753, Japan.
rganic nitrates are the most common medications used by physicians to treat patients with angina pectoris. The primary determinants of nitrate efficacy in preventing or relieving myocardial ischemia are the peripheral arterial and venous vasodilatory actions, resulting in a decrease in myocardial energy requirements related to a lower cardiac preload and afterload.le3 There is considerable evidence that nitrates also have important central or direct coronary actions in coronary artery disease. Nitrates produce an increase in coronary blood flow that is directly related to epicardial coronary artery dilation. 4-6 The sustained-release, orally administered preparation of this organic nitrate is being widely used for prophylactic treatment of angina pectoris. Tolerance develops with the long-term use of nitrates. Concern has been raised not only for the development of tolerance to the therapeutic effect of long-acting drugs such as oral isosorbide dinitrate (ISDN), but also for crossover tolerance impairing the efficacy of sublingual nitroglycerin. 7-L2 This study compares the short-term effects of sublingual ISDN for angina in patients with and without sustained therapy for angina. During cardiac catheterization, the plasma concentrations of ISDN, aortic pressures, left ventricular pressures and coronary artery diameters were assessed before and during sublingual ISDN in patients with and without sustained ISDN therapy.
0
METHODS Patient ae!lecGon: Twenty-four patients with coro-
nary artery disease were randomly divided into 2 groups. Twelve patients (group N) received long-acting ISDN, 20 mg 4 times daily, for >3 weeks. Another 12 patients (group C) did not have ISDN for at least 1 week. All other cardiac medications were stopped in all 24 patients 24 hours before cardiac catheterization. In group N, patients received the last administration of ISDN 2 hours before cardiac catheterization. Each patient signed a written informed consent, after full explanation of the procedure, before the study. Cardiac catheterization: Aortic and left ventricular pressures and plasma ISDN concentrations were obtained before administration of sublingual ISDN. Coronary arteriography was performed by the Sones technique and was followed by sublingual ISDN administration Five minutes after the resolution of sublingual
THE AMERICAN
JOURNAL
OF CARDIOLOGY
SEPTEMBER
15,
1989
565
SUBLINGUAL
NITRATE
TABLE I Patient
Profile
Age (w) Sex (M/F) No. coronary arteries >50% in diameter 0 1 2 3 Left ventricular ejection fraction (%) l
No sustained
nitrate therapy: t sustained
Group C* (n = 12)
Group N+ (n = 12)
65f8 10/2
57 f 8 12/o
0 8 2 2 62f
0 6 5 1 62f8
12
nitrate therapy.
ISDN, we again measured the aortic pressure, left ventricular pressure and plasma ISDN concentration, and repeated the coronary arteriography. The coronary angiography frame was the same as that before sublingual ISDN. Mea-
et plasma keshide
dinitrate con-
eationsr Immediately after blood sampling with a heparinized syringe, plasma was separated and stored in a freezer at -6OOC. ISDN concentrations were measured within a few weeks by gas chromatography according to the method of Rosseel and Bogaert.13 The gas chromatography system used was a Hewlett-Packard model 5710 A equipped with a 63 Ni-ECD and a 3 mm X 90 cm glass column packed with 3% OV-17 on Chromosorb WHP. The column and the detector were heated at 150°C and 2OO”C, respectively. The flow of N2 was at 60 ml/min. The detection limits calculated were 0.3 rig/ml in plasma. titwwlary~diameter measurememts: Our technique for measuring coronary artery diameters has been reported in detail previously.14J5 Briefly, 35-mm coronary angiograms were reviewed on a Vanguard projector. The coronary artery diameters were measured in the 30’ right anterior oblique projection at end-diastole by means of a Vernier caliper. The Sones catheter was measured at its tip, which was positioned within the cor-
(beatr/min)
CmmHe)
(mml-le)
1oa
responding coronary artery ostium. Actual coronary artery diameters were calculated by reference to the Sones catheter tip. The left main trunk, the proximal and distal segments of the left anterior descending coronary artery and the proximal and distal segments of the circumflex coronary artery were measured before and during sublingual ISDN (the investigators were blinded as to which patients were in group C or group N). Specific locations measured in each coronary artery have been described in detail elsewhere.14Js The measurement site was not apparently involved by coronary artery disease. Statistks: All values are expresed as mean f standard deviation. In each patient, the net change in each value was calculated by subtracting the value before sublingual ISDN was given from that obtained during sublingual ISDN. This net change was divided by the value before sublingual ISDN to yield the percent change. Statistical analysis was performed using the Student t test. For all analyses, a p value <0.05 was considered significant. RESULTS Patient protiler The patient profile for each group is listed in Table I. Hemodynamk parametmn: In group N, the plasma ISDN concentration before sublingual ISDN was 8 f 5 rig/ml. During sublingual ISDN, the plasma ISDN concentrations were 145 f 82 rig/ml in group C and 114 f 94 rig/ml in group N (difference not significant). The hemodynamic measurements are listed in Table II. Figures 1 and 2 show the changes in heart rate, aortic systolic and diastolic pressures, and left ventricular enddiastolic pressure before and during sublingual ISDN. Sublingual ISDN increased the heart rate by 9 f 9% in group C and 5 f 5% in group N (difference not significant). The aortic systolic pressure decreased by 20 f 6% in group C and 10 f 6% in group N (p
6nmHg)
1oa
75
150NS
SC
75
T
[
INS
xl 1
loo-
PCO.01 IP
pco.01
F40.01
5a
1 a
PRE
POST
OsGTF
HR
566
THE AMERICAN
a
AoSP
JOURNAL
OF CARDIOLOGY
PRE
POST
AoDP
VOLUME
64
0
PRE POST LVEDP
TABLE
II
Hemodynamic
Data Group C* (n = 12) Sublingual
Group NT (n = 12) Sublingual Nitrate
Nitrate
Before Heart Aortic
During
66% 11
rate (beats/min) systolic pressure
72f14
68f8
71&8
(mm
Hg)
138 f 26
Aortic diastolic pressure (mm Left ventricular end-diastolic pressure (mm Hg) Coronary artery diameter Left main trunk (mm) Proximal LAD (mm) Distal LAD (mm) Proximal Cx (mm) Distal Cx (mm)
Hg)
66 f 7 llf5
65f8 4f3
73f13 12f5
70flO 7f3
3.0 f 0.4 2.0 f 0.4
3.3 i 0.6 2.4 f 0.4
3.2 f 0.5 2.2 f 0.6
3.4 f 0.7 2.4 f 0.7
1.3f0.3 1.8f0.4 1.3f0.4
1.7 f0.4
1.5 f 0.4
1.8 f 0.4
2.3 f 0.5
2.2 f 0.6
1.8f0.6
1.7 f 0.4
2.4 f 0.7 2.0 f 0.6
* No sustained nitrate therapy; t sustained nitrate therapy. Cx = left circumflex coronary artery; IAD = left anterior descending
112i27
coronary
(%I
NS
T-
1 ?--&
__ C
N
113i23
dilated the left main trunk by 11 f 11% in group C and 5 f 10% in group N (difference not significant). The proximal left anterior descending coronary artery was dilated by 24 f 13% in group C and 10 f 8% in group N (p
flGURE2.Pe~rcentchangeshhemodynuniep=ameWsin groupCandlZrollpN.AWrevbtionrasinFigurel.
0
127 f 26
artery.
65 f 16% in group C and 43 f 14% in group N (p
201
During
Before
PRE
LMT
POST
PRE
POST
LAD-P
PRE
POST
LAD-D
PRE
POST
PRE
cx-P
POST
CX-D _1
THE AMERICAN
JOURNAL
OF CARDIOLOGY
SEPTEMBER
15,
1989
567
3UGUNGUAL
NITRATE
duced by the long-term oral administration of ISDN. These results suggest that the short-term effect of sublingual ISDN for the relief of ischemic manifestations might be more significant in patients without sustained ISDN therapy than in those with sustained ISDN therapy. Additional study will be required to compare the short-term effects of sublingual nitrates during ischemic attacks in patients with and without sustained nitrate therapy.
6040200 LMT
C N LAD-P
LAD-D
cx-P
Acknowledgment: We express our gratitude to Toa Eiyo, Ltd. for the measurement of plasma isosorbide dinitrate concentrations.
CX-D
REFERENCES cantly different between initial testing and follow-up testing with high-dose ISDN. The exercise time after sublingual nitroglycerin did not reveal any significant difference between initial testing and follow-up testing. Lee et al8 evaluated the cross tolerance to the antianginal effect of sublingually administered nitroglycerin in patients with long-term oral administration of ISDN. The demonstration in that study of the ability to achieve equivalent improvements in exercise performance before and 1 month after ISDN therapy indicated that longterm oral administration of large doses of this long-acting nitrate does not result in cross tolerance to the antiangina1 action of sublingually administered nitroglycerin. The question, still controversial, of whether ISDN administered orally in large doses induces the develop ment of tolerance, especially in regard to cross tolerance to sublingually administered nitroglycerii, has assumed greater importance. The prevention and relief of angina are mainly attributed to the reduction of afterload and preload, and the dilation of the coronary artery.1-3 In the present study, we used the aortic systolic pressure as an indicator of afterload and the left ventricular end-diastolic pressure as an indicator of preload, and measured the coronary artery diameter. During the administration of sublingual ISDN, the reductions in aortic systolic pressure and left ventricular end-diastolic pressure, and the dilations of coronary artery diameter were significant both in patients with and without sustained ISDN therapy. When these changes were compared between patients with and without sustained ISDN therapy, the patients with sustained ISDN had less reduction in aortic systolic pressure and left ventricular end-diastolic pressure, and less dilation of coronary artery diameter. Our investigation indicates that cross tolerance to the effect of sublingually administered nitrate could be in-
568
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
64
1. Abrams .I. Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 1985;110:216-224. 2. Reichek N. Nitroglycerin in chronic stable angina pectoris. Am J Cardiol 1987,60:15H-l7H. 3. Abrams J. A reappraisal of nitrate therapy. JAM.4
1988;259:396-401.
4. Vatner SF, Pagani M, Rutherford JD, Millard RW, Manders WT. Effects of nitroglycerin on cardiac performance and regional blood flow distribution in conscious dogs. Am J Physiol 1978;234:H244-H252. 5. Brown G, Bolson E, Petersen RB, Pierce CD, Dodge HT. The mechanisms of nitroglycerin action: stenosis vasodilation as a major component of drug response. Circulation
1981,64:1089-1097.
6. Conti CR, Feldman RL, Pepine CJ, Hill JA, Conti JB. Effect of glyceril trinitrate on coronary and systemic hemodynamics in man. Am J Med 1983; 74:28-32. 7. Danahy DT, Burwell DT, Aronow WS. Sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate. Circulation 1977;55:381-387.
8. Lee G, Mason DT, DeMaria AN. Effects of long-term oral administration of isosorbide dinitrate on the antianginal response to nitroglycerin. Absence of nitrate cross-tolerance and self-tolerance shown by exercise testing. Am J Cardiol 1978;41:82-87.
9. Parker JO. Nitrate
therapy
in stable angina pcctoris. N Engl
J &fed
1987;316:1635-1642.
10. Schelling JL, Lasagna L. A study of cross tolerance to circulatory effects of organic nitrates. Clin Pharmacol Ther 1%7;8:256-260. 11. Thadani U, Manyari D, Parker JO. Tolerance to the circulatory effects of oral isosorbide dinitrate: rate of development and cross tolerance to glyceryl trinitrate. Circulation
1980,61:526-535.
Manyari DE, Smith ER, Spragg RT. Isceorbide din&ate and glyceril trinitrate: demonstration of cross tolerance in the capacitance vessels. Am J Cardiol 12.
1985;55:927-931.
13. Rosseel MT, Bogaert MG. GLC determination of nitroglycerin and isceorbide dinitrate in human plasma. J Pharm Sci 1973,62:754-758. 14. Matsuda Y, Ogawa H, Moritani K, Fujii T, Yoshino F, Katayama K, Miura T, Toma Y, Matsuda M, Kusukawa R. Coronary angiography during exerciseinduced angina with ECG changes. Am Heart .I 1984:108:959-966. 19. Matsuda Y, Moritani K, Ogawa H, Kohno M, Kohtoku S, Miura T, Hiro T, Yano M, Matsuda M, Kusukawa R. Response of the coronary artery to a small dose of ergonovine in variant angina. Am Heart J 1986:112:947-952. 16. Lee G, Mason DT, Amsterdam EA, Millar RR, DeMaria AN. Antianginal efficacy of oral therapy with isosorbide dinitrate capsules: prolonged benefit shown by exercise testing in patients with ischemic heart disease. Chest 1978;73:327-332. 17.
Parker JO, Fung HL. Transdermal
Cardiol
nitroglycerin
in angina pectoris. Am J
1984:54:1-7.
18. Parker JO, Vankoughnett KA, Farrell B. Comparison of buccal nitroglycerin and oral isosorbide dinitrate for nitrate tolerance in stable angina pectoris. Am J Cardiol
1985;56:724-728.
19. Parker JO, Vankoughnett KA, Fung HL. Transdermal isosorbide dinitrate in angina pectoria effects of acute and sustained therapy. Am J Cardio/l984;54:813.
To examine the effects of subtingual isosorbide dinitrate (ISDN) in patients receiving sustained ISDN therapy, 24 patients with coronary artery disease were divided into 2 groups. Group C comprised 12 patients without sustained ISDN therapy and group N induded 12 patients with sustained ISDN therapy. Defore and during administration of subiinguai ISDN in both groups, aortic systdic pressure, teft ventricuiar end-diastotic pressure and coronary artery diameter were examined at cardiac catheterization. During subtinguai ISDN, the aortic systogcpressuredecreasedby2Of6%(136f26 to 112 f 27 mm Hg, p
From the Division of Cardiology, Saiseikai Yamaguchi General Hospital, and the Department of Internal Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan. Address for reprints: Hidetoshi Naito, MD, Division of Internal Medicine, Saiseikai Yamaguchi General Hospital, 11 Midori, Yamaguchi, Yamaguchi 753, Japan.
rganic nitrates are the most common medications used by physicians to treat patients with angina pectoris. The primary determinants of nitrate efficacy in preventing or relieving myocardial ischemia are the peripheral arterial and venous vasodilatory actions, resulting in a decrease in myocardial energy requirements related to a lower cardiac preload and afterload.le3 There is considerable evidence that nitrates also have important central or direct coronary actions in coronary artery disease. Nitrates produce an increase in coronary blood flow that is directly related to epicardial coronary artery dilation. 4-6 The sustained-release, orally administered preparation of this organic nitrate is being widely used for prophylactic treatment of angina pectoris. Tolerance develops with the long-term use of nitrates. Concern has been raised not only for the development of tolerance to the therapeutic effect of long-acting drugs such as oral isosorbide dinitrate (ISDN), but also for crossover tolerance impairing the efficacy of sublingual nitroglycerin. 7-L2 This study compares the short-term effects of sublingual ISDN for angina in patients with and without sustained therapy for angina. During cardiac catheterization, the plasma concentrations of ISDN, aortic pressures, left ventricular pressures and coronary artery diameters were assessed before and during sublingual ISDN in patients with and without sustained ISDN therapy.
0
METHODS Patient ae!lecGon: Twenty-four patients with coro-
nary artery disease were randomly divided into 2 groups. Twelve patients (group N) received long-acting ISDN, 20 mg 4 times daily, for >3 weeks. Another 12 patients (group C) did not have ISDN for at least 1 week. All other cardiac medications were stopped in all 24 patients 24 hours before cardiac catheterization. In group N, patients received the last administration of ISDN 2 hours before cardiac catheterization. Each patient signed a written informed consent, after full explanation of the procedure, before the study. Cardiac catheterization: Aortic and left ventricular pressures and plasma ISDN concentrations were obtained before administration of sublingual ISDN. Coronary arteriography was performed by the Sones technique and was followed by sublingual ISDN administration Five minutes after the resolution of sublingual
THE AMERICAN
JOURNAL
OF CARDIOLOGY
SEPTEMBER
15,
1989
565
SUBLINGUAL
NITRATE
TABLE I Patient
Profile
Age (w) Sex (M/F) No. coronary arteries >50% in diameter 0 1 2 3 Left ventricular ejection fraction (%) l
No sustained
nitrate therapy: t sustained
Group C* (n = 12)
Group N+ (n = 12)
65f8 10/2
57 f 8 12/o
0 8 2 2 62f
0 6 5 1 62f8
12
nitrate therapy.
ISDN, we again measured the aortic pressure, left ventricular pressure and plasma ISDN concentration, and repeated the coronary arteriography. The coronary angiography frame was the same as that before sublingual ISDN. Mea-
et plasma keshide
dinitrate con-
eationsr Immediately after blood sampling with a heparinized syringe, plasma was separated and stored in a freezer at -6OOC. ISDN concentrations were measured within a few weeks by gas chromatography according to the method of Rosseel and Bogaert.13 The gas chromatography system used was a Hewlett-Packard model 5710 A equipped with a 63 Ni-ECD and a 3 mm X 90 cm glass column packed with 3% OV-17 on Chromosorb WHP. The column and the detector were heated at 150°C and 2OO”C, respectively. The flow of N2 was at 60 ml/min. The detection limits calculated were 0.3 rig/ml in plasma. titwwlary~diameter measurememts: Our technique for measuring coronary artery diameters has been reported in detail previously.14J5 Briefly, 35-mm coronary angiograms were reviewed on a Vanguard projector. The coronary artery diameters were measured in the 30’ right anterior oblique projection at end-diastole by means of a Vernier caliper. The Sones catheter was measured at its tip, which was positioned within the cor-
(beatr/min)
CmmHe)
(mml-le)
1oa
responding coronary artery ostium. Actual coronary artery diameters were calculated by reference to the Sones catheter tip. The left main trunk, the proximal and distal segments of the left anterior descending coronary artery and the proximal and distal segments of the circumflex coronary artery were measured before and during sublingual ISDN (the investigators were blinded as to which patients were in group C or group N). Specific locations measured in each coronary artery have been described in detail elsewhere.14Js The measurement site was not apparently involved by coronary artery disease. Statistks: All values are expresed as mean f standard deviation. In each patient, the net change in each value was calculated by subtracting the value before sublingual ISDN was given from that obtained during sublingual ISDN. This net change was divided by the value before sublingual ISDN to yield the percent change. Statistical analysis was performed using the Student t test. For all analyses, a p value <0.05 was considered significant. RESULTS Patient protiler The patient profile for each group is listed in Table I. Hemodynamk parametmn: In group N, the plasma ISDN concentration before sublingual ISDN was 8 f 5 rig/ml. During sublingual ISDN, the plasma ISDN concentrations were 145 f 82 rig/ml in group C and 114 f 94 rig/ml in group N (difference not significant). The hemodynamic measurements are listed in Table II. Figures 1 and 2 show the changes in heart rate, aortic systolic and diastolic pressures, and left ventricular enddiastolic pressure before and during sublingual ISDN. Sublingual ISDN increased the heart rate by 9 f 9% in group C and 5 f 5% in group N (difference not significant). The aortic systolic pressure decreased by 20 f 6% in group C and 10 f 6% in group N (p
6nmHg)
1oa
75
150NS
SC
75
T
[
INS
xl 1
loo-
PCO.01 IP
pco.01
F40.01
5a
1 a
PRE
POST
OsGTF
HR
566
THE AMERICAN
a
AoSP
JOURNAL
OF CARDIOLOGY
PRE
POST
AoDP
VOLUME
64
0
PRE POST LVEDP
TABLE
II
Hemodynamic
Data Group C* (n = 12) Sublingual
Group NT (n = 12) Sublingual Nitrate
Nitrate
Before Heart Aortic
During
66% 11
rate (beats/min) systolic pressure
72f14
68f8
71&8
(mm
Hg)
138 f 26
Aortic diastolic pressure (mm Left ventricular end-diastolic pressure (mm Hg) Coronary artery diameter Left main trunk (mm) Proximal LAD (mm) Distal LAD (mm) Proximal Cx (mm) Distal Cx (mm)
Hg)
66 f 7 llf5
65f8 4f3
73f13 12f5
70flO 7f3
3.0 f 0.4 2.0 f 0.4
3.3 i 0.6 2.4 f 0.4
3.2 f 0.5 2.2 f 0.6
3.4 f 0.7 2.4 f 0.7
1.3f0.3 1.8f0.4 1.3f0.4
1.7 f0.4
1.5 f 0.4
1.8 f 0.4
2.3 f 0.5
2.2 f 0.6
1.8f0.6
1.7 f 0.4
2.4 f 0.7 2.0 f 0.6
* No sustained nitrate therapy; t sustained nitrate therapy. Cx = left circumflex coronary artery; IAD = left anterior descending
112i27
coronary
(%I
NS
T-
1 ?--&
__ C
N
113i23
dilated the left main trunk by 11 f 11% in group C and 5 f 10% in group N (difference not significant). The proximal left anterior descending coronary artery was dilated by 24 f 13% in group C and 10 f 8% in group N (p
flGURE2.Pe~rcentchangeshhemodynuniep=ameWsin groupCandlZrollpN.AWrevbtionrasinFigurel.
0
127 f 26
artery.
65 f 16% in group C and 43 f 14% in group N (p
201
During
Before
PRE
LMT
POST
PRE
POST
LAD-P
PRE
POST
LAD-D
PRE
POST
PRE
cx-P
POST
CX-D _1
THE AMERICAN
JOURNAL
OF CARDIOLOGY
SEPTEMBER
15,
1989
567
3UGUNGUAL
NITRATE
duced by the long-term oral administration of ISDN. These results suggest that the short-term effect of sublingual ISDN for the relief of ischemic manifestations might be more significant in patients without sustained ISDN therapy than in those with sustained ISDN therapy. Additional study will be required to compare the short-term effects of sublingual nitrates during ischemic attacks in patients with and without sustained nitrate therapy.
6040200 LMT
C N LAD-P
LAD-D
cx-P
Acknowledgment: We express our gratitude to Toa Eiyo, Ltd. for the measurement of plasma isosorbide dinitrate concentrations.
CX-D
REFERENCES cantly different between initial testing and follow-up testing with high-dose ISDN. The exercise time after sublingual nitroglycerin did not reveal any significant difference between initial testing and follow-up testing. Lee et al8 evaluated the cross tolerance to the antianginal effect of sublingually administered nitroglycerin in patients with long-term oral administration of ISDN. The demonstration in that study of the ability to achieve equivalent improvements in exercise performance before and 1 month after ISDN therapy indicated that longterm oral administration of large doses of this long-acting nitrate does not result in cross tolerance to the antiangina1 action of sublingually administered nitroglycerin. The question, still controversial, of whether ISDN administered orally in large doses induces the develop ment of tolerance, especially in regard to cross tolerance to sublingually administered nitroglycerii, has assumed greater importance. The prevention and relief of angina are mainly attributed to the reduction of afterload and preload, and the dilation of the coronary artery.1-3 In the present study, we used the aortic systolic pressure as an indicator of afterload and the left ventricular end-diastolic pressure as an indicator of preload, and measured the coronary artery diameter. During the administration of sublingual ISDN, the reductions in aortic systolic pressure and left ventricular end-diastolic pressure, and the dilations of coronary artery diameter were significant both in patients with and without sustained ISDN therapy. When these changes were compared between patients with and without sustained ISDN therapy, the patients with sustained ISDN had less reduction in aortic systolic pressure and left ventricular end-diastolic pressure, and less dilation of coronary artery diameter. Our investigation indicates that cross tolerance to the effect of sublingually administered nitrate could be in-
568
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
64
1. Abrams .I. Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 1985;110:216-224. 2. Reichek N. Nitroglycerin in chronic stable angina pectoris. Am J Cardiol 1987,60:15H-l7H. 3. Abrams J. A reappraisal of nitrate therapy. JAM.4
1988;259:396-401.
4. Vatner SF, Pagani M, Rutherford JD, Millard RW, Manders WT. Effects of nitroglycerin on cardiac performance and regional blood flow distribution in conscious dogs. Am J Physiol 1978;234:H244-H252. 5. Brown G, Bolson E, Petersen RB, Pierce CD, Dodge HT. The mechanisms of nitroglycerin action: stenosis vasodilation as a major component of drug response. Circulation
1981,64:1089-1097.
6. Conti CR, Feldman RL, Pepine CJ, Hill JA, Conti JB. Effect of glyceril trinitrate on coronary and systemic hemodynamics in man. Am J Med 1983; 74:28-32. 7. Danahy DT, Burwell DT, Aronow WS. Sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate. Circulation 1977;55:381-387.
8. Lee G, Mason DT, DeMaria AN. Effects of long-term oral administration of isosorbide dinitrate on the antianginal response to nitroglycerin. Absence of nitrate cross-tolerance and self-tolerance shown by exercise testing. Am J Cardiol 1978;41:82-87.
9. Parker JO. Nitrate
therapy
in stable angina pcctoris. N Engl
J &fed
1987;316:1635-1642.
10. Schelling JL, Lasagna L. A study of cross tolerance to circulatory effects of organic nitrates. Clin Pharmacol Ther 1%7;8:256-260. 11. Thadani U, Manyari D, Parker JO. Tolerance to the circulatory effects of oral isosorbide dinitrate: rate of development and cross tolerance to glyceryl trinitrate. Circulation
1980,61:526-535.
Manyari DE, Smith ER, Spragg RT. Isceorbide din&ate and glyceril trinitrate: demonstration of cross tolerance in the capacitance vessels. Am J Cardiol 12.
1985;55:927-931.
13. Rosseel MT, Bogaert MG. GLC determination of nitroglycerin and isceorbide dinitrate in human plasma. J Pharm Sci 1973,62:754-758. 14. Matsuda Y, Ogawa H, Moritani K, Fujii T, Yoshino F, Katayama K, Miura T, Toma Y, Matsuda M, Kusukawa R. Coronary angiography during exerciseinduced angina with ECG changes. Am Heart .I 1984:108:959-966. 19. Matsuda Y, Moritani K, Ogawa H, Kohno M, Kohtoku S, Miura T, Hiro T, Yano M, Matsuda M, Kusukawa R. Response of the coronary artery to a small dose of ergonovine in variant angina. Am Heart J 1986:112:947-952. 16. Lee G, Mason DT, Amsterdam EA, Millar RR, DeMaria AN. Antianginal efficacy of oral therapy with isosorbide dinitrate capsules: prolonged benefit shown by exercise testing in patients with ischemic heart disease. Chest 1978;73:327-332. 17.
Parker JO, Fung HL. Transdermal
Cardiol
nitroglycerin
in angina pectoris. Am J
1984:54:1-7.
18. Parker JO, Vankoughnett KA, Farrell B. Comparison of buccal nitroglycerin and oral isosorbide dinitrate for nitrate tolerance in stable angina pectoris. Am J Cardiol
1985;56:724-728.
19. Parker JO, Vankoughnett KA, Fung HL. Transdermal isosorbide dinitrate in angina pectoria effects of acute and sustained therapy. Am J Cardio/l984;54:813.