- Email: [email protected]
Role of isosorbide dinitrate in patients with unstable angina pectoris
UNSTABLE
ANGINA
Role of isosorbide dinitrate unstable angina pectoris
in patients
with
The development of hemodynamic facilities permitted observations after isosorbide dinitrate (ISDN) administration over a 4-hour period in patients with a history of unstable angina pectoris and documented anatomic coronary artery disease. The patients had no evidence of left ventricular failure and were free of pain during the period of sublingual and oral ISDN administration. Beneficial influences on venous return and arterial blood pressure were manifested as declines in preload and afterload, along with reduction in the mechanical work of the ventricle and, finally, increases in the diastolic compliance of the ventricle. These hemodynamic changes were shown to persist 8 to 12 times as long as the brief influence of nitroglycerin. Thus hemodynamic evidence was provided for the first time on the beneficial influence of oral and sublingual ISDN on venous, arterial, and left ventricular myocardial muscle in patients with unstable angina pectoris. (AM HEART J 110:26g, 1965.)
Charles E. Rackley,
M.D. Washington,
D.C.
Although long-acting nitrates have been prescribed for patients with angina pectoris for several decades, many years elapsed before physiologic measurements documented the circulatory response to these agents.’ Earlier studies had shown circulatory changes persisting for 1 hour with invasive techniques in patients receiving isosorbide dinitrate (ISDN).z A major limitation of such clinical studies was a lack of monitoring capability for prolonged periods in patients with unstable angina. The development of the modern coronary care unit, the Swan-Ganz catheter, and the facilities for hemodynamic monitoring in the coronary intensive care unit provided the necessary environment for clinical investigation in the role of ISDN in angina pectoris.3 METHODS
Unstable angina pectoris is clinically defined as the recent onset or progression of ischemic pain within a 3-month period characterized by rest or nocturnal discomfort. An episode of chest pain must be documented on an ECG with transient ST segment and T wave changes that return to normal after relief of pain. Cardiac enzymes should remain normal, without evidence of myocardial From ter.
the Department
of Medicine,
Georgetown
Reprint requests: Charles E. Rackley, Gec.rgetown University Medical Center, DC 20007.
University
Medical
Cen-
M.D., Department of Medicine, 3800 Reservoir Rd., Washington,
necrosis. Patients meeting these criteria were admitted to the coronary care unit and observed for documentation of chest discomfort with ECG changes.4 Cardiac catheterization was subsequently performed to confirm the presence of anatomic coronary artery disease and to evaluate left ventricular function. During the catheterization a SwanGanz catheter was inserted into the patient’s pulmonary artery and remained following completion of the diagnostic procedure. After the catheterization was completed, the patient was returned to the coronary care unit for hemodynamic monitoring of the pulmonary artery enddiastolic pressure (PAEDP), heart rate, and cardiac output. M-mode echocardiography was used to measure left ventricular dimensions and volume. The patients rested comfortably in bed without chest discomfort, and none had hemodynamic or clinical evidence of congestive heart failure. After baseline hemodynamic observations over a 30-minute period, the patients were given either a sublingual placebo, 0.4 mg of nitroglycerin, 10 mg of ISDN, or 20 mg orally of ISDN. Serial measurements of heart rate, systemic blood pressure, cardiac output, PAEDP, and echocardiograms were obtained at lo-, 20-, and 30-minute intervals and thereafter every 30 minutes for a total of 4 hours. None of the patients experienced chest discomfort during the periods of observation. Derived hemodynamic measurements were calculated from the following formulas: (1) mean arterial pressure equals two-thirds systolic pressure plus diastolic pressure, (2) cardiac index equals cardiac output divided by the body surface area in square meters, and (3) stroke work index equals (mean systolic ejection pressure minus PAEDP) times 0.0136 times stroke index. 269
July,
270
Rackley
American
Heart
1985
Journal
0.4.
02.
.
i \
-O.&I
0 10 20 30
60
90
120 Time
1. Although reductions in diastolic pulmonary artery pressure were minimal, there was a significant decrease at 60 minutes after sublingual ISDN. (From Willis WH, Russell RO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbidedinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15, 1976.) Fig.
StatIstIcally Slgnlflcant * lP<_O.lO) l (P< 0.05)
60
90 Time
120
150
180
values
210
240
mmutes
2. Mean arterial blood pressure was significantly reduced after both sublingual and oral ISDN. Lowest value wasachieved at 30 minutes and persistedfor 4 hours in comparison with placebo control values. (From Willis WH, RussellRO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbidedinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15, 1976.) Fig.
RESULTS
Thirty-seven patients meeting the clinical definition of unstable angina pectoris underwent cardiac catheterization. All patients had anatomic coronary artery disease demonstrated by greater than 50% narrowing of one or more major coronary vessels, but no hemodynamic evidence of left ventricular failure was found. Left ventricular function was normal. Pulmonary artery end-diastolic pressure. The PAEDP was 12 mm Hg or less in all patients, which
150
180
210
c 240
minutes
3. In patients with normal left ventricular function, cardiac index wasnot altered with either sublingual or oral ISDN during I-hour period of observation. (From Willis WH, RussellRO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbidedinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15, 1976.) Fig.
was normal for the laboratory. Following the administration of sublingual nitroglycerin, PAEDP declined 3 mm Hg by 5 minutes and returned to control baseline values by 20 minutes. In the patients receiving sublingual ISDN, the PAEDP gradually declined, reaching the lowest value at 60 minutes (Fig. 1). Both the initial decline and the return to the baseline value were much more gradual with the administration of sublingual ISDN than with nitroglycerin. Mean arterial pressure. The mean arterial pressure fell significantly in patients given either sublingual or oral ISDN, and the lowest values were observed 30 minutes after administration. In both groups, mean arterial pressure remained significantly low for 4 hours in comparison with control values (Fig. 2). The average reduction in mean arterial pressure was 10 mm Hg. Cardiac output and volumes. Thermodilution estimates of cardiac. output were slightly lower in the patients given sublingual ISDN over the 4-hour period of observation, but these differences did not achieve statistical significance (Fig. 3). End-diastolic volume of the left ventricle was calculated from M-mode echocardiograms, analyzed in control patients, and compared with the volume in individuals receiving sublingual ISDN. The end-diastolic volume was significantly smaller in patients receiving sublingual ISDN in comparison with control values; the average reduction was 30 ml. During the first 30 minutes of observation, the end-diastolic volume increased both in the control group and in
Volume
110
Number
1, part 2
ISDN
in unstable
60
90 120 Tfme minutes
angina
pectoris
l
--+%xwxblde -o-lsosorbtde
dmltrate dinitrate
controls sublmgual
-5o-
b io io;o
$0
I
90 Time
120 m,nutesl
50
180
210
2’40
Fig. 4. Echocardiographic
end-diastolic volume was significantly reduced in patients receiving sublingual ISDN at 4 hours in comparison with control subjects. Initial increase in end-diastolic volume was noted in both control subjects and ISDN recipients for first 30 minutes and was attributed to volume overloading because of frequent determinations of thermodilution cardiac output. (From Willis WH, Russell RO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbide dinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15,
1976.)
patients receiving ISDN (Fig. 4). However, during this initial 30-minute period of observation, the patients were having frequent thermodilution measurements of cardiac output every 10 minutes and received an average of 50 ml cold solution for each determination. Therefore, these patients received a minimum of 200 ml of fluid, which produced a volume expansion during the first half-hour of the study period. Following this initial 30-minute period of observation, there was a significant decline in the end-diastolic volume in the individuals receiving sublingual ISDN, and these differences were statistically significant. Stroke work. The stroke index was calculated in control subjects and individuals receiving sublingual as well as oral ISDN. The stroke work index is derived from the systemic arterial pressure, cardiac index, heart rate, and PAEDP. Both the sublingual and the oral ISDN recipients exhibited a reduction in the stroke work index by 30 minutes, and this persisted in both categories. The stroke work index remained reduced for 2% hours in the individuals receiving sublingual ISDN and for 4 hours in those given oral ISDN (Fig. 5). DISCUSSION
These hemodynamic measurements revealed nificant changes after both sublingual and ISDN in patients with unstable angina pectoris anatomic coronary artery disease. None of
sigoral and the
0 10 20 30
150
iRO
210
240
5. Significant reduction in stroke work index was noted in patients receiving oral ISDN. There was also a reduction in stroke work index in patients receiving sublingual ISDN, but these values were not statistically significant. (From Willis WH, Russell RO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbide dinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15, 1976.) Fig.
patients experienced ischemic pain during the period of study, and there was no hemodynamic evidence of left ventricular failure. The hemodynamic parameters were normal at rest in all of these individuals, and observed changes would therefore be expected to be small. These clinical studies were the first to demonstrate prolonged hemodynamic changes with ISDN by both the sublingual and the oral routes in patients with unstable angina pectoris. These hemodynamic events reflect venodilation and reduced venous return to the right and left ventricles.“-’ Therefore a primary mechanism was a reduction in preload of the left ventricle. In addition, the arteriolar dilation, reflected as a decline in systemic blood pressure, indicates the beneficial effects on afterload reduction.s Both the preload and afterload reduction would significantly reduce the mechanical work of the left ventricle as reflected by the stroke work index. The stroke work index is the major mechanical requirement for myocardial oxygen consumption of the left ventricle. Finally, the decrease in enddiastolic volume seen on the echocardiograms confirms the reduction in preload in the left ventricle. It is of interest that the initial increase in the enddiastolic volume caused by volume overloading of the left ventricle from the frequent thermodilution cardiac output measurements occurred when there was a slight but measurable decline in the filling pressure of the ventricle. Thus an increase in enddiastolic volume attended by a decline in enddiastolic pressure suggests an increase in the compli-
272
Rackley
ante of the left ventricle.‘0 This could be interpreted as a direct influence of long-acting nitrates on the myocardium on the left ventricle. The vasodilating effects on the smooth muscle of the venous and arterial beds would also be augmented by an increase in the elastic properties of the myocardiurn. These hemodynamic changes in patients with a history of unstable angina pectoris indicate a beneficial influence of sublingual and oral ISDN on preload, afterload, ventricular compliance, and mechanical work of the ventricle. These mechanical changes would reduce the myocardial oxygen requirements of the left ventricle. For the first time these studies demonstrated the prolonged benefits of sublingual and oral ISDN in patients with unstable angina pectoris and documented anatomic coronary artery disease. These hemodynamic benefits persisted for 8 to 12 times longer than sublingual nitroglycerin and up to 4 hours in duration. REFERENCES
1. Russek HI: The therapeutic role of coronary vasodilators: Glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate. Am J Med Sci 251:9, 1966.
American
July, 1985 Heart Journal
2. Sweatman T, Strauss E, Seizer A, Cohn KE: The long-acting hemodynamic effects of isosorbide dinitrate. Am J Cardiol 29:475, 1972. 3. Racklev CE, Russell RO Jr, Mantle JA, Rodgers WJ. Panapietro SE: Physiologic clinical considerations for hemodynamic monitoring. In Russell RO Jr, Rackley CE, editors: Hemodynamic monitoring in a coronary intensive care unit, ed 2. Mount Kisco, NY, 1981, Futura Publishing Co, Inc, p 149. 4. Willis WH Jr, Russell RO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbide dinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15, 1976. 5. Mason DT, Braunwald E: The effects of nitroglycerin and amyl nitrite on arteriolar and venous tone in the human forearm. Circulation 32:755, 1965. 6. Williams JG, Glick G, Braunwald E: Studies on cardiac dimensions in intact unanesthetized man. V. Effects of nitroglycerin. Circulation 32:767, 1965. 7. Lee SJK, Sung YK, Zaragoza AJ: Effects of nitroglycerin on left ventricular volumes and wall tension in patients with ischemic heart disease. Br Heart J 32:790, 1970. 8. Burggraf GW, Parker JO: Left ventricular volume changes after amvl nitrite and nitroglvcerin in man as measured bv ultrasound. Circulation 49:136, 1974. 9. Ratshin RA, Rackley CE, Russell RO Jr: Determination of left ventricular preload and afterload using quantitative echocardiography in man: Calibration of the method. Circ Res 34:711, 1974. 10. Smith M, Russell RO Jr, Feild BJ, Rackley CE: Left ventricular compliance and abnormally contracting segments in postmyocardial infarction patients. Chest 65:368, 1974.
ANGINA
Role of isosorbide dinitrate unstable angina pectoris
in patients
with
The development of hemodynamic facilities permitted observations after isosorbide dinitrate (ISDN) administration over a 4-hour period in patients with a history of unstable angina pectoris and documented anatomic coronary artery disease. The patients had no evidence of left ventricular failure and were free of pain during the period of sublingual and oral ISDN administration. Beneficial influences on venous return and arterial blood pressure were manifested as declines in preload and afterload, along with reduction in the mechanical work of the ventricle and, finally, increases in the diastolic compliance of the ventricle. These hemodynamic changes were shown to persist 8 to 12 times as long as the brief influence of nitroglycerin. Thus hemodynamic evidence was provided for the first time on the beneficial influence of oral and sublingual ISDN on venous, arterial, and left ventricular myocardial muscle in patients with unstable angina pectoris. (AM HEART J 110:26g, 1965.)
Charles E. Rackley,
M.D. Washington,
D.C.
Although long-acting nitrates have been prescribed for patients with angina pectoris for several decades, many years elapsed before physiologic measurements documented the circulatory response to these agents.’ Earlier studies had shown circulatory changes persisting for 1 hour with invasive techniques in patients receiving isosorbide dinitrate (ISDN).z A major limitation of such clinical studies was a lack of monitoring capability for prolonged periods in patients with unstable angina. The development of the modern coronary care unit, the Swan-Ganz catheter, and the facilities for hemodynamic monitoring in the coronary intensive care unit provided the necessary environment for clinical investigation in the role of ISDN in angina pectoris.3 METHODS
Unstable angina pectoris is clinically defined as the recent onset or progression of ischemic pain within a 3-month period characterized by rest or nocturnal discomfort. An episode of chest pain must be documented on an ECG with transient ST segment and T wave changes that return to normal after relief of pain. Cardiac enzymes should remain normal, without evidence of myocardial From ter.
the Department
of Medicine,
Georgetown
Reprint requests: Charles E. Rackley, Gec.rgetown University Medical Center, DC 20007.
University
Medical
Cen-
M.D., Department of Medicine, 3800 Reservoir Rd., Washington,
necrosis. Patients meeting these criteria were admitted to the coronary care unit and observed for documentation of chest discomfort with ECG changes.4 Cardiac catheterization was subsequently performed to confirm the presence of anatomic coronary artery disease and to evaluate left ventricular function. During the catheterization a SwanGanz catheter was inserted into the patient’s pulmonary artery and remained following completion of the diagnostic procedure. After the catheterization was completed, the patient was returned to the coronary care unit for hemodynamic monitoring of the pulmonary artery enddiastolic pressure (PAEDP), heart rate, and cardiac output. M-mode echocardiography was used to measure left ventricular dimensions and volume. The patients rested comfortably in bed without chest discomfort, and none had hemodynamic or clinical evidence of congestive heart failure. After baseline hemodynamic observations over a 30-minute period, the patients were given either a sublingual placebo, 0.4 mg of nitroglycerin, 10 mg of ISDN, or 20 mg orally of ISDN. Serial measurements of heart rate, systemic blood pressure, cardiac output, PAEDP, and echocardiograms were obtained at lo-, 20-, and 30-minute intervals and thereafter every 30 minutes for a total of 4 hours. None of the patients experienced chest discomfort during the periods of observation. Derived hemodynamic measurements were calculated from the following formulas: (1) mean arterial pressure equals two-thirds systolic pressure plus diastolic pressure, (2) cardiac index equals cardiac output divided by the body surface area in square meters, and (3) stroke work index equals (mean systolic ejection pressure minus PAEDP) times 0.0136 times stroke index. 269
July,
270
Rackley
American
Heart
1985
Journal
0.4.
02.
.
i \
-O.&I
0 10 20 30
60
90
120 Time
1. Although reductions in diastolic pulmonary artery pressure were minimal, there was a significant decrease at 60 minutes after sublingual ISDN. (From Willis WH, Russell RO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbidedinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15, 1976.) Fig.
StatIstIcally Slgnlflcant * lP<_O.lO) l (P< 0.05)
60
90 Time
120
150
180
values
210
240
mmutes
2. Mean arterial blood pressure was significantly reduced after both sublingual and oral ISDN. Lowest value wasachieved at 30 minutes and persistedfor 4 hours in comparison with placebo control values. (From Willis WH, RussellRO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbidedinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15, 1976.) Fig.
RESULTS
Thirty-seven patients meeting the clinical definition of unstable angina pectoris underwent cardiac catheterization. All patients had anatomic coronary artery disease demonstrated by greater than 50% narrowing of one or more major coronary vessels, but no hemodynamic evidence of left ventricular failure was found. Left ventricular function was normal. Pulmonary artery end-diastolic pressure. The PAEDP was 12 mm Hg or less in all patients, which
150
180
210
c 240
minutes
3. In patients with normal left ventricular function, cardiac index wasnot altered with either sublingual or oral ISDN during I-hour period of observation. (From Willis WH, RussellRO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbidedinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15, 1976.) Fig.
was normal for the laboratory. Following the administration of sublingual nitroglycerin, PAEDP declined 3 mm Hg by 5 minutes and returned to control baseline values by 20 minutes. In the patients receiving sublingual ISDN, the PAEDP gradually declined, reaching the lowest value at 60 minutes (Fig. 1). Both the initial decline and the return to the baseline value were much more gradual with the administration of sublingual ISDN than with nitroglycerin. Mean arterial pressure. The mean arterial pressure fell significantly in patients given either sublingual or oral ISDN, and the lowest values were observed 30 minutes after administration. In both groups, mean arterial pressure remained significantly low for 4 hours in comparison with control values (Fig. 2). The average reduction in mean arterial pressure was 10 mm Hg. Cardiac output and volumes. Thermodilution estimates of cardiac. output were slightly lower in the patients given sublingual ISDN over the 4-hour period of observation, but these differences did not achieve statistical significance (Fig. 3). End-diastolic volume of the left ventricle was calculated from M-mode echocardiograms, analyzed in control patients, and compared with the volume in individuals receiving sublingual ISDN. The end-diastolic volume was significantly smaller in patients receiving sublingual ISDN in comparison with control values; the average reduction was 30 ml. During the first 30 minutes of observation, the end-diastolic volume increased both in the control group and in
Volume
110
Number
1, part 2
ISDN
in unstable
60
90 120 Tfme minutes
angina
pectoris
l
--+%xwxblde -o-lsosorbtde
dmltrate dinitrate
controls sublmgual
-5o-
b io io;o
$0
I
90 Time
120 m,nutesl
50
180
210
2’40
Fig. 4. Echocardiographic
end-diastolic volume was significantly reduced in patients receiving sublingual ISDN at 4 hours in comparison with control subjects. Initial increase in end-diastolic volume was noted in both control subjects and ISDN recipients for first 30 minutes and was attributed to volume overloading because of frequent determinations of thermodilution cardiac output. (From Willis WH, Russell RO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbide dinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15,
1976.)
patients receiving ISDN (Fig. 4). However, during this initial 30-minute period of observation, the patients were having frequent thermodilution measurements of cardiac output every 10 minutes and received an average of 50 ml cold solution for each determination. Therefore, these patients received a minimum of 200 ml of fluid, which produced a volume expansion during the first half-hour of the study period. Following this initial 30-minute period of observation, there was a significant decline in the end-diastolic volume in the individuals receiving sublingual ISDN, and these differences were statistically significant. Stroke work. The stroke index was calculated in control subjects and individuals receiving sublingual as well as oral ISDN. The stroke work index is derived from the systemic arterial pressure, cardiac index, heart rate, and PAEDP. Both the sublingual and the oral ISDN recipients exhibited a reduction in the stroke work index by 30 minutes, and this persisted in both categories. The stroke work index remained reduced for 2% hours in the individuals receiving sublingual ISDN and for 4 hours in those given oral ISDN (Fig. 5). DISCUSSION
These hemodynamic measurements revealed nificant changes after both sublingual and ISDN in patients with unstable angina pectoris anatomic coronary artery disease. None of
sigoral and the
0 10 20 30
150
iRO
210
240
5. Significant reduction in stroke work index was noted in patients receiving oral ISDN. There was also a reduction in stroke work index in patients receiving sublingual ISDN, but these values were not statistically significant. (From Willis WH, Russell RO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbide dinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15, 1976.) Fig.
patients experienced ischemic pain during the period of study, and there was no hemodynamic evidence of left ventricular failure. The hemodynamic parameters were normal at rest in all of these individuals, and observed changes would therefore be expected to be small. These clinical studies were the first to demonstrate prolonged hemodynamic changes with ISDN by both the sublingual and the oral routes in patients with unstable angina pectoris. These hemodynamic events reflect venodilation and reduced venous return to the right and left ventricles.“-’ Therefore a primary mechanism was a reduction in preload of the left ventricle. In addition, the arteriolar dilation, reflected as a decline in systemic blood pressure, indicates the beneficial effects on afterload reduction.s Both the preload and afterload reduction would significantly reduce the mechanical work of the left ventricle as reflected by the stroke work index. The stroke work index is the major mechanical requirement for myocardial oxygen consumption of the left ventricle. Finally, the decrease in enddiastolic volume seen on the echocardiograms confirms the reduction in preload in the left ventricle. It is of interest that the initial increase in the enddiastolic volume caused by volume overloading of the left ventricle from the frequent thermodilution cardiac output measurements occurred when there was a slight but measurable decline in the filling pressure of the ventricle. Thus an increase in enddiastolic volume attended by a decline in enddiastolic pressure suggests an increase in the compli-
272
Rackley
ante of the left ventricle.‘0 This could be interpreted as a direct influence of long-acting nitrates on the myocardium on the left ventricle. The vasodilating effects on the smooth muscle of the venous and arterial beds would also be augmented by an increase in the elastic properties of the myocardiurn. These hemodynamic changes in patients with a history of unstable angina pectoris indicate a beneficial influence of sublingual and oral ISDN on preload, afterload, ventricular compliance, and mechanical work of the ventricle. These mechanical changes would reduce the myocardial oxygen requirements of the left ventricle. For the first time these studies demonstrated the prolonged benefits of sublingual and oral ISDN in patients with unstable angina pectoris and documented anatomic coronary artery disease. These hemodynamic benefits persisted for 8 to 12 times longer than sublingual nitroglycerin and up to 4 hours in duration. REFERENCES
1. Russek HI: The therapeutic role of coronary vasodilators: Glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate. Am J Med Sci 251:9, 1966.
American
July, 1985 Heart Journal
2. Sweatman T, Strauss E, Seizer A, Cohn KE: The long-acting hemodynamic effects of isosorbide dinitrate. Am J Cardiol 29:475, 1972. 3. Racklev CE, Russell RO Jr, Mantle JA, Rodgers WJ. Panapietro SE: Physiologic clinical considerations for hemodynamic monitoring. In Russell RO Jr, Rackley CE, editors: Hemodynamic monitoring in a coronary intensive care unit, ed 2. Mount Kisco, NY, 1981, Futura Publishing Co, Inc, p 149. 4. Willis WH Jr, Russell RO Jr, Mantle JA, Ratshin RA, Rackley CE: Hemodynamic effects of isosorbide dinitrate vs nitroglycerin in patients with unstable angina. Chest 69:15, 1976. 5. Mason DT, Braunwald E: The effects of nitroglycerin and amyl nitrite on arteriolar and venous tone in the human forearm. Circulation 32:755, 1965. 6. Williams JG, Glick G, Braunwald E: Studies on cardiac dimensions in intact unanesthetized man. V. Effects of nitroglycerin. Circulation 32:767, 1965. 7. Lee SJK, Sung YK, Zaragoza AJ: Effects of nitroglycerin on left ventricular volumes and wall tension in patients with ischemic heart disease. Br Heart J 32:790, 1970. 8. Burggraf GW, Parker JO: Left ventricular volume changes after amvl nitrite and nitroglvcerin in man as measured bv ultrasound. Circulation 49:136, 1974. 9. Ratshin RA, Rackley CE, Russell RO Jr: Determination of left ventricular preload and afterload using quantitative echocardiography in man: Calibration of the method. Circ Res 34:711, 1974. 10. Smith M, Russell RO Jr, Feild BJ, Rackley CE: Left ventricular compliance and abnormally contracting segments in postmyocardial infarction patients. Chest 65:368, 1974.