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PubMed1985

Isosorbide dinitrate and exercise performance in patients with congestive heart failure.

Nitrates are widely used for the management of congestive heart failure (CHF), as well as angina pectoris. In both situations, nitrates significantly increase exercise capacity. The mechanism of this beneficial effect is unclear, especially in CHF. Isosorbide dinitrate reduces pulmonary capillary wedge pressure (PCWP) after a first dose. The improvement in exercise capacity is not apparent in the short term but is evident after long-term nitrate administration. Nitrates do not affect hemodynamics at maximal exercise but do reduce PCWP during submaximal exercise in patients with CHF. This observation, in addition to increased oxygen extraction at peak exercise during nitrate administration, suggests a "training like" peripheral effect of nitrates in CHF. Lowering of PCWP by nitrates may be important, since vasodilators that do not reduce PCWP also do not improve exercise capacity in CHF. How PCWP influences exercise performance in CHF is unknown, but the mechanism may relate to effects of PCWP on pulmonary hemodynamics more than on ventilation and blood oxygenation.

Angina Pectoris↗
PubMed1985

Isosorbide dinitrate and nifedipine in variant angina pectoris.

The efficacy of isosorbide dinitrate (ISDN) in variant angina is enhanced by the addition of a calcium antagonist. A prospective double-blind, crossover trial of ISDN, 40 to 120 mg/day, and nifedipine, 40 to 120 mg/day, in 19 patients with variant angina and various degrees of coronary atherosclerosis showed that although both agents were equally effective in controlling angina of vasospastic origin, some patients responded better to one or the other drug. Such response could not be predicted by demographic factors, ECG changes, or degree of coronary atherosclerosis. Since quantitative angiography done in a similar group of patients showed that intracoronary nitroglycerin, 200 micrograms, was a more potent vasodilator than sublingual nifedipine, 10 mg (p less than 0.01), the calcium antagonists may have a different mechanism of preventing variant angina attacks and may act in an additive or synergistic fashion when administered in combination with long-acting nitrates. Such a combination will increase coronary blood flow, reduce ventricular volume and end-diastolic pressure, and reduce systemic arterial resistance. Coronary vasospasm may be directly prevented by a general inhibition of smooth muscle contraction by the calcium antagonist. Clinical studies suggest that combination therapy significantly improves the long-term prognosis of patients with variant angina and reduces the need for bypass surgery. Thus combining ISDN with a calcium antagonist is a rational and effective treatment for variant angina.

Angina Pectoris, Variant↗
PubMed1985

Role of isosorbide dinitrate in patients with unstable angina pectoris.

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.

Angina Pectoris↗
PubMed1985

The role of isosorbide dinitrate in the treatment of perioperative hypertension.

Intravenous nitroglycerin (NTG) has recently been found to be useful for the control of blood pressure during the perioperative period, especially during coronary artery bypass procedures. The objective of this study was to determine whether intravenous isosorbide dinitrate (ISDN) could play a similar role. Sixty-seven patients undergoing coronary artery bypass grafting at three centers were randomly assigned to an ISDN or NTG treatment group. The hemodynamic performance of all patients was assessed by the methods commonly used for cardiac patients (ECG, arterial line, thermodilution pulmonary artery catheter). One of the two nitrates was infused whenever the systolic blood pressure or the pulmonary capillary wedge pressure exceeded predetermined values. Treatment by either agent was considered successful if the elevated values returned to normal. NTG reduced the blood pressure in a higher percentage of hypertensive events. The rates of success were 84% for NTG vs 72% for ISDN in the prebypass phase, 93% vs 64% in the postbypass phase, and 71% vs 54% in the postoperative phase. Increased ISDN effectiveness may be attained with the use of a bolus administration before continuous infusion or with the use of a rapid rate of infusion.

Clinical Trials as Topic↗
PubMed1985

High-dose isosorbide dinitrate in management of angina pectoris.

The hypothesis was tested that selected patients with coronary artery disease whose rate of angina attacks do not respond to low doses of isosorbide dinitrate (ISDN) (40 mg/day) may respond to high doses (480 mg/day), tolerate them, and maintain their responsiveness over the long term. Twenty-four patients with grade 3 stable angina pectoris were given a placebo for 4 weeks and then had their ISDN dosages titrated up to 120 mg four times a day during another 6 weeks in a single-blind fashion. The 20 patients who responded to (and tolerated) a high dose of ISDN were maintained at that dose for an average of 1 year. The weekly rate of angina attacks fell by 74%, from 6.05 during placebo to 1.6 (p less than 0.01) during long-term ISDN treatment. Nitroglycerin consumption fell similarly. Patient assessment of activity level, well-being, and angina threshold improved in the majority of patients. The within-patient trend of their weekly rate of angina episodes was stable in 13 patients, downward in six, and upward in only one patient. Exercise performance evaluated by a submaximal graded multistage treadmill test showed a small but nonsignificant improvement of 1.8%. It is concluded that (1) some patients who do not respond to the antianginal action of low-dose ISDN may respond to a high dose and tolerate it, (2) this responsiveness and tolerability may last for over a year, and (3) ISDN may be clinically useful in patients with coronary disease even when exercise performance is not significantly improved.

Adult↗
PubMed1985

Combination therapy with isosorbide dinitrate: current status and the future.

The excellent safety and predictable efficacy of isosorbide dinitrate (ISDN) have been demonstrated repeatedly during the past 25 years in a number of studies in which the agent has been used alone or in combination with other antianginal agents. Clinical studies to investigate the additive or synergistic effect of ISDN have been difficult to conduct because of the complexity of protocol design and length of studies required. However, combination therapy is well accepted in the clinical practice of medicine and cardiology and is used to obtain additive therapeutic effects while minimizing the side effects. The addition of ISDN not only to other standard and proven antianginal agents but also to calcium antagonists should prove to be a fruitful area for further clinical research benefiting patients with angina pectoris (caused by either coronary artery spasm or occlusive coronary artery disease), hypertension, and congestive heart failure. Noncardiovascular uses of ISDN may include the treatment of hyperspasticity of other smooth muscle beds, such as esophageal spasm and achalasia.

Angina Pectoris↗
PubMed1985

Hemodynamic effects of molsidomine, isosorbide dinitrate, and nifedipine at rest and during exercise.

In the first study the hemodynamic effects of standard doses of molsidomine (2 mg intravenously), isosorbide dinitrate (ISDN) (5 mg sublingually), and nifedipine (20 mg sublingually) were assessed at rest and under exercise conditions in a group of 30 patients with coronary heart disease. With the patients at rest both molsidomine and ISDN were associated with prompt reductions in left ventricular end-diastolic pressure and mean pulmonary artery pressure, whereas nifedipine was associated with slight reductions in left ventricular end-diastolic pressure and mean pulmonary artery pressure that did not attain statistical significance. Nifedipine and ISDN caused a decrease in mean aortic blood pressure, which resulted in a reactive increase in heart rate that was only significant with nifedipine. After administration of molsidomine, there was no significant change in mean aortic pressure at rest. There were reductions in stroke volume index and cardiac index after administration of molsidomine and ISDN. Nifedipine, however, was associated with significant increases in stroke volume index and cardiac index. None of the three test substances caused changes of contractility parameters. Under exercise conditions reductions in left ventricular end-diastolic pressure, mean pulmonary pressure, and mean aortic pressure were documented following administration of molsidomine, ISDN, and nifedipine. There were no major changes in maximum heart rate or stroke volume index during exercise with any of the three drugs. However, nifedipine was associated with a significant increase in cardiac index, whereas molsidomine and ISDN produced no major changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Alterations in myocardial perfusion during exercise after isosorbide dinitrate infusion in patients with coronary disease: assessment by thallium-201 scintigraphy.

We studied the effect of intravenous isosorbide dinitrate (ISDN) on myocardial perfusion of patients with coronary artery disease, by using exercise thallium-201 (TI-201) myocardial scintigraphy. A control study was conducted initially to assess regional myocardial perfusion rate. Left ventricular myocardium was divided into six parts: anterior, lateral, apical, inferior, posterior, and septal segments. The segmental myocardial perfusion was characterized according to TI-201 initial uptake index (IUI) of relative distribution and redistribution index (RDI) of TI-201 washout. The normal limit of IUI and RDI was established from the data of 17 persons with normal coronary arteries, and then the IUI less than or equal to 84% and the RDI greater than or equal to 1.12 was defined as abnormal. Based on IUI and RDI, each segment was characterized into three types: A type = IUI less than or equal to 84%, RDI greater than or equal to 1.12; B type = IUI less than or equal to 84%, RDI less than 1.12; and C type = IUI greater than 84%, RDI less than 1.12. ISDN was given as a dose of 0.1 mg/kg/hr, and then treadmill testing was repeated for the same duration of exercise time using the same protocol as in the control period. The segments of A type showed a significant improvement in IUI and RDI after receiving ISDN infusion, while the B and C type segments showed no change. It was also shown that the improvement of IUI and RDI of the A type segments was not as marked in multivessel disease as in cases of single-vessel disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Dose- and time-related vasodilator response of conduit coronary arteries to intracoronary isosorbide dinitrate in human beings.

The time course of the vasodilation of different segments of the epicardial coronary vasculature after three different doses of intracoronary isosorbide dinitrate (ISDN) was investigated in angiographically normal coronary arteries in 10 patients with quantitative coronary angiography. In five patients, 0.1 mg and 0.3 mg ISDN were injected intracoronary 30 minutes apart, and the effect of each dose was assessed at 1, 5, 10, and 15 minutes after the administration by serial angiograms. In five additional patients, a single dose of 3 mg was injected and coronary vasodilation was assessed at 1, 5, 10, 15, and 20 minutes. After each dose, dilation of epicardial coronary arteries occurred within 1 minute, peaked at 5 minutes and progressively decreased thereafter. Relative to control, peak percent diameter increase was (mean +/- SEM) 10% +/- 0.9% (p less than 0.01), 18.5% +/- 1.5% (p less than 0.01), and 26% +/- 2.1% (p less than 0.01) after 0.1, 0.3, and 3.0 mg, respectively. When small (1 to 2 mm), medium (2 to 3 mm), and large (greater than 3 mm) vessels were separately analyzed, peak response was respectively 12% +/- 1.3% (p less than 0.01), 9% +/- 1.9% (p less than 0.01), and 7% +/- 1% (p less than 0.05) after 0.1 mg ISDN; 22% +/- 1.8% (p less than 0.01), 16% +/- 1.3% (p less than 0.01), and 12% +/- 0.8% (p less than 0.01) after 0.3 mg; and 38% +/- 2.4% (p less than 0.01), 22% +/- 2.1% (p less than 0.01), and 17% +/- 2% (p less than 0.01) after 3.0 mg. The duration of the response increased with the dose, but was inversely related to the size of the vessel.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Reduced infarct size in nonreperfused myocardial infarction by combined infusion of isosorbide dinitrate and streptokinase.

The value of thrombolytic therapy in myocardial infarction is well established, while any beneficial effect of adjunct therapy is more uncertain. In a double-blind, randomized, parallel-group study the effect of combined intravenous infusions of streptokinase and isosorbide dinitrate (ISDN) on enzyme-estimated infarct size was investigated. One hundred consecutive patients with strong clinical and electrocardiographic suspicion of myocardial infarction, admitted to the coronary care unit within 8 hours after the onset of symptoms, were given a streptokinase infusion of 1.5 million units for 1 hour and a titrated dose of ISDN or placebo for 48 hours. From isoenzyme B of creatine kinase (CK-B) values measured every 4 hours, the infarct size was calculated and the possible presence of reperfusion was evaluated. The infarct size in patients receiving ISDN infusion was reduced (p = 0.04, one-sided test) compared with placebo. By subdividing the patients according to whether or not reperfusion had occurred, the infarct size appeared to be similar following ISDN and placebo in patients with reperfusion (419 versus 369 U/L), whereas the infarct size in patients not reperfused was markedly reduced after treatment with ISDN (223 versus 1320 U/L, p = 0.003). In conclusion, the present study demonstrates that the infarct size may be reduced by other means than reperfusion and it supports the use of combined infusion of thrombolytic agents and nitrates in patients with suspected myocardial infarction.

Adult↗
PubMed1994

Effects of continuous intravenous infusion of isosorbide dinitrate on development of tolerance to vasodilating action in human epicardial coronary arteries.

This study was performed to determine the effects of long-term intravenous infusion on the coronary vasodilating actions of continuous intravenous and bolus intracoronary administration of isosorbide dinitrate (ISDN). With quantitative coronary angiography, the coronary diameter and the vasodilating response to intracoronary ISDN (1 mg) at angiographically normal segments were studied before and after intravenous administration of ISDN, 10 to 60 micrograms/min for 1 hour, 2 days, or 5 days. The vasodilating effects of intravenous ISDN were 72% +/- 13%, 65% +/- 21%, and 6% +/- 11% of the response to intracoronary ISDN in the baseline study in each group. Irrespective of the duration of intravenous infusion, subsequent intracoronary ISDN dilated coronary arteries to extent similar to that observed in each baseline study. In conclusion, significant coronary vasodilating effects of intravenous ISDN were observed after a 2-day infusion, whereas tolerance to the vasodilating effects apparently developed within 5 days of infusion. The vasodilating response to bolus intracoronary ISDN was preserved even when the vasodilating effects of intravenous ISDN were no longer present.

Angina Pectoris↗
PubMed1984

Nitrate cross-tolerance: effect of sublingual isosorbide dinitrate and nitroglycerin during sustained nitrate therapy.

In a randomized, single-blind, crossover study, 10 patients with stable, exercise-induced angina pectoris were studied during sustained therapy with oral isosorbide dinitrate (ISDN). Circulatory changes and exercise performance were evaluated before and 6 hours after therapy with oral ISDN. One-half hour after this therapy, sublingual ISDN or nitroglycerin (NTG) was administered and exercise testing repeated. Treadmill walking time 6 hours after oral ISDN was similar to the control value. Subsequent administration of sublingual ISDN improved walking time from 429 +/- 156 to 513 +/- 166 seconds (p less than 0.005), whereas after NTG improved from 411 +/- 159 to 480 +/- 158 second (p less than 0.005). The improvement in walking time with ISDN (23%) and NTG (18%) and the absolute walking times were not different. The standing systolic blood pressure decreased from 124 +/- 23 to 112 +/- 22 mm Hg (p less than 0.02) after therapy with sublingual ISDN and 122 +/- 23 to 110 +/- 24 mm Hg (p less than 0.005) after administration of NTG. This study demonstrates that (1) during sustained ISDN therapy, walking time returns to control values by 6 hours; (2) administration of either sublingual ISDN or NTG results in significant circulatory changes and improvement in walking time; and (3) the changes in circulatory and exercise variables after administration of NTG in patients taking sustained ISDN therapy cannot be taken as evidence of an absence of cross-tolerance between these agents.

Aged↗
PubMed1984

Transdermal isosorbide dinitrate in angina pectoris: effect of acute and sustained therapy.

Twelve patients with chronic, stable angina pectoris underwent hemodynamic investigations and treadmill exercise testing before and during a 24-hour period after the application of 100 mg of transdermal isosorbide dinitrate (ISDN) and matching placebo. Compared with placebo, there were no changes in systolic blood pressure or heart rate at rest or during exercise; but treadmill walking time to the onset of angina and to the development of moderate angina was significantly prolonged at 2, 4 and 8 hours, but not at 24 hours, after drug application. Patients subsequently received these same treatment regimens for 7 to 10 days and underwent repeat exercise testing. During this sustained phase of the investigation, treadmill walking time to the onset of angina and to the development of moderate angina was similar 4, 8 and 24 hours after application of ISDN and placebo. Thus, transdermal ISDN in a dose of 100 mg is effective for 8 hours during acute therapy, but during sustained therapy tolerance developed and no antianginal effects of ISDN persisted.

Administration, Topical↗
PubMed1984

Dose-response relation of antianginal activity of isosorbide dinitrate.

Eleven men with angiographic evidence of coronary heart disease and stable, exercise-induced angina pectoris were given placebo (P) or isosorbide dinitrate (ISDN) in a daily dose of 30, 120, 240 or 480 mg, in a randomized single-blind trial. The daily doses were administered 6 times a day as single oral doses of 5, 20, 40 and 80 mg. Each dose or placebo was given for 7 days. Before therapy was begun, and on the seventh day of each treatment period, an exercise ECG with standardized level and duration of exercise was recorded. Subsequently, a 4-week treatment period with 480 mg/day was carried out at the end of which another stress test was performed. The was followed by a final 2-week placebo period. The frequency of anginal attacks per week tended to decrease with increasing nitrate doses, but decreased significantly only after the highest dose (480 mg/day) compared with placebo. Continuation of therapy with 480 mg/day maintained the reduced rate of anginal attacks. The ischemic response, expressed as the sum of ST-segment depressions in the exercise ECG, revealed a dose-dependent reduction of 26% (30 mg/day), 39% (120 mg/day) (p less than 0.01), 63% (240 mg/day) (p less than 0.01) and 72% (480 mg/day) (p less than 0.01), respectively. At the end of the 4-week treatment period with 480 mg/day, antianginal efficacy was found to be moderately reduced, showing a 56% reduction of ischemic response compared to the placebo trial. The time of onset of angina during exercise testing was also delayed in relation to the dosage given.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1984

Inhibition of platelet function by injectable isosorbide dinitrate.

The possibility that isosorbide dinitrate (ISDN) inhibits platelet function in humans has been explored in vitro and in vivo. Incubation of citrated platelet-rich plasma from healthy subjects with scalar concentrations (1.25, 12.5 and 125 micrograms/ml) of ISDN for 5 and 10 minutes resulted in a decrease in platelet aggregation after ADP, adrenaline, and arachidonic acid at the highest drug concentration (mean decrease: 72% [p less than 0.01], 56% [p less than 0.05] and 62% [p less than 0.05], respectively, with the 10-minute incubation). Also, a significant reduction (30%) in generated thromboxane (TX)B2 levels was observed after arachidonic acid (p less than 0.01). ISDN was then infused at rate of 4 mg/hour for 30 minutes in 11 patients with angina and at a rate of 30 mg/hour for 20 minutes in 8. The smaller dose, which caused minor changes in arterial pressure and heart rate, was accompanied by a marked, significant decrease in ADP- and adrenaline-induced aggregation, with a nadir at 60 minutes from the infusion stop (decreases of 40% and 51% respectively). Circulating platelet aggregates also decreased, with a minimum (-41%, p less than 0.05) at the end of the infusion. The higher infusion rate, causing marked hemodynamic effects, was not accompanied by the occurrence of clear antiplatelet effects. Thus, ISDN can affect platelet function both in vitro and in vivo. The in vivo effect occurs at lower concentrations than in vitro but is blunted when a marked hemodynamic response occurs.

Adenosine Diphosphate↗
PubMed1985

Isosorbide dinitrate and glyceryl trinitrate: demonstration of cross tolerance in the capacitance vessels.

Cross tolerance to the arterial effects of sublingual glyceryl trinitrate (GTN) has been demonstrated in subjects taking oral isosorbide dinitrate (ISDN). To determine if cross tolerance also develops in the venous system, the effects of 0.6 mg of GTN on venous capacitance were assessed before (stage A) and during (stage B) therapy with ISDN. Venous capacitance was assessed using the radionuclide blood pool method, with relative changes in regional blood volume measured in the forearm in 6 patients and the splanchnic circulation in 4 patients. Heart rate, blood pressure and blood volume were measured before and at 1-minute intervals for 10 minutes after GTN; there was less than 2% variability in regional blood volume during 6 control measurements. During stage A, 5 minutes after GTN, systolic blood pressure (mean +/- standard deviation) decreased by 14% (from 125 +/- 15 to 107 +/- 19 mm Hg, p less than 0.01) and heart rate increased by 17% (from 68 +/- 14 to 80 +/- 17 beats/min, p less than 0.001), while regional blood volume increased to 101 +/- 2% at 1 minute (difference not significant [NS]), 111 +/- 2% at 5 minutes (p less than 0.001) and 107 +/- 3% at 10 minutes (p less than 0.01) relative to baseline measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Comparison of buccal nitroglycerin and oral isosorbide dinitrate for nitrate tolerance in stable angina pectoris.

Sixteen patients with chronic stable angina pectoris were studied to compare the hemodynamic and antianginal effects of buccal nitroglycerin (GTN) in a dose of 3 mg administered 3 times daily and oral isosorbide dinitrate (ISDN) in a dose of 30 mg administered 4 times daily. Compared with placebo, both oral ISDN and buccal GTN treatment induced a decrease in systolic blood pressure at rest over a 5-hour period during acute but not during sustained therapy. Neither buccal GTN nor oral ISDN modified the changes in systolic blood pressure during exercise. Both treatment programs were associated with a higher exercise heart rate during acute therapy. During sustained treatment with buccal GTN, the heart rate during exercise remained greater than that during placebo throughout the 5-hour test period, but during treatment with oral ISDN, only the exercise heart rate at 1 hour was greater than that seen with placebo. Treadmill walking time to the onset of angina and to the development of moderate angina increased significantly during acute therapy with both buccal GTN and oral ISDN. The clinical efficacy of buccal GTN was maintained after 2 weeks of 3-times-daily therapy. In contrast, during 4-times-daily therapy with oral ISDN, treadmill walking time was prolonged for only 1 hour after drug administration. This investigation indicates that tolerance develops during 4-times-daily therapy with oral ISDN, but 3 times daily therapy with buccal GTN is not associated with diminished antianginal effects.

Aged↗
PubMed1986

Acute effects of sublingual isosorbide dinitrate on global and regional left ventricular diastolic filling in normal persons.

To study the acute effects of isosorbide dinitrate (ISDN) on global and regional left ventricular (LV) diastolic filling, gated radionuclide ventriculographic studies were conducted in 21 normal persons before and after sublingual administration of ISDN. ISDN treatment caused significant increases in ejection fraction and peak LV ejection rate and it caused a delay in occurrence of peak LV filling, without statistically significant changes in peak LV filling rate globally and regionally. The ratios of peak LV filling rate to peak LV ejection rate decreased significantly both globally and regionally. These alterations induced by ISDN could be interpreted as indicating a failure of improvement of the early diastolic filling despite increased systolic function and heart rate in the global left ventricle and in regions of the left ventricle. Furthermore, ISDN caused early diastolic asynchronous filling. There was a negative correlation between this early diastolic asynchronous filling and the ratio of global peak LV filling to global peak LV ejection rate (r = -0.66, p less than 0.001), indicating that administration of ISDN to normal persons may produce early diastolic asynchronous filling associated with failure of improvement of diastolic filling despite increased systolic function and heart rate.

Administration, Oral↗