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.     

Coronary artery dilation and hemodynamic responses after isosorbide dinitrate therapy in patients with coronary artery disease

The response to sublingual isosorbide dinitrate (ISDN) was studied in 10 men with suspected coronary artery disease undergoing coronary arteriography. A Swan-Ganz catheter was placed in the pulmonary artery to record hemodynamic response. Diseased coronary segments were identified during routine Judkins selective coronary angiograms. Sublingual isosorbide dinitrate (ISDN) (5 or 10 mg) was then given with the catheters in place. Multiple sequential single-view coronary angiograms and pulmonary and systemic hemodynamic responses were recorded over 30 minutes after drug administration. At 30 minutes, there was a 53% reduction (p less than 0.01) in pulmonary capillary wedge pressure and a 15% decrease (p less than 0.05) in systemic and pulmonary vascular resistance, with a net 13% decrease (p less than 0.01) in cardiac output and 20% decrease (p less than 0.01) in mean arterial pressure. Quantitative arteriography demonstrated substantial dilation of luminal cross-sectional area in both normal and diseased coronary arterial segments. Normal epicardial segments were grouped according to luminal area (1 to 4, 4 to 8 and more than 8 mm2) and demonstrated maximal area dilation at 10 minutes of 55% (p less than 0.01), 29% (p less than 0.01) and 16% (p less than 0.05), respectively. Diseased epicardial segments (stenosis 50% or greater) dilated 51% (p less than 0.01) at 10 minutes. Calculated stenosis resistance decreased 40% (p less than 0.01). Diseased segments in small and middle-sized arteries (1 to 8 mm2) are 4 times more reactive than those in larger arteries (more than 8 mm2), with peak dilation of 77 vs 21% (p less than 0.01) at 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of sublingual nitroglycerin in patients receiving transdermal nitroglycerin for coronary artery disease: Prevention of cross-tolerance

The systemic hemodynamic and coronary dilative responses to sublingual nitroglycerin were studied in patients receiving transdermal nitroglycerin. A total of 48 patients with coronary artery disease were divided into 4 groups: 12 patients receiving 1 tablet of sublingual nitroglycerin without transdermal nitroglycerin (Group 1), 12 patients receiving 1 tablet of sublingual nitroglycerin with 12-hour-daily intermittent therapy of transdermal nitroglycerin (Group 2), 12 patients receiving 1 tablet of sublingual nitroglycerin with continuous therapy of transdermal nitroglycerin (Group 3), and 12 patients receiving 2 tablets of sublingual nitroglycerin with continuous therapy of transdermal nitroglycerin (Group 4). Before and during administration of sublingual nitroglycerin, aortic pressure, left ventricular pressure, and coronary artery diameter were examined at diagnostic cardiac catheterization in all patients. During sublingual nitroglycerin, the decreases of aortic systolic pressure and left ventricular end-diastolic pressure were greater in Group 1, 2, and 4 than in Group 3. Dilation of coronary arteries by sublingual nitroglyerin tended to be greater in Group 1, 2, and 4 than in Group 3. Thus, the effects of sublingual nitroglycerin for the relief of ischemia might be more prominent in patients with intermittent therapy of transdermal nitroglycerin than in those with continuous therapy. The increased dose of sublingual nitroglycerin for the relief of ischemia might be more effective in patients with continuous therapy of transdermal nitroglycerin.     

Postural changes and isosorbide dinitrate. A polygraphic study in patients with coronary artery disease

Sitting or orthostatic positions and trinitrine-like drugs reduce venous return. We focused on the non-invasive assessment of postural-induced cardiovascular stress and isosorbide dinitrate (IDN) induced changes in 8 male patients with coronary artery disease (CAD), using polygraphic recordings by means of a Thermistor Pulse Transducer. The pre-ejection period (PEP) is sensitive to reduced preload and to the positive inotropic state of the myocardium. In addition, the % diastole (RR interval--electromechanical systole/RR interval) has been recently demonstrated to be correlated to coronary perfusion in CAD patients. We observed that IDN in clinostatism and the sitting position reduced preload (longer PEP) with increased heart rate (HR) and did not affect % diastole. In orthostatism, while controls showed an increased HR and prolonged PEP, the HR was higher after IDN, with a fall in PEP and a significant decrease in % diastole. We ascribed this change to adrenergic stimulation by the hypotensive actions of IDN (lowered mean blood pressure) in orthostatism and with a fall in coronary perfusion. Caution should be taken in CAD patients when postural stress could occur during IDN treatment. Moreover, polygraphic studies can be useful to detect individual responses to nitrates and serial recordings could be employed to assess late responses to chronic management with IDN.     

Effect of sublingual isosorbide dinitrate in portal hypertension

Nitrates decrease portal pressure by decreasing portal venous inflow and resistance. We studied over 20 minutes the effect of 10 mg isosorbide dinitrate sublingual on intrasplenic pulp pressure, mean arterial pressure and heart rate, in 13 patients with cirrhotic or non-cirrhotic portal hypertension. The pulp pressure fell progressively over 20 minutes, from mean 43.6 +/- 2.4 (SEM) to 35.6 +/- 1.8 cm H2O (p less than 0.001). This was accompanied initially by a significant fall in mean arterial pressure (85.8 +/- 1.9 to 80.4 +/- 2.7 mmHg at 4 minutes; p less than 0.01) and rise in heart rate (92.5 +/- 5.0 to 102.6 +/- 5.9 per minute at 6 minutes; p less than 0.02), following which these parameters remained stable. One patient developed giddiness due to hypotension at 15 minutes. We conclude that sublingual isosorbide dinitrate decreases pulp pressure in cirrhotic and non-cirrhotic portal hypertensives, but this is initially accompanied by significant hemodynamic changes.     

Response to changing plasma concentrations of isosorbide-bound NO2 during acute and sustained treatment with isosorbide dinitrate in patients with coronary artery disease

BACKGROUND: The mechanisms behind development of tolerance to nitrate effects during sustained, asymmetric isosorbide dinitrate (ISDN) therapy are not fully understood. HYPOTHESIS: The study was undertaken to investigate the changes of the relationships between left ventricular (LV) function and plasma concentrations of ISDN and its vasoactive metabolites (2- and 5-ISMO) during acute and sustained, asymmetric ISDN therapy. METHODS: Left ventricular function and plasma concentrations of ISDN, 2- and 5-isosorbide mononitrates (P-ISDN, P-2- and 5-ISMO) were measured at rest and at supine exercise before and for 4 h after peroral 30 mg ISDN in 15 patients with coronary artery disease, all with initial exercise pulmonary artery wedge pressure (PAWP) > 25 mmHg. Seven patients were untreated (acute group), while eight received 30 mg ISDN b.i.d. for 2 weeks before the invasive study. P-ISDN and the concentration of available isosorbide-bound nitrate (NO2) in plasma (P-ISDN.2 + P-2-ISMO + P-5-ISMO) (P-NO2) were used as measures of the nitric oxide (NO) offer to the tissues. RESULTS: Throughout the study, after administration of medication, all plasma concentrations, in particular P-ISDN, were higher in the chronic than in the acute group. Peak P-ISDN was reached after 15 min in the chronic group and after 25 min in the acute group, while P-2- and 5-ISMO reached maximum only after 40 min in both groups. At rest, the full effect on PAWP was observed after 10 min in both groups, but at markedly higher levels of P-ISDN and P-NO2 in the chronic group. Afterward, no further changes in PAWP were observed. During exercise, 1 h after medication, PAWP and stroke index to PAWP ratio (SI/PAWP) were normal in both groups. Thereafter, at slowly declining P-NO2, PAWP rose and SI/PAWP declined toward the initial level in the chronic group, but remained unchanged in the acute group, in spite of higher P-NO2 and greater NO release in the former. CONCLUSIONS: Patients receiving sustained, asymmetric 30 mg ISDN b.i.d. dosing had the same immediate beneficial effects on LV function during exercise after a morning dose as did untreated patients. However, in spite of higher P-NO2 and higher rate of NO release during sustained treatment, the effects deteriorated gradually 2 to 3 h after medication. The changes in metabolism and/or distribution of isosorbide-bound NO2 may possibly be part of the tolerance induced by long-term treatment, even with asymmetric dosing.     

Vasodilator therapy in acute myocardial infarction. Use of sublingual isosorbide dinitrate.

The haemodynamic effect of a long-acting vasodilator isosorbide dinitrate has been studied in 10 patients after an acute myocardial infarct, all of whom had evidence of left ventricular failure. Left ventricular filling pressure measured as the mean pulmonary artery wedge pressure was raised in all patients and fell significantly from 20+/-6 to 13+/-5 mmHg (P less than 0-001) within 10 minutes of sublingual isosorbide dinitrate. This 35 per cent fall in left ventricular preload was accompanied by significant fall in mean pulmonary artery pressure from 30+/-7 to 20+/-4 mmHg (P +less than 0-001) and mean right atrial pressure from 11+/-3 to 6+/-2 mmHg but cardiac output measured by thermodilution was unchanged. Mean systemic blood pressure was also significantly reduced. This improvement in left ventricular performance resulting from a reduction in left ventricular filling pressure and systemic blood pressure indicates that there may be a place for long-acting vasodilator in the treatment of acute myocardial infarction.     

Myocardial infarction following sublingual administration of isosorbide dinitrate

A 78-year-old with healed septal necrosis suffered a recurrent myocardial infarction of the anterior wall following the administration of isosorbide dinitrate 5 mg sublingually. After detailing the course of events, we discuss the role of paradoxical coronary spasm and hypotension-mediated myocardial ischemia occurring downstream to significant coronary arterial stenosis in the pathophysiology of acute coronary insufficiency.     

Plasma concentrations and coronary vasodilation after sublingual and intracoronary administration of isosorbide dinitrate

To investigate the relationship between plasma levels and coronary vasodilation after administration of isosorbide dinitrate (ISDN), the plasma concentration and diarneters of six segments of the left coronary artery were measured before and after sublingual (SL) ISDN (5 mg) and left intracoronary (IC) administration of ISDN (3 mg) in 12 patients. After SL-ISDN, the systolic aortic pressure decreased with no significant concomitant changes in heart rate or diastolic aortic pressure. After IC-ISDN, all hemodynamic parameters showed significant changes, and these were greater after IC-ISDN than those after SL-ISDN. The individual mean vasodilation of six segments induced by SL- and IC-ISDN, were 23± 9 and 35± 11% (p<0.01), respectively. Before SL-ISDN, ISDN was not detected in plasma. After SL- and IC-ISDN, however, the plasma values of the ISDN were 36.1± 53.3 and 101.5± 90.0 ng/ml (p<0.01), respectively. Thus, both coronary vasodilative responses and plasma ISDN levels after IC-ISDN were significantly greater than those after SL-ISDN. However, neither the individual mean coronary vasodilation nor the hemodynamic changes correlated significantly with plasma ISDN levels. Consequently, with administration of the same dose, the coronary vasodilative response to ISDN did not correlate with plasma levels. Furthermore, IC-ISDN dilates coronary arteries more effectively than SL-ISDN.     

美多心安、硝酸异山梨醇酯对心绞痛患者心率变异性影响的比较

目的：探讨美多心安、硝酸异山梨醇酯对心绞痛患者心率变异性（ＨＲＶ）影响的异同。方法：对服用美多心安及服用硝酸异山梨醇酯的心绞痛患者分别在服药前及服药后７ｄ做ＨＲＶ检验并进行比较。结果：服用美多心安７ｄ后连续正常Ｒ－Ｐ间期差值的均方根、低频峰绝对面积（ＬＦ）较服药前有显著性差异（Ｐ＜０．０５），极低频峰绝对面积、中频峰绝对面积及ＬＦ与高频峰绝对面积（ＨＦ）的比值（ＬＦ／ＨＦ）较服药前有极显著性差异（Ｐ＜０．０１）；服用硝酸异山梨醇酯７ｄ后，除ＬＦ／ＨＦ较服药前有显著性差异（Ｐ＜０．０５）外，其他指标无显著变化。结论：两药均可改善心绞痛患者的ＨＲＶ，但美多心安作用更强     

Dilation of coronary artery stenoses after isosorbide dinitrate in man.

The effect of isosorbide dinitrate (ISDN), 5 mg sublingually, on the diameters of coronary artery stenoses (n = 27) was examined in 20 patients. Another 18 patients with angiographically normal coronary arteries received the same amount of ISDN and were used as controls. Prestenotic and stenotic diameters were measured with a vernier calliper having an accuracy of 0.05 mm. The degree of stenosis was expressed as percentage of cross-sectional area reduction. ISDN caused uniform dilatation of every normal epicardial artery; mean increase in diameter was 21 per cent (range: 17 to 26%). In 18 stenoses (28 to 95% obstruction) there was very little change after ISDN. The mean prestenotic diameter increased from 2.82 +/- 0.48 mm to 3.05 +/- 0.43 mm and the mean stenotic diameter from 1.45 +/- 0.49 mm to 1.59 +/- 0.51 mm. However, in the nine other stenoses (35 to 89% obstruction) the mean degree of obstruction decreased significantly from 68 +/- 15.6 per cent to 47 +/- 15.6 per cent after ISDN. This improvement was a result of a significant increase of the mean stenotic diameter from 1.71 +/- 0.47 mm to 2.41 +/- 0.55 mm, whereas the prestenotic diameter showed only an insignificant increase from 3.17 +/- 0.63 mm to 3.31 +/- 0.58 mm after ISDN. In four patients with two obstructions in different coronary branches ISDN dilated one without significantly affecting the other lesion. From the data we conclude that ISDN can dilate some coronary artery stenoses but that this response may vary from one site to another even in the same patient.     

Effects of sublingual isosorbide dinitrate on left ventricular performance during exercise in patients with myocardial infarction

In order to investigate left ventricular performance during exercise in patients with myocardial infarction and evaluate the effects of sublingual isosorbide dinitrate (ISDN) on left ventricular performance, we performed a symptom-limited multigraded exercise test using a bicycle ergometer in supine position. Thirty-seven patients with myocardial infarction were evaluated in order to clarify the hemodynamic responses to exercise with and without sublingual ISDN. Patients were subdivided into 3 groups according to the level of pulmonary capillary pressure (PCP) and cardiac index (CI) at peak exercise as follows: Group I (14 patients); PCP less than 18 mmHg, CI greater than or equal to 5.0 or CI less than 5.0 L/min/m2, Group II (11 patients); PCP greater than or equal to 18 mmHg, CI greater than or equal to 5.0 L/min/m2, Group III (12 patients); PCP greater than or equal to 18 mmHg, CI less than 5.0 L/min/m2. Exercise capacity without ISDN (control study) was correlated with left ventricular performance during exercise. Although left ventricular performance in patients who complained of dyspnea or chest pain at peak exercise was worse than those who complained of leg fatigue, we could not predict hemodynamics during exercise from the level of hemodynamic parameters at rest in each patient. Determinant factors of left ventricular performance during exercise were age, previous history of myocardial infarction, the severity of coronary artery lesion and the extent of left ventricular wall motion abnormality which was estimated by left ventriculogram as an index of infarct size. After sublingual ISDN (ISDN study), exercise capacity was improved. No patient terminated exercise because of chest pain and only one did because of dyspnea.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary circulation in patients with and without coronary artery disease and the effects of chewable isosorbide dinitrate.

Coronary arteriograms of 38 patients with suspected coronary artery disease (CAD) were first evaluated to decide whether or not the disease was present and, if so, whether easily recognizable collateral channels were demonstrated. In this evaluation, we found CAD in 26 of the 38 patients. Eighteen of 21 patients with severe obstructions or occlusions had functioning collateral vessels. The films were then evaluated a second and third time to determine the effects of chewable isosorbide dinitrate (ISDN) on the coronary circulation. Visual inspection of the arteriograms revealed significant increases in 1) the apparent number and diameter of collateral vessels, 2) the opacification of vessels distal to occlusions, and 3) the diameter of coronary arteries following the administration of 2.5, 5, or 10 mg chewable ISDN. Computer analysis of the arteriograms showed an average 16% increase in the diameters of specific segments of major coronary arteries following ISDN. All patients showed some degree of vasodilatation following ISDN; however, patients without CAD consistently showed more vasodilatation than patients with disease. Mean aortic blood pressure decreased an average of 10% following ISDN. These results demonstrate that the chewable form of ISDN reliably dilates the coronary arteries in patients both with and without CAD and enhances the collateral circulation to the ischemic areas in patients with CAD.     

Effects on the systemic and coronary circulation of 2 nitrate derivatives, intravenous trinitrin and sublingual isosorbide dinitrate, administered during atrial pacing]

The changes in the systemic and coronary circulations produced by intravenous trinitrin 0.38 +/- 0.125 mg/hour and sublingual isosorbide dinitrate 5 mg were studied in 24 patients with coronary artery disease. When given during rapid atrial pacing both drugs decreased pulmonary capillary pressures (p less than 0.001), cardiac and coronary output (p less than 0.001 and p less than 0.01) and myocardial oxygen consumption (p less than 0.01). At these dosages, intravenous trinitrin has no significant effect on average systemic blood pressure or left ventricular work index; the coronary arterial resistances increased (p less than 0.005). Isosorbide dinitrate significantly decreased average systemic blood pressure and the left ventricular work index (p less than 0.001); there was no significant difference in the coronary arterial resistances; the decrease in coronary blood flow observed after sublingual isosorbide dinitrate seems partly due to a decreased perfusion pressure. The beneficial effect of these nitrite derivatives seems to be mainly related to a reduced preload.     

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.