Effects of isosorbide dinitrate and hydralazine on regional metabolic responses to arm exercise in patients with heart failure

The reduced exercise capacity of patients with heart failure is thought to be due in part to impaired skeletal muscle oxygen delivery. To determine if hydralazine and isosorbide dinitrate improve skeletal muscle oxygen delivery in such patients, the effects of these agents on regional metabolic responses to forearm exercise were examined in 16 patients with heart failure. Arm oxygen extraction and brachial venous lactate concentration were measured at rest and during 3 minutes of rhythmic handgrip and then remeasured after administration of oral hydralazine (nine patients) or sublingual isosorbide dinitrate (nine patients). Hydralazine increased mean (± standard deviation) cardiac output at rest from 3.5 ± 0.5 to 4.9 ±1.0 liters/min (p < 0.01) and decreased arm oxygen extraction from 39 ± 8 to 33 ± 10 percent (probability [p] < 0.01), suggesting improved resting limb oxygen delivery. However, hydralazine did not reduce arm oxygen extraction during exercise (control 63 ± 4, hydralazine 60 ± 12 percent; p = notsignificant[NS]) or venous lactate during exercise (control 16.6 ± 7.8, hydralazine 17.1 ± 4.8 mg/100 ml; p = NS). Isosorbide dinitrate increased the cardiac output from 3.6 ± 0.7 to 4.5 ± 0.7 liters/min (p < 0.01) but had no effect on arm oxygen extraction at rest (control 40 ± 11, isosorbide dinitrate 38 ± 11 percent; p = NS) and during exercise (control 66 ± 5, isosorbide dinitrate 64 ± 8 percent; p = NS) or on venous lactate during exercise (control 17.9 ± 6.4, isosorbide dinitrate 17.1 ± 3.9 mg/100 ml; p = NS). These data suggest that hydralazine and isosorbide dinitrate do not improve skeletal muscle oxygen delivery during exercise in patients with heart failure.     

Comparative effects of theophylline and isosorbide dinitrate on exercise capacity in stable angina pectoris, and their mechanisms of action

While the role of nitrates in the prevention and treatment of myocardial ischemia is well established, the use of theophylline, proposed almost a century ago, is still controversial. Also controversial is its mechanism of action, initially thought to be coronary dilation. In this randomized, single-blind study, the acute effects on exercise capacity of sublingual isosorbide dinitrate (10 mg) and of intravenous theophylline ethylenediamine (7 mg/kg) were assessed in 10 patients with chronic stable angina and positive exercise test. After the administration of theophylline, the time to onset of angina, the heart rate-blood pressure product at 1-mm ST-segment depression and the exercise duration were similar to that after isosorbide dinitrate administration (9.8 +/- 2.3 vs 9.3 +/- 1.7 minutes, 207 +/- 41 vs 207 +/- 48 beats/min.mm Hg.10(-2) and 10.8 +/- 2 vs 10.4 +/- 2 minutes, respectively). Both drugs significantly (p less than 0.001) improved all these parameters compared to the baseline exercise test. The effect of the 2 drugs on the diameters of angiographically normal segments of large epicardial coronary arteries was then assessed using computerized quantitative angiography in 10 other patients with stable angina. Whereas theophylline failed to increase the coronary diameters compared to that in the baseline angiogram (2.9 +/- 0.6 vs 2.9 +/- 0.6 mm, respectively), the subsequent administration of isosorbide dinitrate resulted in an increase up to 3.2 +/- 0.7 mm (p less than 0.02). Thus, in patients with stable angina, theophylline delays the onset of angina, increases the ischemic threshold and prolongs the exercise duration to the same degree as isosorbide dinitrate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of sustained release isosorbide dinitrate on exercise performance

The duration of action and hemodynamic mechanisms of isosorbide dinitrate in a sustained release formula (ISDSR) were examined over a 24-hour period. 20 patients with effort angina pectoris were divided randomly into two groups, one group received a single dose of 40 mg ISDSR (at 07.30 h) and the other, two doses of 40 mg ISDSR (at 07.30 and 13.30 h). Every patient had four exercise tests on the first (placebo) day and second (ISDSR) day and a single test on the third (placebo) day. Effort tolerance was improved significantly (p less than 0.05) with ISDSR and this lasted for more than 10 h. The double product was compared to ISDSR. Improvement was achieved by a decrease in blood pressure and an increase in heart rate. There were no signs of increased ischemia (ST segment depression) with the prolongation of exercise time. The antianginal and hemodynamic effects of ISDSR were more pronounced in the patients who received two doses of ISDSR. Thus, ISDSR improved effort tolerance for a prolonged period by inducing a sustained decrease of blood pressure and increase in heart rate in patients with effort-induced angina pectoris.     

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)     

Haemodynamic effects of isosorbide dinitrate in patients with congestive cardiac failure at rest and during submaximal supine exercise.

Eight patients with chronic congestive cardiac failure secondary to ischaemic heart disease performed submaximal supine exercise before and after 5 mg sublingual isosorbide dinitrate (ISDN) at the time of cardiac catheterisation. Exercise before ISDN produced a poor response in left ventricular performance. After ISDN this response was significantly improved. Compared with the control exercise period cardiac index (CI) increased from mean 2.9 to 3.5 l/mn/m2 (p = less than 0.0025), stroke volume index (SVI) from mean 24 to 29 ml/m2 (p = less than 0.0005) and left ventricular stroke work index (LVSWI) from mean 22 to 28 g-m/m2 (p = less than 0.0025). Although ISDN reduced LVEDP significantly at rest, there were associated small but significant falls in CI, SVI and LVSWI. The improvement in exercise cardiac index was related to the ejection fraction, or the ejection fraction of the contractile section where a left ventricular aneurysm was present. ISDN may be effective in improving exercise tolerance in ambulant patients with chronic congestive cardiac failure.     

Improvement in supine bicycle exercise performance in refractory congestive heart failure after isosorbide dinitrate: radionuclide and hemodynamic evaluation of acute effects

The acute effects of oral isosorbide dinitrate on exercise performance in congestive heart failure were evaluated in 11 patients. All patients underwent rest and supine bicycle exercise equilibrium radionuclide ventriculography and hemodynamic measurements before and after oral administration of isosorbide dinitrate, 40 mg four times a day for 24 hours. Ninety minutes after the last dose, isosorbide dinitrate increased the duration of exercise (+ 28 percent, probability [p] < 0.01) and the total work performed (+ 32 percent, p < 0.01); with this drug, significantly (p < 0.05) fewer patients terminated exercise because of dyspnea. At rest, the left ventricular ejection fraction increased after administration of isosorbide dinitrate (+ 14 percent of value before administration, p < 0.02); there were decreases in mean pulmonary arterial pressure (? 23 percent, p < 0.02), mean arterial pressure (? 8 percent, p < 0.05), systemic vascular resistance (? 18 percent, p < 0.005) and pulmonary vascular resistance (? 46 percent, p < 0.001). During comparable levels of exercise, isosorbide dinitrate decreased pulmonary capillary wedge pressure (? 19 percent, p < 0.001), mean pulmonary arterial pressure (? 23 percent, p < 0.001), mean arterial pressure (? 7 percent, p < 0.001), heart rate (? 5 percent, p < 0.01), systemic vascular resistance (? 20 percent, p < 0.01) and pulmonary vascular resistance (? 37 percent, p < 0.01), and increased cardiac index (+ 15 percent, p < 0.02), stroke volume index (+ 19 percent, p < 0.01) and stroke work index (+ 16 percent, p < 0.05). Ejection fraction did not change significantly (+ 7 percent, difference not significant [NS]). During maximal exercise, isosorbide dinitrate produced decreases in pulmonary capillary wedge pressure (? 15 percent, p = 0.05), mean pulmonary arterial pressure (? 15 percent, p < 0.01), systemic vascular resistance (? 23 percent, p < 0.05) and pulmonary vascular resistance (? 30 percent, p < 0.01) and increases in cardiac index (+ 30 percent, p < 0.001), stroke volume index (+ 31 percent, p < 0.001) and stroke work index (+ 40 percent, p < 0.001). Ejection fraction did not change significantly (+ 9 percent, p = NS). Ten minutes after exercise, isosorbide dinitrate produced decreases in pulmonary capillary wedge pressure (? 34 percent, p < 0.02), mean pulmonary arterial pressure (? 23 percent, p < 0.02), mean arterial pressure (? 10 percent, p < 0.01) and systemic vascular resistance (? 24 percent, p < 0.001) and increases in stroke volume index (+ 18 percent, p < 0.05) and ejection fraction (+ 12 percent, p < 0.05). It is concluded that oral isosorbide dinitrate, by causing reductions in preload and afterload, produces significant beneficial acute effects on left ventricular performance during exercise in patients with refractory chronic congestive heart failure.     

Systemic and regional hemodynamic effects of isosorbide dinitrate in patients with liver cirrhosis and portal hypertension

In a group of 17 cirrhotic patients with portal hypertension, we have investigated the effects of 5 mg sublingual administration of isosorbide dinitrate (IDN) on central hemodynamics, on regional (hepatic and renal) hemodynamics and on blood gases. Fifteen min after drug administration, we observed a decrease in the right atrial mean pressure from 4 +/- 1 to 3 +/- 1 mmHg (mean +/- S.E.M., P less than 0.02) and of pulmonary arterial wedge pressure from 7 +/- 1 to 4 +/- 1 mmHg (P less than 0.001) with decreases of the cardiac index from 4.2 +/- 0.2 to 3.7 +/- 0.2 l/min/m2 (P less than 0.001) and the mean arterial pressure from 89 +/- 4 to 72 +/- 3 mmHg (P less than 0.001) and an increase in heart rate from 86 +/- 4 to 94 +/- 5 beats/min (P less than 0.001). Arterial PO2 decreased from 73 +/- 2 to 66 +/- 2 mmHg (P less than 0.001). As a consequence of both cardiac index and arterial PO2 reductions, O2 transport to the tissues was reduced from 602 +/- 32 to 518 +/- 26 ml/min.m2 (P less than 0.001). The hepatic venous pressure gradient decreased from 17 +/- 1 to 14 +/- 1 mmHg (P less than 0.001) and hepatic vein PO2 did not change. The hepatic blood flow (HBF) determined in 7 patients remained unchanged. Renal blood flow (RBF) determined in 5 patients decreased from 0.76 +/- 0.11 to 0.68 +/- 0.11 l/min (P less than 0.001). In conclusion, isosorbide dinitrate reduces portal hypertension in patients with liver cirrhosis without compromising hepatic perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate.

Twenty-one patients with documented coronary atherosclerotic heart disease were studied to determine the effect of high dose oral isosorbide dinitrate (ISDN) on heart rate, blood pressure, and exercise time until angina pectoris. Patients were tested in two phases, initially with 0.4 mg of sublingual nitroglycerin and with sublingual placebo, and then with oral ISDN, mean dose 29 mg, and oral placebo. Both phases of the study were conducted in a randomized, double-blind, crossover manner. After ISDN was compared to oral placebo, heart rate increased at 30 to 300 min (P less than 0.01) (peak increase 18 beats/min at 60 min), and systolic blood pressure decreased from 45 to 300 min (P less than 0.005) (peak decrease 18 mm Hg at 60 min). Exercise time at 2 min after sublingual nitroglycerin increased 51% as compared to oral placebo, exercise time increased 54% at 1 hr (P less than 0.005), 37% at 3 hr (P less than 0.01), and 12% at 5 hr (NS). Twelve of 21 patients (57%) improved their exercise time until angina larger than or equal to 25% at 1 hr after oral ISDN. The exercise response to sublingual nitroglycerin was a good predictor of this response to oral ISDN.     

Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure

The cause of exercise intolerance in congestive heart failure is unclear. Hemodynamic and ventilatory responses were measured during symptomatic maximal upright bicycle exercise in 28 patients with chronic severe left ventricular failure who achieved a maximal oxygen uptake of only 12 +/- 4 ml/min/kg (+/- standard deviation). All patients reached anaerobic metabolism as the respiratory exchange ratio rose and arterial pH fell significantly. Pulmonary capillary wedge pressure increased from 20 +/- 10 mm Hg at rest to 38 +/- 9 mm Hg at peak exercise and cardiac index increased from 2.51 +/- 0.73 to 4.54 +/- 1.65 liters/min/m2 (both p less than 0.001). Systemic vascular resistance decreased, but pulmonary vascular resistance did not change during exercise. Despite the marked pulmonary venous hypertension at peak exercise, blood gases were unchanged (PaO2, 96 +/- 15 mm Hg; PaCO2, 35 +/- 7 mm Hg). Systemic arterial oxygen content increased from 16 +/- 2 to 17 +/- 2 vol% (p less than 0.01). Changes in pulmonary capillary wedge pressure did not correlate with changes in arterial oxygen content. Results were similar whether patients were limited by dyspnea or fatigue. Thus, exercise intolerance in patients with severe left ventricular failure is associated with marked elevation of pulmonary capillary wedge pressure and anaerobic metabolism without hypoxemia or altered carbon dioxide tension. These findings suggest that exercise ability in congestive heart failure is more dependent on cardiac output than on ventilatory consequences of pulmonary congestion.     

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)     

Effects of isosorbide dinitrate on portal hypertension in alcoholic cirrhosis

It has recently been reported that vasodilators lower portal pressure in patients with cirrhosis. This effect, however, is not definitively proven. The effect of isosorbide dinitrate (5 mg sublingually) on splanchnic and systemic hemodynamics was investigated in 13 patients with alcoholic cirrhosis and portal hypertension. The administration of isosorbide dinitrate reduced hepatic venous pressure gradient by 34% (P less than 0.001), mean arterial pressure by 30% (P less than 0.001), cardiac index by 17% (P less than 0.001) and systemic vascular resistance by 11% (P = 0.05). Hepatic blood flow was not affected by the treatment. Significant correlations were found between the decrease in hepatic venous pressure gradient and that of cardiac index (P less than 0.05) and mean arterial pressure (P less than 0.05). These data indicate that isosorbide dinitrate lowers portal pressure in patients with cirrhosis. Decrease in cardiac output, rise in splanchnic arterial vascular resistance and decrease in porto-hepatic resistance seem to participate in determining the effect.     

Left ventricular aneurysm and congestive heart failure: Value of exercise stress and isosorbide dinitrate in predicting hemodynamic results of aneurysmectomy

In 12 patients with left ventricular aneurysm and chronic congestive heart failure, left ventricular functional reserve was assessed from the hemodynamic response to exercise stress after administration of isosorbide dinitrate. Two to 23 months (mean 8.6 months) after left ventricular aneurysmectomy hemodynamic measurements were made with the patient at rest and during exercise and were analyzed with respect to preoperative data. Left ventricular aneurysmectomy reduced mean left ventricular filling pressure from 25 to 17 mm Hg at rest (p < 0.02) and from 39 to 32 mm Hg during exercise (p < 0.05). There was no significant change in mean stroke volume index at rest or during exercise.Changes in resting and exercise hemodynamic indexes of left ventricular function produced by aneurysmectomy were inversely related to preoperative left ventricular function. Hence, hemodynamic status was less likely to improve In patients with good preoperative left ventricular function. Similarly, resting and exercise values for left ventricular function tended to improve in patients with reduced ejection fraction of the contractile section of the left ventricle. Left ventricular aneurysmectomy was generally effective in reducing left ventricular filling pressure but failed to achieve clinically important improvement in left ventricular performance during exercise. In patients with chronic congestive heart failure, left Ventricular aneurysmectomy should be performed only after careful assessment of preoperative left ventricular functional reserve.