Early hemodynamic effects at rest with acute and chronic isosorbide dinitrate treatment in patients with ischemic heart disease

Asymmetric dosage regimens are used to circumvent development of nitrate tolerance and are believed to restore totally the hemodynamic responsiveness to an acute dosage of nitrates. This study assessed invasively the hemodynamics during supine rest before and for 50 min after peroral 30 mg isosorbide dinitrate (ISDN) in 16 patients with stable ischemic heart disease; 8 previously untreated patients (NT group) and 8 patients treated asymmetrically b.i.d. with 30 mg ISDN for 14 days prior to the invasive investigation (T group). Before initiation of treatment, both groups had identical mean arterial pressure (MAP) and heart rate (HR). On the day of invasive investigation, before intake of ISDN, MAP was higher in the T group but unchanged in the NT group. After the intake of ISDN, right atrial pressure (RAP), mean pulmonary arterial pressure, and pulmonary arterial wedge pressure declined markedly within 10 to 15 min in both groups, while MAP showed a more protracted decline, reaching a new level only after 25 to 30 min. In the NT group, HR accelerated markedly and remained elevated throughout the observation period, whereas in the T group HR showed no significant alteration after ISDN intake. At the end of the observation period, the cardiac index (CI) was definitely reduced in the NT group, but remained unchanged in the T group, while the systemic vascular resistance index was unchanged in the former and was clearly reduced in the latter. It is concluded that the fall in MAP in the NT group was solely due to a fall in CI, and that the decline in RAP and venous return in the NT group induced neurohumoral reflexes leading to a rise in HR and prevention of arterial dilation, whereas in the T group, already influenced by chronic treatment, such acute counterregulatory responses were markedly attenuated or absent.     

Long-term effect of isosorbide dinitrate and nifedipine, singly and in association, in patients with chronic heart failure

The effect of 2-month treatment with isosorbide dinitrate (120 mg day-1), nifedipine (2 x 20 mg day-1) and their combination has been assessed in 16 patients with mild to moderate chronic cardiac failure. Isosorbide dinitrate decreased right atrial (-23%), pulmonary wedge (-20%) and pulmonary arterial (-17%) pressures but did not significantly change either cardiac output or systemic and pulmonary vascular resistance. Nifedipine increased cardiac output (+13%) and decreased systemic and pulmonary vascular resistance (both -17%) with no change of pressures. Combined therapy with both drugs decreased ventricular filling pressures (-8% and -15%), systemic (-20%) and pulmonary (-13%) arterial pressures, increased cardiac output (+26%) and decreased both systemic (-29%) and pulmonary (-29%) vascular resistances. Changes during exercise were almost the same as at rest. The effect of both drugs was more pronounced in patients with more severely pathological haemodynamic measurements before treatment. We conclude that combined treatment with both preload- and afterload-reducing agents can preserve or even potentiate a favourable haemodynamic effect of individual drugs.     

Comparison of nifedipine and isosorbide dinitrate when added to maximal propranolol therapy in stable angina pectoris

A study was performed to compare isosorbide dinitrate and nifedipine as adjunctive therapy in 14 patients with coronary artery disease and stable angina pectoris taking maximal beta-blocking drugs. Drug titration phases ensured maximal therapy of propranolol, isosorbide or nifedipine. The combination of nifedipine and propranolol was more effective than the combination of isosorbide and propranolol in reducing angina and increasing exercise capacity (323 vs 416 seconds, p less than 0.005) during exercise treadmill testing. Nifedipine produced a greater reduction in systolic blood pressure at submaximal exercise than isosorbide. Global and regional ejection fraction at rest and exercise was assessed with radionuclide ventriculography. The substitution of nifedipine for isosorbide depressed the global ejection fraction at rest (0.61 to 0.56 p less than 0.05) and produced a slight improvement in exercise ejection fraction (0.47 to 0.51, difference not significant). The decrease in ejection fraction from rest to exercise was 0.14 to 0.04 with nifedipine (p less than 0.005). The benefit of nifedipine compared with isosorbide occurred in regions with marked exercise-induced ischemia. In patients treated with maximal beta-blocking therapy, nifedipine is an effective alternative to isosorbide as a combination agent with propranolol. The salutary effects of nifedipine included afterload reduction with exercise and possible improvements in coronary blood supply.     

Influence of glyceryl trinitrate on venous and arterial effects of chronic,asymmetric isosorbide dinitrate treatment in patients with ischemic heart disease

Asymmetric dosage regimes have been introduced to circumvent development of nitrate tolerance. This study assessed invasively the hemodynamics during supine rest and exercise before and after 4 weeks treatment with 30 mg isosorbide dinitrate (ISDN) or placebo asymmetrically b.i.d. in 14 randomized patients with stable ischemic heart disease in a double-blinded study. An intravenous infusion of glyceryl trinitrate (GTN) was used to assess possible nitrate tolerance. During the initial, medication-free exercise all patients had increased pulmonary arterial wedge pressure (PAWP) 31.4 ± 5.56 mmHg (mean ± SD), showing impaired left ventricular function, while mean arterial pressures (MAP) rose from 112 ± 16.3 mmHg at rest to 141 ± 15.9 mmHg during exercise. After 4 weeks ISDN treatment, mean exercise PAWP and MAP, 3 h after morning dose, were reduced to 22.4 ± 7.09 mmHg and 127 ± 18.2 mmHg, respectively. Before the ISDN treatment, GTN reduced exercise PAWP to 13.9 ± 5.27 mmHg and MAP to 119 ± 11.2 mmHg, whereas after 4 weeks ISDN treatment, the addition of GTN did not reduce exercise PAWP and MAP to the same low levels. Thus, the applied ISDN regimen improved the hemodynamics, but induced a definite, partial nitrate tolerance.     

Comparative effects of nifedipine, verapamil, isosorbide dinitrate and propranolol on exercise-induced angina pectoris.

According to the experimental model of a 5 X 5 Latin square, 5 treatments were studied single blind in 5 patients, affected by stable-effort angina, by means of exercise tests. In the period of maximal supposed effect the following treatments were investigated: placebo (P), 1 tablet, orally; isosorbide dinitrate (ISDN), 5 mg, sublingually; propranolol (Pr), 40 mg, orally; nifedipine (N), 10 mg, orally; verapamil (V), 160 mg, orally. Placebo, compared with its own control tests, did not change any of the examined parameters. Comparison of the 'active' treatments with P showed the following results. All the treatments increased the duration of work before ECG positivity appearances. An increase in duration of work and total work performed before angina was seen after administration of ISIDN, N and V; the improvement observed after treatment with Pr was not significant. Comparison of treatments showed that work performance before angina was the same after administration of ISDN, N and V; these treatments were more effective than that with 40 mg Pr. Duration of work before ECG positivity was significantly longer after ISDN and N than after Pr. The changes in heart rate, maximal arterial pressure, ejection time index and triple product confirmed the activity of the administered doses. According to the observed effects on exercise tolerance, in comparison with P the same level of work was performed with the same triple product after Pr, and with lower triple products after ISDN, N and V.     

Hemodynamic time course of acute and chronic isosorbide dinitrate treatment at rest and during exercise in patients with stable ischemic heart disease

Hypothesis: The study was undertaken to establish differences between venous and arterial isosorbide dinitrate (ISDN) effects during acute and chronic treatment, hemodynamics at rest, and during supine exercise. Methods: These effects were assessed invasively in 16 patients with stable ischemic heart disease before and at hourly intervals for 4 h after administration of peroral 30 mg ISDN. Eight patients were previously untreated (acute group), and eight were treated with 30 mg ISDN asymmetrically b.i.d. for two weeks (chronic group). Results: Prior to ISDN administration, right atrial, mean pulmonary artery, pulmonary artery wedge, and mean arterial pressure (RAP, MPAP, PAWP, and MAP) rose from normal resting to pathologic values during exercise. One h after ISDN administration, all exercise pressures were normalized (p<0.001). During the following 3 h, exercise RAP rose similarly in both groups (p<0.01), while MPAP rose particularly in the chronic group (p<0.001). Exercise PAWP and MAP, however, remained low in the acute group, but increased markedly in the chronic group (p<0.01), particularly from the third to the fourth hour after ISDN. Conclusion: The daily, asymmetric administration of 30 mg ISDN b.i.d. maintained beneficial, anti-ischemic effects for 2 to 3 h after a morning dose of the drug, but thereafter attenuation of the effects occurred in the arteries but not in the veins.     

Double-blind crossover comparison of the antianginal effects of nifedipine and isosorbide dinitrate in patients with exertional angina receiving propranolol

A double-blind crossover study was performed on 27 patients with proved fixed coronary artery disease and stable angina pectoris. The study was designed to compare the relative efficacy of two combination therapies, nifedipine plus propranolol and isosorbide dinitrate plus propranolol, in terms of antianginal response and effect on exercise tolerance by evaluation of treadmill testing. The combination of nifedipine and propranolol was superior to the combination of isosorbide and propranolol in reducing the number of anginal attacks (p = 0.03), increasing total exercise time (p less than 0.02), increasing oxygen consumption achieved at end of exercise (p less than 0.03), increasing time to onset of pain (p = 0.003) and increasing oxygen consumption achieved at onset of pain (p = 0.003). Analysis of the rate-pressure products suggests that the difference in these results may be explained by the greater effect of nifedipine on afterload reduction. Although nitroglycerin consumption was reduced from baseline levels during combination nifedipine therapy (p less than 0.001), there was no statistical difference between nifedipine combination therapy and isosorbide combination therapy. In conclusion, although both combination therapies were superior to propranolol therapy alone, the combination of nifedipine and propranolol was more effective than the combination of isosorbide and propranolol in reducing the incidence of angina and improving exercise performance. Side effects were experienced at a similar frequency during both combination therapies.     

Comparison of the antianginal effectiveness of nifedipine, verapamil, and isosorbide dinitrate in patients receiving propranolol: a double-blind study

Ten men with stable angina not fully relieved by optimal doses of propranolol were given on each of four mornings a single dose of 10 mg nifedipine, 120 mg verapamil, isosorbide dinitrate (5 to 30 mg, previously titrated to lower systolic blood pressure by 15 to 20 mm Hg), or placebo, in double-blind fashion. Bicycle exercise to angina was performed hourly for 8 hr thereafter. All three vasodilators increased exercise time by at least 50% by the first hour (p less than .001), with a gradually diminishing effect persisting for 6 to 8 hr (p less than .01). Although for the group there were no differences in magnitude and duration of effect among the three drugs, in five of the individual patients there were important differences in response favoring one or another vasodilator. We conclude that nifedipine, verapamil, and isosorbide dinitrate are equally effective and reasonably long-acting antianginal supplements to propranolol, although some patients may benefit more from one than another of the three.     

Effect of isosorbide dinitrate (isoket) on central hemodynamics and myocardial contraction in patients with ischemic heart disease

The authors studied the effect of isoket on the central hemodynamics and myocardial contractility as well as on the conditions of myocardial functioning in 38 patients aged 28-53 years and suffering from coronary heart disease. The infusion of 2 mg of isoket at a rate of 400 micrograms/min was followed by a decrease in the arterial pressure with the maximum drop seen on the seventh minute (by 26% from the baseline value), a reduction in the end-diastolic pressure by 50%, and a lengthening of the preejection period without any significant changes in either the cardiac output or the total peripheral resistance. Taken as a whole these changes justify the conclusion that the influence of dinitrate isosorbite (isoket) on the central hemodynamics is largely due to its venodilating action leading to a reduction of the pre-load which in turn improves myocardial functioning.     

Combined helium-neon laser therapy in patients with ischemic heart disease

The paper describes the combined helium-neon-laser (HNL) therapy (intravenous and topical) developed by the authors to treat patients with coronary heart disease. A high efficacy of this therapy mode was demonstrated in patients over 70 years of age with Functional Classes III-IV angina refractory to antianginal agents. The mechanisms responsible for therapeutic efficiency of laser irradiation were studied at the membraneous and cellular levels. There is evidence that the combined HNL-therapy had advantages over topical HNL exposure in terms of higher clinical efficiency and patterns of abnormal chemical changes.     

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     

Vasodilator treatment with isosorbide dinitrate and hydralazine in chronic heart failure.

Several reports have suggested that because isosorbide dinitrate and hydralazine have different and additive haemodynamic effects at rest in patients with chronic heart failure, these agents should be administered in combination. Some studies, however, indicate thay they are effective individually as well. Since most patients with heart failure are symptomatic only with activity, we examined the haemodynamic effects of these drugs given individually and in combination, at rest and during upright bicycle exercise. As has been noted previously, at rest isosorbide significantly lowered both ventricular filling pressures and did not change cardiac output; hydralazine increased cardiac output and had only a slight effect on pulmonary capillary wedge pressure; combined treatment produced both beneficial effects. In contrast, during exercise isosorbide dinitrate also raised cardiac output while hydralazine more dramatically lowered the wedge pressure. Combined treatment produced significantly greater improvement in each haemodynamic index than either drug alone, with a resulting 54 per cent increase in exercise cardiac output, and a 33 per cent reduction in exercise wedge pressure. Maximal oxygen consumption increased acutely during combined treatment. These findings suggest that isosorbide dinitrate and hydralazine may each be effective in some patients, but that they are even more beneficial in combination.     

Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm

The effects of nifedipine and isosorbide dinitrate on the frequency of angina and consumption of nitroglycerin were studied in 19 patients with coronary arterial spasm. After a lead-in phase, the patients were randomized to treatment with either nifedipine or isosorbide dinitrate. After dose titration (40 to 120 mg/day) and evaluation, they were given the alternate therapy. During the initial segment of the double-blind phase, one patient died suddenly (nifedipine phase), one dropped out of the study (nifedpine phase) and another was unable to tolerate therapy (isosorbide dinitrate phase). In the other 16 patients, the mean frequency of angina was less during therapy with both nifedipine (0.69 episode/day, p < 0.05) and isosorbide dinitrate (0.77 episode/day, p < 0.05) phases than during the lead-in phase (1.71 episodes/day). The mean frequency of angina was similar in the nifedipine and isosorbide dinitrate phases. A 50 percent or greater decrease in frequency of angina compared with lead-in phase values occurred in 13 of 18 patients during treatment with nifedipine and in 10 of 16 during treatment with isosorbide dinitrate. Of the 16 patients who completed both double-blind phases, 7 showed greater improvement (that is, a 50 percent or greater decrease in frequency of angina) with nifedipine than with isosorbide dinitrate); 6 others showed greater improvement with isosorbide dinitrate, and the other 3 had a less than 50 percent difference in frequency of angina with the two drugs. These findings in a limited number of patients suggest that both nifedipine and isosorbide dinitrate are effective in certain patients with coronary spasm but that neither drug is clearly superior.     

Comparison of acute haemodynamic effects of nifedipine and isosorbide dinitrate in patients with heart failure following acute myocardial infarction

The acute haemodynamic effects of nifedipine (10 mg sublingually) and isosorbide dinitrate (5 mg sublingually) were compared in 13 patients with heart failure due to acute myocardial infarction. Nifedipine induced a significant reduction in systolic (from 122 ± 5 to 107 ± 3 mm Hg: mean ± SEM; P < 0.002) and diastolic blood pressure (from 85 ± 3 to 75 ± 2 mm Hg; P < 0.01). Heart rate did not change significantly, nor did mean right atrial pressure. The mean pulmonary arterial pressure was lowered from 31 ± 2 to 27 ± 2 mm Hg (P < 0.005). The left ventricular filling pressure decreased from 24 ± 1 to 19 ± 1 mm Hg (P < 0.0001). A significant increase in cardiac index (from 2.33 ± 0.13 to 2.69 ± 0.15 l/min per m²; P < 0.001) and in stroke volume index (from 24 ± 2 to 28 ± 2 ml/beats per m²; P < 0.005) was registered. Systemic vascular resistance fell from 1742 ± 145 to 1308 ± 85 dynes/sec per cm⁻⁵ (P < 0.00005). After isosorbide dinitrate was administered a significant reduction in mean right atrial pressure (from 9.5 ± 1.6 to 5.1 ± 1.2 mm Hg; P < 0.0001), in mean pulmonary arterial pressure (from 32 ± 1 to 23 ± 1 mm Hg; P < 0.00001) and in left ventricular filling pressure (from 23 ± 1 to 16 ± 1 mm Hg; P < 0.0001) was seen. No significant change in systolic and diastolic blood pressure, heart rate, cardiac index, stroke volume index and systemic vascular resistance was registered. No side-effects were seen after nifedipine and isosorbide dinitrate were administered.     

The effects of isosorbide dinitrate spray on the coronary artery and its modification by the preceding chronic oral therapy with long acting isosorbide dinitrate]

The vasodilatory effect of a new formula of isosorbide dinitrite (ISDN) spray on the left coronary artery was studied by comparing its effects in 46 consecutive patients who subsequently received intracoronary injection with ISDN (2.5 mg). In addition, the influence long acting and ISDN for chronic cases on the vasodilatory effects of ISDN spray and on subsequent intracoronary injection of ISDN was investigated. The patients were divided into two groups, those who had had chronic oral ISDN (Group N; 29 patients) and those who had not (Group O; 17 patients). The vasodilatory effect of ISDN spray was evaluated in segments; 5, 6, 8, 11 and 12 by AHA classification and it dilated those segments by 9.9%, 13.2%, 21.5%, 15.6% and 23.5% respectively. Subsequent intracoronary injection of ISDN dilated those segments by 10.4%, 14.0%, 27.2%, 17.9% and 29.1% respectively. The differences in the degree of vasodilation caused by ISDN spray and that caused by injection in segments 8, 11, 12 were statistically significant. However, the per cent dilation of ISDN spray in segments 5 in group N was 5.9%, and 18.4% in group O, revealing a significant difference depending on previous chronic administration of long acting ISDN. We conclude that ISDN spray did dilate the coronary artery, and subsequent intracoronary administration of ISDN dilated it further in the distal portions of the left coronary artery. Long acting oral ISDN for chronic cases seemed to attenuate the vasodilatory action of ISDN.     

Comparison of nifedipine, propranolol and isosorbide dinitrate on angiographic progression and regression of coronary arterial narrowings in angina pectoris

Calcium antagonists and beta blockers may retard or inhibit atherogenesis. This study investigated whether nifedipine or propranolol influences coronary atherosclerosis in humans. In selected patients with effort angina and proven coronary artery disease, the cineangiographic pattern after 2-year therapy with nifedipine (group 1, 39 patients), propranolol (group 2, 36 patients) or isosorbide dinitrate (group 3, 38 patients) was compared to that before treatment. The disease evolved to a different extent in the 3 groups. Patients with evidence of progression of old narrowings and appearance of new narrowings were significantly fewer in group 1 (31% and 10%) than in group 2 (53% and 34%) and group 3 (47% and 29%). The number of stenoses with evidence of progression was significantly smaller after nifedipine (14), and larger after propranolol (39) compared with group 3 (24). Thus, nifedipine seemed more protective than the other 2 drugs against coronary atherosclerosis. The coronary risk factors were normal in the nifedipine group and remained so with treatment, suggesting that they were dissociated from influences on atherosclerosis. The evolution, as judged by the number of narrowings with progression, appeared significantly (p less than 0.01) worse with propranolol than with isosorbide dinitrate. Propranolol caused unfavorable modifications of serum lipids; there was a 28% increase in total triglycerides and a 25% decrease in high density lipoprotein cholesterol at 12 months in group 2.