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PubMed1985

[Hemodynamic effects of a new long-acting isosorbide dinitrate].

The following hemodynamic parameters were measured at rest and 1, 2, 4, 6, 8, 12 and 24 hours after 100 mg of ISDNSR p.o. in 10 patients with dilated cardiomyopathy (NYHA class III-IV): mean pulmonary artery, pulmonary capillary wedge (PCW) and arterial pressures (AP), and cardiac output (thermodilution). Plasma levels of ISDN were determined by capillary gas chromatography at the same intervals and correlated with the hemodynamic changes. PCW fell from 24 +/- 1.5 (SE) to 18 +/- 1.8 mm Hg after 1 hour (p less than 0.05) and after 2 hours to 16.9 +/- 1.6 mm Hg. This change was sustained for 8 hours. At 12 hours PCW had increased again to 21 +/- 1.5 mm Hg and at 24 hours to 22 mm Hg. AP dropped from 89 +/- 5 to 81 +/- 4 mm Hg at 1 hour (p less than 0.2) and remained 80-84 mm Hg for 8 hours. It returned to baseline levels at 12 hours. Heart rate, cardiac index, systemic vascular resistance, stroke index and left ventricular work index did not change significantly during the observation period. Plasma levels of ISDN remained between 3 and 12 ng/ml for 16 hours. Thus, ISDNSR is an effective long-acting nitrate preparation which reduces preload for 8-12 hours. After this interval, nitrate tolerance starts to develop.

Blood Pressure↗
PubMed1982

Glyceryl trinitrate (nitroglycerin) ointment and isosorbide dinitrate: a review of their pharmacological properties and therapeutic use.

Sublingual glyceryl trinitrate (nitroglycerin) is the most widely used drug in the treatment of angina pectoris, but its use is limited due to its short acting effect. Recent investigations have shown that some longer acting nitrates administered orally or topically have a long acting antianginal effect. The mechanism of the antianginal effect of nitrates is multifactorial. Nitrates increase oxygen supply to the myocardium by causing redistribution of coronary blood flow. In addition, nitrates decrease myocardial oxygen demand by reducing left ventricular volume, intramyocardial tension, and left ventricular afterload. The use of nitrates for the treatment of congestive heart failure has also been established in recent years. Nitrates have a predominant venodilatory effect resulting in peripheral blood pooling and decreased venous return to the heart, thereby decreasing left ventricular filling pressure. The effect of nitrates on the arteriolar circulation is small, and there is usually little or no change in cardiac output. Some reduction in systemic blood pressure can be seen, while there is usually no change in heart rate. In a small number of patients with myocardial infarction complicated by congestive heart failure, the use of long acting nitrates has resulted in haemodynamic and symptomatic improvement. Nitrates has also bee shown to improve variant angina. Nitrates are usually well tolerated in most patients. However, some troublesome side effects can occur, including headache, postural hypotension, and methaemoglobinaemia.

Angina Pectoris↗
PubMed1989

[High-dose single administration of isosorbide dinitrate: effect on diurnal distribution of transitory myocardial ischemia in patients with stable angina pectoris].

We studied the effect of a monotherapy of isosorbiddinitrate on symptomatic and asymptomatic ischemic episodes in 15 ambulatory patients with chronic stable angina pectoris, positive exercise test, and coronary stenosis greater than 70%. Transient ST-segment depression (greater than 0.1 mV for at least 1 min) was documented by 48-h Holter monitoring during a control period without anti-ischemic therapy and at the end of 14 days of treatment with 120 mg o.d. isosorbiddinitrate slow-release. In the control period, 68 asymptomatic and 28 symptomatic ischemic episodes were detected; most of the episodes occurred in the morning between 6.00h and 12.00h (41 episodes) and in the afternoon between 12.00h and 18.00h (36 episodes). Under anti-ischemic therapy the number of episodes and the total duration of ischemia was reduced by 46% and 53%, respectively (p less than 0.01). The anti-ischemic effect was most evident during the morning and the afternoon; the ischemic episodes during the evening and the night were not significantly diminished. It is concluded that in patients with stable angina pectoris a single high-dose of isosorbiddinitrate significantly reduces the number and duration of transient ischemic episodes during daily life.

Aged↗
PubMed1983

Sustained antianginal efficacy of oral high-dose isosorbide dinitrate in patients with coronary heart disease.

Ten patients with angiographically proven coronary heart disease, stable exercise-induced angina pectoris, and reproducible ST-segment depression were treated with ISDN tablets in daily doses of 240 mg (6 X 40 mg) and placebo for 28 days each on the basis of a randomized double-blind protocol with intraindividual crossover. On the 1st, 7th and 28th days of each treatment cycle an exercise stress test was performed 1 h after the second dose of the day. ISDN treatment resulted in a sustained reduction of anginal attacks, with a weekly rate ranging from 1.4 to 3.9 (mean values) as compared to 10.5 to 11.7 attacks during placebo treatment (2 p less than 0.001). Exercise-induced ST-segment depression during ISDN-therapy (constant work-load) was found to be significantly improved as compared to placebo: day 1, ISDN: 5.3 +/- 1.5 mm vs. placebo: 12.1 +/- 2.2 mm (2p less than 0.01); day 7, ISDN: 7.6 +/- 2.0 mm vs. placebo: 10.8 +/- 2.1 mm (2p less than 0.05); day 28, ISDN: 5.7 +/- 1.2 mm vs. placebo: 11.2 +/- 2.1 mm (2p less than 0.01). Heart rate in the upright position (tilting table) was significantly different between ISDN and placebo on day 7: ISDN 92 +/- 3 bpm vs. placebo 85 +/- 4 bpm (2p less than 0.001), but not on day . 28.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Effect of isosorbide dinitrate infusion on the canine left ventricular force-length relationship.

Recently, the slope (Ec) of the left ventricular (LV) end-systolic force-diameter (Fes-Des) relationship has been proposed as a new index for assessing myocardial contractility. Using this relationship, the effects of ISDN on LV myocardial contractility were evaluated in 10 healthy adult mongrel dogs. After the intravenous infusion of propranolol and atropine to produce autonomic blockade, the inferior vena cava was gradually occluded for 20 sec to decrease preload while the dogs were kept apneic. The LV diameter was measured by ultrasonic crystals and LV pressure was measured by a micromanometer. After the control measurements, the dogs received intravenous ISDN (1, 5, 10, or 50 micrograms/kg/min), and inferior vena caval occlusion was repeated. Ec and the extrapolated diameter intercept (D0) of the LV Fes-Des relationship were determined for each dog from the end-systolic data. The differences in heart rate between the control state and ISDN infusion at any dose were not statistically significant. The Ec and D0 values also showed no significant changes with ISDN infusion (Ec: 80 +/- 19, 83 +/- 20, 84 +/- 17, 82 +/- 24, and 87 +/- 24 g/cm for 0, 1, 5, 10, and 50 micrograms/kg/min, respectively. D0: 1.38 +/- 0.42, 1.38 +/- 0.40, 1.38 +/- 0.38, 1.34 +/- 0.40, and 1.36 +/- 0.40 cm for 0, 1, 5, 10, and 50 micrograms/kg/min, respectively). These findings suggested that intravenous ISDN did not affect myocardial contractility in the normal in situ canine left ventricle.

Animals↗
PubMed1989

[Long-term therapy following myocardial infarct with isosorbide dinitrate in a low and high dose].

The favorable response to nitrates in the case of coronary heart diseases is based on both reduction in left ventricular pre- and afterload and improvement in coronary flow. These effects were studied in the setting of a long-term ISDN therapy with reference to the prognosis of patients after myocardial infarction. Following acute treatment in the respective hospitals, 608 patients with myocardial infarctions were allocated to two double-blind treatment groups with different ISDN dosage levels (group 1 = 5 x 2.5 mg i.d.; group 2 = 5 x 40 mg i.d.) and followed up over a period of 2 years. No differences were found with regard to the end points sudden cardiac death, reinfraction, and indication for revascularization. There was, however, a more frequent additional administration of calciumantagonists to patients of the low-dose group (p less than 0.05), a more frequent drop-out due to the lack of beneficial therapeutic results, and a more exceptional drop-out due to side effects in patients treated with low doses of ISDN (n.s.). The absence of any significant difference with regard to the end points might be attributed to; 1) a loss of potency of high-dose ISDN and simultaneous ineffectiveness of low-dose ISDN; 2) an efficacy of low doses; 3) an absence of actual influence on the target parameters, and 4) an inadequate follow-up time period.

Coronary Circulation↗
PubMed1990

[Clinical evaluation of isosorbide dinitrate (ISDN) spray: a study on the plasma concentrations of ISDN and on its hemodynamic effects using three administration routes].

The effects of ISDN spray has been evaluated using oral, nasal or tracheal routes in patients under enflurane anesthesia. These 30 patients were in ASA I or II physical status without cardiovascular, kidney or liver diseases. Under enflurane anesthesia, hemodynamic parameters (blood pressure and heart rate), blood gas and plasma concentration of ISDN were measured at several points before and after drug administration. The plasma concentration reached a maximum point (C max) 4 min after drug administration in the oral group (O-group) and nasal group (N-group), and the values obtained were 48.4 +/- 5.4 ng.ml-1 and 87.4 +/- 13.8 ng.ml-1 respectively. The C max of the N-group was significantly higher than that of O-group (P less than 0.05). In the O- and N-groups, systolic blood pressure decreased 10% and 17%, after 4 min (P less than 0.05) and recovered 20 after min. Diastolic blood pressure decreased in both groups after 4 min (P less than 0.05). Heart rate significantly increased in the N-group (P less than 0.05), and continued to change up to 60 min after drug administration. In both groups, PaO2/FIO2 decreased 14% and 9% after 10 min (P less than 0.01). In the tracheal group, plasma concentration did not increase and these hemodynamic changes were not observed. These results suggest that nasal route of ISDN spray is the best route of administration.

Administration, Intranasal↗
PubMed2000

Does diabetes mellitus affect the progress of tolerance to isosorbide dinitrate (ISDN) in corporal tissue?

For erection to take place, the penile arteries and sinusoids have to dilate, thereby increasing the blood flow into the penis. There is increasing evidence that release of l-arginine derived nitric oxide (NO) from nonadrenergic-noncholinergic (NANC) nerves and from the sinusoidal endothelium is a major event in penile smooth muscle relaxation and promotes the endogenous formation of cyclic guanosine monophosphate (cGMP). Nitrovasodilators can be attributed to the activation of soluble guanylate cyclase, resulting in an increase in intracellular level of cyclic guanosine monophosphate, but prolonged exposure to high levels of nitroglycerine and other organic nitroesters induces tolerance against the cardiovascular effect. In this study, the aim was to determine the effect of diabetes on the corporal smooth muscle relaxant effect of ISDN and the effect of diabetes on the process of tolerance to the drug. For this purpose, alloxan-induced diabetic rabbits were used to form diabetes group. The responses of the corpus cavernous strips obtained from control and alloxan-induced diabetic rabbit were studied in organ chamber. In conclusion, prolonged in vitro exposure of corpus cavernosum strips obtained from control and diabetic groups to high concentrations of ISDN caused significant desensitization to the relaxant effect the drug. So, prolonged exposure of corporal tissue to the agents like nitroglycerine, used for treatment of impotence, may render ineffective the therapy in diabetic erectile impotence. However, intolerance to nitric oxide provides a rationale for the concept of using nitro oxide agents (like SNP) in the treatment of diabetic erectile dysfunction.

Alloxan↗
PubMed1984

[Prevention of the development of tolerance to isosorbide dinitrate in interval therapy].

A number of carefully controlled studies in recent years have unequivocally documented evidence of tolerance development with respect to anti-ischemic effects during longterm treatment with nitrates [1, 3, 4, 5, 7, 8]. To determine to what extent tolerance development can be circumvented through an interval regimen, a study was performed in ten patients with stable angina pectoris and reproducible ST-segment depression according to a randomized, double-blind, cross-over, placebo-controlled protocol. Analysis of the anti-ischemic effect of 20 mg ISDN was carried out after acute administration and during chronic treatment on an interval regimen with the administration of 20 mg ISDN in the morning (at 8 a.m.) and at midday (1 p.m.) (Figure 1). On acute administration, 20 mg ISDN led to a reduction in ST-segment depression from 2.15 to 0.40 mm (p less than 0.01) and during longterm treatment from 2.25 to 0.40 mm (p less than 0.01) (Figure 2, Table 1). After acute administration the plasma concentration of ISDN was 9 ng/ml, 2-ISMN 34 ng/ml and 5-ISMN 149 ng/ml (Figure 5, Table 2). Of the control values during longterm treatment, a detectable level was found only for 5-ISMN with a concentration of 36 ng/ml while that of both 2-ISMN and ISDN was 0 ng/ml. On renewed administration, there was an increase of ISDN to 9 ng/ml, 2-ISMN to 37 ng/ml and 5-ISMN to 208 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1983

Tolerance development during isosorbide dinitrate treatment: can it be circumvented?

Based on studies carried out according to randomized, double-blind, crossover, placebo-controlled protocols, analysis was performed to assess the antiischemic effects of (a) 40 mg ISDN, both after acute administration and during long-term treatment with four doses daily, (b) treatment with 20 mg ISDN twice daily (at 8 a.m. and 1 p.m.), and (c) 0.8 mg sublingually administered NTG during treatment with 40 mg ISDN four times daily. After acute administration of 40 mg ISDN there was a reduction in ST-segment depression from 2.05 to 0.18 mm (p less than 0.01). During chronic treatment, statistically-significant changes were no longer detectable. Sublingual administration of 0.8 mg NTG led to a reduction of ST-segment depression during the acute phase of ISDN from 1.20 to 0.15 mm (-87%; p less than 0.01) and during chronic treatment from 1.90 to 0.90 mm (-53%; p less than 0.01). Accordingly, as compared with changes induced in the acute and placebo phases, the effectiveness of NTG during chronic ISDN treatment was diminished. After acute administration of 20 mg ISDN, ST-segment depression was reduced from 2.15 to 0.40 mm (p less than 0.01) and to a comparable degree during long-term twice-daily treatment, from 2.25 to 0.40 mm (p less than 0.01). There was a significant reduction in the rate of anginal attacks and nitrate consumption. Thus, with respect to the anti-ischemic effectiveness of ISDN, tolerance development is incurred during repeated administration. Concomitantly, the effectiveness of NTG is not essentially negated, but rather diminished.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Trials as Topic↗
PubMed1984

Evidence for isosorbide dinitrate (ISDN) promoting effect on prostacyclin release by the lung and prostacyclin implication in ISDN-induced inhibition of platelet aggregation in humans.

We investigated thromboxane B2 (TxB2), 6-keto-PGF1 alpha (6KPGF1 alpha reflecting prostacyclin), PGE2 and PGF2 alpha plasma levels; TxB2, PGE2 and PGF2 alpha platelet production and platelet aggregation response in ascending aorta (reflecting trans-pulmonary difference) and in venous coronary sinus (reflecting transcardiac difference) simultaneously in patients with ischemic heart disease, before and after right-atrial administration of 3 mg ISDN bolus. Transcardiac differences were scarce before as well as after ISDN administration. In aortic blood, ISDN administration into the right atria resulted in a significant increase in prostacyclin and PGF2 alpha plasma levels (472% and 242%, respectively), a decrease of both PGE2 plasma level (-173%) and PGE2 platelet production (-485%) and a marked lowering of platelet aggregation response to ADP, concomittantly. In contrast, TxB2-related features were poorly affected by ISDN. In coronary sinus blood, the aortic increase in 6KPGF1 alpha and PGF2 alpha plasma levels was detected to a lower extent whereas the characteristics of platelet aggregation had returned to control levels. By contrast, PGE2 plasma level (-191%) and PGE2 platelet production (-133%) were lower than prior ISDN administration. The results we report here, strongly support the view that ISDN promotes release of prostacyclin and PGF2 alpha from the lung and inhibit PGE2 production. These prostanoids may be responsible for the concomittant platelet reactivity lowering, thus providing a basis for understanding how ISDN might relieve myocardial ischemia favoring prostanoid mediated vasodilation and inhibition of platelet reactivity.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Identification of asynergic but viable myocardium in patients with chronic coronary artery disease by gated blood pool scintigraphy during isosorbide dinitrate and low-dose dobutamine infusion: comparison with thallium-201 scintigraphy with reinjection.

To evaluate the ability of low-dose dobutamine and isosorbite dinitrate (ISDN) gated blood pool scintigraphy (GBPS) and thallium SPECT with reinjection to identify viability in asynergic myocardium, both procedures were performed in 38 consecutive patients with chronic coronary artery disease and left ventricular dysfunction. Twenty-two of the 38 patients with successful revascularization were analyzed. GBPS was performed at the baseline and during continuous infusion of low dose dobutamine (5 micrograms/kg/min) and ISDN (2 micrograms/kg/min). Cine mode GBPS wall motion was scored from normal (0) to dyskinesis (4) semiquantitatively. Forty-seven of 110 segments with severe asynergy at the baseline were analyzed. Viability determined by GBPS was defined as wall motion score improvement by more than 1 grade. Thallium viability was defined as the segment with redistribution or fill in with severe initial perfusion defect. GBPS was 76.7% sensitive and 70.6% specific for predicting post vascularization wall motion improvement (p < 0.005). Of 47 segments with severe asynergy, concordance of judgement was obtained in 40 segments (85.1%), and reversibility was correctly diagnosed in 34 of 40 patients (85.0%), but thallium with reinjection correctly identified tissue viability in 6 of 7 segments with discordance between 2 studies. These data suggest that most cases of reversible asynergy (hibernating myocardium) respond to ISDN and dobutamine, suggesting the possibility of predicting improvement by revascularization, although some underestimation of tissue viability remained to be resolved. Thallium with reinjection is superior to low-dose dobutamine + ISDN GBPS for the assessment of myocardial viability.

Adult↗
PubMed1988

The effects of antianginal drugs on left ventricular function in patients with effort angina pectoris. Comparison among isosorbide dinitrate, nifedipine and propranolol by PANOVA.

To study the acute effects of ISDN, nifedipine, propranolol and placebo on cardiac function in patients with myocardial ischemia and to characterize their hemodynamic effects by PANOVA, we repetitively performed exercise radionuclide angiography (RNA) following random assignment of each drug in 20 patients with effort angina pectoris. We obtained exercise response curves of hemodynamic parameters determined by RNA. ANOVA was performed to analyze the sizes (average height) of those response curves, and PANOVA (principal component analysis, PCA, combined with ANOVA) to analyze differences in the profiles (patterns) of the curves. By conventional analysis of variance followed by a Scheffé type multiple comparison, end-diastolic volume after ISDN, which was significantly smaller than those after the other drugs at rest (p less than 0.01), was similar to those after nifedipine and propranolol during exercise (96.4 +/- 4.6 ml/m2 vs. 94.8 +/- 5.1 ml/m2 and 97.1 +/- 4.9 ml/m2, respectively). Systemic vascular resistance after nifedipine, which was also significantly lower than those after the other drugs at rest (p less than 0.05), was not different from that after placebo during exercise (16.9 +/- 1.1 units vs. 18.7 +/- 1.3 units). Thus, this analysis was considered insufficient to fully differentiate the characteristics of each drug. By PANOVA, the profiles of LVEF with these three antianginal drugs were similar, and significantly differentiated from that of placebo (p less than 0.05). This indicated that the antianginal effect could be represented by the profiles of the response curves of LVEF, using PANOVA. Evaluating the underlying hemodynamic mechanisms of these drugs by PANOVA, ISDN was significantly differentiated from nifedipine and propranolol by the profile of end-diastolic volume (p less than 0.05). The characteristics of nifedipine were clearly demonstrated by the size and profile of systemic vascular resistance, and those of propranolol were also differentiated by the size and profile of the double product and P-V index. Hence, it is concluded that with the aid of PANOVA, the changes in hemodynamic parameters during ischemia can be evaluated in a manner that is highly effective in differentiating the characteristics of the effects of antianginal drugs in patients with angina pectoris.

Aged↗
PubMed1999

Nitric oxide generation, tachyphylaxis and cross-tachyphylaxis from nitrovasodilators in vivo.

Nitric oxide (NO) increments in exhaled air and changes in mean arterial pressure of anaesthetised rabbits were measured in order to study the NO generation from NO donors and tachyphylaxis in NO formation from nitroglycerin. Continuous infusions of isosorbide dinitrate, isosorbide-5-mononitrate and 3-morpholino-sydnonimine (SIN-1) evoked dose-dependent increases in exhaled NO, paralleled by decrements in mean arterial pressure. Repeated infusions of nitroglycerin resulted in attenuation (P<0.01) of the NO increase from a given dose. Concurrent infusions of isosorbide dinitrate, isosorbide-5-mononitrate or nitroglycerin reduced the amount of NO emanating from the bioconversion of a given dose nitroglycerin as measured in the expired air (P<0.01 for all drugs), indicating cross-tachyphylaxis. SIN-1 did not exhibit such cross-tachyphylaxis. In conclusion, measurements of exhaled NO can be a useful tool for exploration of nitrovasodilator tachyphylaxis. Cross-tachyphylaxis is only shared between some nitrovasodilators and is possibly not due to feedback from the generated NO.

Animals↗