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PubMed1994

Effects of treatment with oral isosorbide dinitrate on platelet function in vivo; a double-blind placebo-controlled study in patients with stable angina pectoris.

1. A randomised double-blind placebo-controlled cross-over study was performed to investigate the effects of oral isosorbide dinitrate (ISDN; 20 mg twice daily for 2 weeks) on various aspects of platelet function in vivo in 20 patients with stable angina pectoris. Measurements were performed at rest and after platelet activation by physical exercise (bicycle ergometry). 2. Compared with placebo, treatment with ISDN significantly decreased systolic blood pressure at rest by 7 (-14 to -1) mm Hg (mean and 95% CI) and tended to increase exercise capacity by 7 (-1 to 14) W and attenuate perceived chest pain during maximal work. The dosage was high, as judged by side-effects reported (mainly headache). Compliance was good, as assessed by electronic counter equipped tablet bottles (Medication Event Monitoring System); only one patient had a compliance rate below 60%. 3. Exercise significantly increased platelet aggregability as measured by filtragometry ex vivo; the time taken for platelet aggregates in whole blood drawn directly from an antecubital vein to occlude a microfilter was significantly decreased from 155 to 95 s (antilog of mean log values). Platelet secretion in vivo also increased, as indicated by significant elevations of beta-thromboglobulin in plasma; from 22 to 35 ng ml-1 (P = 0.006). 4. ISDN treatment did not inhibit platelet function. Relative to placebo, filtragometry readings (ISDN/placebo ratios; mean and 95% CI) were not altered either at rest (1.05 (0.83 to 1.32)) or immediately after exercise (0.98 (0.80 to 1.20)). Similarly, beta TG in plasma was unaltered by ISDN treatment; 1.09 (0.98 to 1.21) at rest, and 1.04 (0.82 to 1.30) immediately after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

The plasma concentrations of isosorbide 5-mononitrate (5-ISMN) administered in an extended-release form to patients with acute myocardial infarction.

Eighteen patients with acute myocardial infarction (AMI) followed the same extended-release isosorbide 5-mononitrate dosage regimen as was used in the Fourth International Study of Infarct Survival (ISIS-4). Plasma drug concentrations, blood pressure and heart rate were measured over 5 to 7 days following acute and repeated administrations. After the initial 30 mg dose on the first day of infarction, mean +/- standard deviation Cmax was 1237 +/- 284 nmol l-1 with a median tmax of 4 h (range 1 to 10 h). Following the last 60 mg dose, Cmax was 2685 +/- 497 nmol l-1 with a median tmax of 4 h (2 to 7 h). The plasma concentrations of this extended-release 5-ISMN in patients with acute myocardial infarction were similar to those seen in studies with healthy volunteers. However, drug absorption following the acute dose was protracted in some patients, possibly due to the concomitant administration of morphine. The kinetics of 5-ISMN at steady state were similar for all patients, and none showed protracted 5-ISMN absorption.

Adult↗
PubMed1995

Effect of isosorbide-5-mononitrate on plasma and urine levels of cyclic GMP in relation to exercise in coronary patients compared with control subjects.

Nitric oxide (NO) and atrial natriuretic peptide (ANP) relax vascular smooth muscle increasing levels of cyclic guanosine 3':5' monophosphate (cGMP). Nitrovasodilators act as exogenous nitric oxide donors. The aim of this study was to ascertain the response of cGMP to exercise without medication and after the administration of 20 mg of isosorbide-5-mononitrate (IS-5-MN) in coronary patients (n = 8) and healthy control subjects (n = 9). A third group of 10 normal volunteers was studied to test plasma cGMP response to second exercise test without IS-5-MN administration. Plasma cGMP increased significantly in both patients (P < 0.02) and controls (P < 0.01) after the first ergometry. After IS-5-MN administration, plasma cGMP did not increase either before or after exercise. In normal volunteers without IS-5-MN plasma cGMP increased significantly after first (P < 0.004) and second (P < 0.0008) exercise test. In conclusion, plasma cGMP increases during exercise. Administration of IS-5-MN does not raise plasma cGMP and neither does performance of further exercise after its administration.

Angina Pectoris↗
PubMed1989

Intravenous administration of isosorbide dinitrate attenuates the pressor response to laryngoscopy and tracheal intubation.

In order to evaluate the effect of isosorbide dinitrate (ISDN), administered as a bolus intravenous injection, on the circulatory response to tracheal intubation, mean arterial pressure (MAP), and heart rate (HR) in response to laryngoscopy for 30 s followed by tracheal intubation were compared in patients not receiving ISDN (control) and receiving 40 micrograms/kg or 80 micrograms/kg of ISDN 45 s before starting laryngoscopy. Each group consisted of 10 patients undergoing elective surgery. Forty-five seconds after starting laryngoscopy, MAP was significantly (P less than 0.01) lower in patients receiving 80 micrograms/kg ISDN than in those receiving no or 40 micrograms/kg ISDN. HR increased to a similar extent in the three groups. These results indicate that a bolus injection of ISDN (80 micrograms/kg) is a simple, practical and highly effective means of attenuating the hypertensive response to direct laryngoscopy and tracheal intubation.

Adult↗
PubMed1994

Isosorbide dinitrate does not interfere with heparin anticoagulation: a placebo-controlled comparison with nitroglycerin in patients scheduled for coronary artery surgery.

The possible nitrate-induced heparin resistance was studied intraoperatively in 40 patients undergoing coronary artery bypass grafting. The patients were randomized to receive a continuous infusion of placebo, nitroglycerin (0.5 microgram kg-1 min-1) or isosorbide dinitrate (0.5 or 2.5 micrograms kg-1 min-1). After the infusion had been administered, prior to the institution of cardiopulmonary bypass, for at least 60 min, porcine intestine heparin 300 I.U. kg-1 (as divided in two consecutive doses of 100 and 200 I.U. kg-1, respectively) was administered to achieve systemic anticoagulation. Activated coagulation time values and plasma heparin anti-X, activity showed no significant differences between the groups before and after the administration of heparin. It is concluded that in doses given in the present study, organic nitrates do not interfere with the anticoagulation effect of large doses of heparin required for the conduction of cardiopulmonary bypass.

Adult↗
PubMed1986

Cardiovascular effects of isosorbide dinitrate infused intravenously into anaesthetized dogs.

The cardiohaemodynamic response and the development of tolerance to isosorbide dinitrate (ISDN) were examined in anaesthetized, open-chest dogs. ISDN, infused intravenously (i.v.) for 2 h at a rate of 10 or 30 micrograms/kg per min, decreased systemic blood pressure (systolic, mean and diastolic; SBP), left ventricular (LV) systolic and end-diastolic pressure, LVdP/dt max, pressure-rate product and coronary blood flow. No significant changes in heart rate (HR) and coronary vascular resistance were observed. Intravenous ISDN significantly attenuated the vasodilator effect of bolus intracoronary (i.a.) glyceryl trinitrate (GTN, 1 micrograms), and ISDN (30 micrograms), whereas that of bolus i.a. nicorandil (mononitrate, 20 micrograms) remained unaffected. Just after acute tolerance towards i.a. ISDN was provoked 1 h after starting ISDN infusion (30 micrograms/kg per min, i.v.), the combined infusion of ISDN (i.v.) and nicorandil (30 micrograms/kg per min) was instigated for a further hour. Also, 1 h after the onset of vehicle infusion (i.v.), the combined infusion of vehicle and nicorandil (30 micrograms/kg per min, i.v.) was started. There were essentially no significant differences between the corresponding values concerning the coronary vascular responses obtained from the two combined infusion groups.

Animals↗
PubMed2005

Withdrawal of intravenous glyceryl trinitrate: absence of rebound phenomena with transition to oral isosorbide dinitrate.

1. Glyceryl trinitrate (GTN) is frequently infused intravenously as a component of the management of acute coronary syndromes (ACS). Abrupt cessation of GTN infusion after periods of more than 24 h administration often induces rebound vasoconstriction reflecting 'pseudotolerance'; this is also the basis of the 'zero hour phenomenon' during chronic nitrate therapy. The efficacy of oral nitrate regimens to prevent vasoconstriction following cessation of intravenous GTN has not been previously examined. Therefore, we investigated the effects of transition from intravenous GTN to oral isosorbide dinitrate (ISDN) on a parameter of apparent arterial stiffness in patients with ACS. 2. The effects of GTN infusion at 5 microg/min on augmentation index (AIx) were quantified in patients (n = 10) with stable angina pectoris in order to establish the magnitude of effect on apparent arterial stiffness. 3. This infusion rate of GTN reduced AIx from 23 +/- 10% (SD) to 3 +/- 14% (SD) (P < 0.01). The effect of transition from GTN infusion of greater than 24 h duration to ISDN (10 mg tds) were examined in patients (n = 16) with ACS (unstable angina/non-Q-wave myocardial infarction). No patient developed recurrent angina during the 24 h following cessation of GTN infusion. The level of AIx was 8 +/- 4% (SD) prior to GTN cessation and fell to 5 +/- 6% (SD) on ISDN (P = 0.05). 4. Thus, in patients treated for ACS, transition from intravenous GTN to low dose oral ISDN is associated with an incremental vasodilatation and no evidence of 'rebound' ischaemia.

Administration, Oral↗
PubMed1983

Actions of isosorbide dinitrate on smooth muscle cells of rabbit vascular tissues.

To investigate the mechanism of the anti-anginal actions of isosorbide dinitrate (ISDN), the effects of this agent on smooth muscle cells of intact and skinned preparations of the rabbit mesenteric artery and vein, and of the coronary artery were studied. ISDN (less than 10(-5) M) had no effect on the membrane potential or resistance of smooth muscle cells of the mesenteric artery and vein under resting conditions, nor when the membrane was depolarized by the presence of various concentrations of [K]o or noradrenaline (NA). The amplitude of spike evoked by outward current pulse after pretreatment with 10 mM tetraethylammonium (TEA) in the mesenteric artery was slightly inhibited by application of 10(-5) M ISDN. The K-induced and NA-induced contractions in the mesenteric artery were not affected by 10(-5) M ISDN, while those evoked in the mesenteric vein were inhibited in concentrations above 10(-6) M. The amplitude and facilitation of excitatory junction potentials evoked by perivascular nerve stimulation in the mesenteric artery were not affected by 10(-5) M ISDN. In skinned muscles, the free calcium concentration (pCa)-tension relationships observed in the mesenteric artery and vein were not affected by 10(-5) M ISDN. This agent had no effect on Ca accumulation into and Ca release from the stores in muscle cells of the mesenteric artery and vein, in skinned preparations. In the rabbit coronary artery, the membrane potential, resistance and spike evoked in the presence of 10 mM TEA were not affected by application of 10(-5) M ISDN. The contraction evoked by excess concentrations of [K]o was not affected. The contraction evoked by a low concentration of acetylcholine (3 X 10(-7) M) but by high concentrations (greater than 10(-6) M) was slightly inhibited by 10(-5) M ISDN. A tonic contraction induced in 39 mM [K]o was reduced by 10(-5) M nitroglycerine but not by 10(-5) M ISDN. Thus in rabbit vascular tissues, ISDN mainly acts on the venous system in vitro. The induced vasodilatation may lead to a reduction in the venous return and hence, reduce oxygen consumption in the cardiac muscles. This effect of ISDN may relate to the anti-anginal actions.

Animals↗
PubMed1986

Attenuation by isosorbide dinitrate of coronary occlusion-induced acidosis in the dog myocardium.

In dogs anaesthetized with pentobarbitone, the thorax was opened and myocardial pH measured continuously by the use of a glass pH electrode inserted in the left ventricular wall. The left anterior descending coronary artery (LAD) was partially occluded so that the LAD flow could be reduced to a half or one-third of the original flow (partial occlusion). LAD partial occlusion was continued for 90 min, drug or saline being infused for the last 60 min of this period. LAD occlusion decreased myocardial pH significantly by 0.41 to 0.67 pH units, and increased ST segment of the surface electrocardiogram from 11.7 to 12.1 mV. In dogs with non-ischaemic normal hearts, isosorbide dinitrate (ISDN; 1 mg kg-1) did not change markedly either the LAD flow, myocardial pH or heart rate, whereas it decreased myocardial contractile force (determined by a strain gauge arch) slightly and both the systolic and diastolic blood pressure markedly. In dogs with partial LAD occlusion, ISDN (1 mg kg-1) increased myocardial pH significantly and decreased blood pressure, but did not change ST segment elevation in an epicardial lead. These results indicate that ISDN attenuates ischaemia-induced acidosis without attenuating ischaemia-induced ST elevation in the dog myocardium.

Acidosis↗
PubMed1987

The effect of isosorbide dinitrate on the arterial vascular bed: a dose response study in dogs.

Isosorbide dinitrate (ISDN) was infused stepwise intraarterially into the left hindlimb (5.7-364.8 micrograms/kg/min.) into six dogs. The mean local vascular resistance was decreased by 32% in the left hindlimb after a dose of up to 91.2 micrograms/kg/min. corresponding to a 1.6-fold increase in the left femoral artery blood flow, without significant changes in the control limb or central haemodynamics. The muscular blood flow in the adductor magnus muscle obtained by the Xenon washout technique remained unchanged in 6 of 7 other dogs at ISDN infusion rates of 91.2 micrograms/kg/min., indicating that the increase in femoral artery blood flow was not a consequence of increased muscular blood flow. The arterio-venous extraction fraction of radioactive microspheres was lower in the experimental leg during ISDN infusion when compared with the control leg, suggesting that AV-shunts are opened during ISDN infusion. In addition to the well-known effect on preload, the present results confirm that ISDN also acts on afterload. Thus, ISDN may be classified as a mixed agent acting on both pre- and afterload which is in agreement with some previous studies.

Animals↗
PubMed2005

Hemodynamic effects of sildenafil citrate and isosorbide mononitrate in men with coronary artery disease and erectile dysfunction.

INTRODUCTION: Mild hemodynamic effects have been reported with sildenafil citrate therapy. AIM: To compare the hemodynamic effects of sildenafil and isosorbide mononitrate (ISMN) in men with coronary artery disease and erectile dysfunction. METHODS: A total of 31 men aged 35 years or older with coronary artery disease (at least 50% narrowing of the left main stem or at least 70% narrowing of any other coronary artery) and erectile dysfunction (receiving medication for erectile dysfunction or scoring less than 26 out of a maximum score of 30 on the erectile function domain questions of International Index of Erectile Function) were randomized to sildenafil 100 mg (n = 10), ISMN 40 mg (n = 11), or placebo (n = 10) in this single-dose multicenter study. MAIN OUTCOME MEASURES: Hemodynamic parameters were measured at baseline, 1, 2, 4, and 6 hours post dose. RESULTS: Compared with baseline, cardiac index increased slightly with sildenafil (0.29 L/min/m2 at 1 hour) and decreased slightly with placebo (-0.12 L/min/m2 at 4 hours) and ISMN (-0.14 L/min/m2 at 1 hour). The stroke volume index increased from baseline at each time point post dose with sildenafil (4.4 mL/m2 at 2 hours), but decreased with ISMN (-5.8 mL/m2 at 1 hour) and placebo (-2.8 mL/m2 at 4 hours). ISMN reduced mean arterial pressure more than sildenafil did (-22 vs. -10 mm Hg at 2 hours, respectively). Both sildenafil and ISMN increased heart rate (4 vs. 7 beats/minute at 1 hour, respectively) and decreased systemic vascular resistance, but sildenafil produced greater reductions in pulmonary vascular resistance. There were no serious adverse events in the sildenafil group. CONCLUSIONS: Sildenafil 100 mg was well tolerated and induced smaller changes in central and peripheral hemodynamic pressures compared with ISMN 40 mg. Moreover, sildenafil selectively reduced pulmonary resistance, which may have clinical importance in pulmonary hypertension.

Adult↗
PubMed1990

The sorption of isosorbide-5-mononitrate to intravenous delivery systems.

The sorption of isosorbide-5-mononitrate, diluted in 0.9% NaCl or 10% glucose solutions, to intravenous delivery systems was investigated. Infusion bags, burettes, a syringe, infusion tubings and end-line filters were tested in static and in dynamic experiments. No clinically significant sorption was detected during those experiments. The use of PVC tubings of different hardness did not influence the results.

Adsorption↗
PubMed1993

Sorption of isosorbide dinitrate to central venous catheters.

As several studies demonstrated the sorption of isosorbide dinitrate (ISDN) to intravenous delivery systems, a study on the sorption of ISDN to several central venous catheters was performed. Fourteen different catheters were perfused during a 2 h period, under simulated infusion conditions, with ISDN (250 micrograms mL-1) in 0.9% (w/v) sodium chloride. The drug loss to a polyethylene and a silicone catheter was 0.2 and 6.1%, respectively. The sorption to a polyvinylchloride heparin-coated thermodilution catheter was 1-6.9% depending on the length of the catheter. The drug loss to polyurethane catheters of different composition varied between 3.8 and 28.9%. For polyurethane catheters composed of cycloaliphatic polyurethanes an inverse relation was shown between Shore A hardness and sorption.

Adsorption↗
PubMed1993

Absence of desensitization to the relaxant activity of streptozotocin in isosorbide dinitrate-tolerant rat aorta.

The effect of in-vitro isosorbide dinitrate (ISDN)-induced tolerance on the vasodilatory actions of streptozotocin, a nitric oxide containing compound, and papaverine was studied in rat aortic strips precontracted by phenylephrine. Aortas made tolerant to ISDN remained fully responsive to streptozotocin but exhibited a greater response to low concentrations of papaverine compared with control strips. Methylene blue produced parallel displacement to the right of the relaxant concentration-effect curves of both ISDN and streptozotocin, whereas responses to only low concentrations of papaverine were significantly antagonized. These results indicate that the relaxant activity of streptozotocin is due to the stimulation of guanylate cyclase and impaired activity of this enzyme is not likely to be the operating mechanism for nitrate tolerance. It is also suggested that the vasodilating action of papaverine is partly dependent on the tissue cGMP level.

Animals↗
PubMed1988

Effect and mechanism of action of isosorbide-5-mononitrate.

Nitrates have been shown to decrease portal pressure in cirrhotic patients with portal hypertension and this has been attributed to decreased portal venous resistance. We studied the effect and mechanism of action of oral administration of isosorbide-5-mononitrate (Is-5-Mn) (20 mg), which, unlike the dinitrate, does not require hepatic biotransformation to a vasoactive metabolite on portal and systemic haemodynamics in 11 patients with portal hypertension complicating cirrhosis. A significant reduction in portal pressure gradient (WHVP-FHVP) (from 23.9 (3.4) to 21.8 (3.4) mmHg: p less than 0.005) occurred 60 minutes after Is-5-Mn due entirely to a fall in WHVP, associated with decreased estimated liver blood flow (from 1940 (159) to 1639 (179) ml/min: p less than 0.05). Right atrial and pulmonary artery pressures and cardiac index fell significantly whilst mean arterial pressure remained unaffected. Heart rate and the calculated systemic vascular resistance index increased significantly. Significant correlations existed between the reduction in portal pressure gradient and fall in cardiac index (r = 0.65, p less than 0.05) and increase in systemic vascular resistance index (r = 0.72, p less than 0.02). The observed decrease in estimated liver blood flow, in association with an increase in systemic vascular resistance index, suggests that baroreceptor mediated splanchnic vasoconstriction may be one of the factors responsible for the fall in portal pressure, rather than portal venous dilatation.

Female↗
PubMed1995

Portal and systemic haemodynamic response to acute and chronic administration of low and high dose isosorbide-5-mononitrate in patients with cirrhosis.

Oral isosorbide-5-mononitrate (Is-5-Mn) was given in doses of 10 and 40 mg acutely and chronically (twice daily for four weeks), allowing a nitrate free interval to 25 patients with cirrhosis. Both 10 mg and 40 mg Is-5-Mn reduced the hepatic venous pressure gradient acutely and chronically, without evidence of tolerance. This was achieved by a reduction in the wedged hepatic venous pressure. The effect on mean azygos blood flow was variable with no significant mean change seen acutely or after chronic use with either dose. The variability was dependent not on the dose used but on the initial azygos flow; the flow in patients with initially low values increased and those with high azygos flows decreased after nitrate challenge. The development of the porto-collateral flow seems an important parameter in predicting haemodynamic response to Is-5-Mn.

Adult↗
PubMed1996

Pathophysiological aspects and clinical outcome of intra-anal application of isosorbide dinitrate in patients with chronic anal fissure.

BACKGROUND: Relaxation of the internal anal sphincter can be achieved by local application of exogenous nitric oxide donors. AIM: To evaluate the influence of topical application of isosorbide dinitrate (ISDN) on anal pressure, anodermal blood flow, and fissure healing. PATIENTS: Thirty four consecutive patients (male/female: 18/16; mean age (SEM): 39 (10)) with a chronic anal fissure were studied. METHODS: All patients were treated for at least six weeks or a maximum period of 12 weeks. Before treatment and at three and six weeks 22 patients underwent conventional anal manometry and laser Doppler flowmetry of the anoderm. RESULTS: Within 10 days the fissure related pain was resolved in all patients. At six, nine, and 12 weeks the anal fissure was completely healed in 14, 22, and 30 patients respectively. At three and six weeks manometry was performed at least one hour after the last application of ISDN. These recordings showed a reduction of the maximum resting anal pressure (mean (SD), pretreatment 111 (26) mm Hg; three weeks 86 (19); six weeks 96 (27), p < 0.001). Simultaneous recordings of anodermal blood flow showed a significant increase of flow (pretreatment 0.53 (0.17); three weeks 0.80 (0.16); six weeks 0.76 (0.31), p < 0.005). The mean (SEM) duration of follow up after successful outcome was 11 (5) months. Within this period fissure relapsed in two of 30 patients (7%), eight and 10 weeks after treatment had been stopped. CONCLUSIONS: Local application of ISDN reduces anal pressure and improves anodermal blood flow. This dual effect results in a fissure healing rate of 88% at 12 weeks. This new and simple treatment modality seems to be an attractive alternative for the current available surgical procedures.

Adult↗