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PubMed1993

Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: Congestive heart failure is a clinical syndrome characterized by neuroendocrine activation. Measurements of plasma norepinephrine and plasma renin activity were performed in the Vasodilator-Heart Failure Trial II (V-HeFT II) to characterize the effect of therapy on neuroendocrine activation and to examine the responses to therapy among patients with different degrees of activation. METHODS AND RESULTS: The baseline median plasma norepinephrine value (n = 743) was 490 pg/mL and the baseline median plasma renin activity (n = 737) was 6.9 ng.mL-1 x hr-1. Baseline plasma renin activity and plasma norepinephrine correlated poorly with each other (r = 0.12), implying that these two neuroendocrine systems are being activated by separate processes. By univariate analysis, the logarithms of the plasma norepinephrine (p < 0.0001) and the plasma renin activity (p = 0.01) were significantly related to all-cause mortality. In a multivariate analysis that included other significant univariate prognostic variables (i.e., baseline ejection fraction, peak oxygen consumption during exercise, and cardiothoracic ratio), log plasma norepinephrine but not plasma renin activity remained a significant (p = 0.02) predictor of mortality. Baseline plasma norepinephrine correlated poorly with baseline left ventricular ejection fraction (r = -0.18), peak oxygen consumption (r = -0.15), and cardiothoracic ratio (r = 0.11). Neither the plasma norepinephrine (r = 0.09) nor the plasma renin activity (r = 0.18) was closely associated with a quality of life assessment at baseline. The baseline plasma norepinephrine level in patients randomized to enalapril (mean, 593 +/- 388 [SD] pg/mL; n = 372) and to hydralazine and isosorbide dinitrate (mean, 544 +/- 297 pg/mL; n = 371) were similar. Thirteen weeks after randomization, plasma norepinephrine did not change (-5 +/- 393 pg/mL) in 312 patients randomized to enalapril but increased significantly by 74 +/- 311 pg/mL (p < 0.0001) in 300 patients assigned to hydralazine-isosorbide dinitrate. The plasma norepinephrine increased significantly more in patients assigned to hydralazine-isosorbide dinitrate than those on enalapril at both 13 weeks (p = 0.01) and at 1 year (p = 0.04) (90 +/- 302 pg/mL [n = 240] versus 14 +/- 376 pg/mL [n = 265]). Based on previous reports and examination of survival among several plasma norepinephrine strata, the baseline plasma norepinephrine data were grouped into three relatively homogeneous strata for further analysis. The cumulative mortality was significantly different between the three strata (p < 0.0001). The patients with plasma norepinephrine > 900 pg/mL had a higher mortality than those with corresponding values from 601 to 900 pg/mL or < 600 pg/mL. The survival benefit of enalapril compared with hydralazine-isosorbide dinitrate was most evident in those patients with a plasma norepinephrine value > 900 pg/mL. Although the plasma renin activity was not strongly associated with survival, patients in the upper quartile (> 16 ng.mL-1 x hr-1) had the worst prognosis. Among this group, the patients on enalapril demonstrated significantly better survival than those on hydralazine-isosorbide dinitrate (p = 0.02). CONCLUSIONS: This study confirms that plasma norepinephrine is an independent predictor of prognosis in patients with congestive heart failure. Hydralazine-isosorbide dinitrate treatment, unlike enalapril treatment, was associated with increased plasma norepinephrine concentration during the first year of follow-up. The enalapril group had a significantly lower mortality, and this survival benefit of enalapril as compared with hydralazine-isosorbide dinitrate was most evident among patients with the most marked neuroendocrine activation. Neuroendocrine activation is an important prognostic factor for patients with congestive heart failure and is an important determinant of the differential response to vasodilators.

Drug Therapy, Combination↗
PubMed1993

Enalapril decreases prevalence of ventricular tachycardia in patients with chronic congestive heart failure. The V-HeFT II VA Cooperative Studies Group.

BACKGROUND: Patients with heart failure have a high prevalence of serious arrhythmias and sudden cardiac-death. METHODS AND RESULTS: Male patients aged 18-75 years with chronic heart failure were randomized to enalapril or hydralazine-isosorbide dinitrate. Short-term (4-hour to 8-hour) Holter tape recordings were performed before randomization, at 3 months, at 1 year, and yearly thereafter. Of 804 patients randomized to therapy, 715 had Holters at baseline. Couplets were noted in 56% versus 60% and ventricular tachycardia (VT) (three or more consecutive ventricular premature beats) in 27% versus 29% of patients randomized to enalapril versus hydralazine-isosorbide dinitrate, respectively. The presence of VT at 3 months, 1 year, and 2 years predicted significantly higher mortality during the subsequent year (p < 0.0001, p < 0.001, and p < 0.037, respectively). In the enalapril group, VT prevalence decreased by 27% at 1 year (p < 0.02). A decrease in prevalence of VT was not seen in the hydralazine-isosorbide dinitrate group. New VT was seen in 11% of enalapril patients versus 24% of hydralazine-isosorbide dinitrate patients at 1 year (p < 0.002). When compared with hydralazine-isosorbide dinitrate at 1 and 2 years, there was a 52% and 49% reduction, respectively, in sudden deaths in the enalapril group. Thus, at 1 and 2 years, the decrease in sudden deaths in the enalapril group coincided with the decrease in VT prevalence and the decrease in new VT emergence. CONCLUSIONS: In patients with heart failure, VT and couplets predict increased mortality. When compared with hydralazine-isosorbide dinitrate, enalapril decreases both the persistence of baseline VT at 3 months and the emergence of new VT at 1 and 2 years. The reduction in VT prevalence parallels a reduction in sudden death. The effect of enalapril on survival over hydralazine-isosorbide dinitrate may be related to its ability to reduce prevalence of ventricular arrhythmia.

Death, Sudden, Cardiac↗
PubMed1994

Clinical pharmacokinetics of nitrates.

The pharmacokinetics of organic nitrates are discussed with emphasis on the possible clinical relevance. For glyceryl trinitrate, the measurement of plasma concentrations is very difficult. Its pharmacokinetics are unusual, with a very rapid disappearance from plasma, and large intraindividual and interindividual variations. After oral administration, there seems to be a very extensive first-pass hepatic extraction and the plasma concentrations are often below the detection limit; after sublingual administration, glyceryl trinitrate appears in plasma. With transdermal glyceryl trinitrate controlled-release systems, plasma concentrations of glyceryl trinitrate can be maintained over 24 hours, although with fluctuations and important intraindividual and interindividual variability. After administration of glyceryl trinitrate via different routes, glyceryl dinitrates and mononitrates are present in plasma. The pharmacokinetics of isosorbide dinitrate are somewhat easier to understand. The substance disappears less rapidly from the plasma than does glyceryl trinitrate. After oral administration, there is also a hepatic first-pass extraction; the plasma concentrations can be prolonged by administering slow-release products. Sublingual administration leads to higher plasma concentrations than oral administration. Isosorbide dinitrate is metabolized in the organism to isosorbide 5-mononitrate and isosorbide 2-mononitrate, which both have vasodilator activity: after administration of isosorbide dinitrate, the mononitrates, and mainly the 5-mononitrate, reach very high concentrations in plasma. Isosorbide 5-mononitrate has been studied in its own right as an antianginal agent: it is completely absorbed after oral administration; it has a half-life of around 4 hours, and oral standard and controlled-release formulations have been extensively studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1996

Cardiovascular adaptation to orthostatic stress during vasodilator therapy.

BACKGROUND: Orthostatic hypotension is a dangerous problem in elderly patients, often exacerbated by vasodilator medications. Age- and disease-related impairments in cardioacceleration and diastolic ventricular function may make older patients particularly vulnerable to the hypotensive effects of these drugs. Therefore we aimed to determine mechanisms of postural blood pressure regulation in elderly patients with coronary artery disease and to compare the effects of isosorbide dinitrate and nicardipine hydrochloride on postural blood pressure homeostasis in these patients. METHODS: Twenty elderly subjects with stable coronary artery disease (age, 76 +/- 4 [SD] years) underwent a baseline evaluation followed by a double-blind, randomized crossover comparison of nicardipine (20 mg by mouth t.i.d.) versus isosorbide (20 mg by mouth t.i.d.). Doppler echocardiography and a 15-minute 60-degree head-up tilt test were conducted on no study medications and then after successive 3-week treatment periods with nicardipine or isosorbide. Blood pressure, heart rate, vascular resistance, cardiac output, and spectral characteristics of heart rate and blood pressure variability were measured before and during each tilt. RESULTS: Isosorbide treatment was associated with a higher prevalence of symptoms of cerebral hypoperfusion and a failure to increase systemic vascular resistance during tilt. While taking isosorbide subjects were able to preserve cardiac output and maintain upright blood pressure through enhanced cardioacceleration. During nicardipine treatment systemic vascular resistance and low-frequency blood pressure variability were reduced, but the ability to increase systemic vascular resistance during tilt was preserved. CONCLUSIONS: Although nicardipine may decrease vascular responsiveness to sympathetic activation, the baroreflex-mediated vasoconstrictor response to upright tilt remains intact. In contrast, isosorbide impairs the systemic vascular response to orthostatic stress in elderly patients with stable coronary artery disease.

Aged↗
PubMed1999

Evaluation of nitrate tolerance in patients with coronary heart disease by vascular ultrasonography and treadmill exercise.

The aim of this study was to evaluate nitrate tolerance in patients with coronary heart diseases by vascular ultrasonography and treadmill exercise. According to the dosage interval of isosorbide dinitrate, 66 patients with coronary heart disease were divided into group A and group B in a random, control and double-blind method. Isosorbide dinitrate was given every 6 hours in group A and every 12 hours in group B for one week. Before and after the therapeutic period, the diameters of brachial arteries were measured by vascular ultrasonography at baseline and 5 min after sublingual administration of 10 mg isosorbide dinitrate, and the treadmill exercise test was performed in all subjects. The results showed that diameters of brachial arteries were increased significantly after sublingual isosorbide dinitrate in both groups before the therapeutic period. After the therapeutic period, dilation of brachial arteries induced by sublingual isosorbide dinitrate was more marked in group B than in group A. Compared with those before the therapeutic period, sigmaST segment depression decreased and treadmill walking time increased significantly in group B but not in group A after the therapeutic period. These findings suggest that less frequent doses of isosorbide dinitrate may prevent development of nitrate tolerance, which is confirmed by vascular ultrasonography combined with treadmill exercise in patients with coronary heart disease.

Adult↗
PubMed1986

Coronary vasodilation by nitrates is not mediated by the prostaglandin system: a quantitative cineangiographic study.

The possible role of prostaglandins in mediating large coronary artery vasodilation by nitrates was investigated by quantitative magnification coronary angiography. The effects of aspirin (1 g systemically and 100 mg intracoronary) in preventing large coronary artery vasodilation induced by intracoronary isosorbide dinitrate was investigated in 16 patients. Of these, 5 received 0.3 mg (Group 1A) and 11 received 3 mg (Group 1B) intracoronary isosorbide dinitrate, before and 15 minutes after aspirin. Relative to control, 0.3 mg isosorbide dinitrate induced a 19 +/- 9% (mean +/- SD) (p less than 0.01) and 19.5 +/- 11% (p less than 0.01) increase in coronary diameter before and after aspirin, respectively (p = NS). Changes after 3 mg isosorbide were 23 +/- 12% (p less than 0.01) and 26.5 +/- 14% (p less than 0.01), respectively, before and after aspirin (p = NS). In 10 additional patients (Group 2), the effect of the same dose of aspirin on rest coronary artery tone was assessed: changes relative to control were 0.9 +/- 5.5% (p = NS) minutes after aspirin. The intracoronary administration of 3 mg isosorbide dinitrate produced a 24.7 +/- 11% increase in coronary diameter (p = NS versus pre- and postaspirin isosorbide in Group 1B). Urinary 6-ketoprostaglandin-F1 alpha values in urine samples collected in the 8 hours before and the 8 hours after the study in five patients in Group 1B and five patients of Group 2, revealed a 36 +/- 14% (mean +/- SD) reduction in excretion of prostacyclin (p less than 0.01). These data rule out a role for prostaglandins both in mediating dilation of large coronary arteries by nitrates and in affecting their vascular tone at rest.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Nitrates in myocardial infarction: influence on infarct size, reperfusion, and ventricular remodelling.

OBJECTIVE: To assess the possible benefits of intravenous isosorbide dinitrate in acute myocardial infarction and oral isosorbide mononitrate in subacute myocardial infarction. METHODS: 316 patients presenting with acute myocardial infarction were entered into double blind placebo controlled clinical trials assessing infarct size by enzyme release, ventricular size and function by echocardiography, reperfusion by continuous 12 lead ST segment monitoring and late potentials by high resolution electrocardiography. RESULTS: 301 patients, of whom 292 (97%) received thrombolytic treatment, were randomised on admission to intravenous isosorbide dinitrate or placebo. Overall, there was no significant effect of treatment on infarct size, ST segment resolution, ventricular remodelling, or late potentials at day 3. A trend was observed towards a reduction in infarct size in patients with non-Q wave infarction treated with isosorbide dinitrate. Heterogeneity of nitrate effect was observed in relation to the degree of ST segment elevation on presentation with a clear benefit of isosorbide dinitrate in patients with moderate ST segment elevation (472 U/l v 704 U/l, P = 0.003) and a trend towards a deleterious effect in patients with marked ST segment elevation (1152 U/l v 1058 U/l, P = 0.2). ST segment re-elevation was more common among patients receiving nitrate treatment than in those assigned to placebo (29 v 16, P < 0.05). Some 160 patients underwent a further randomisation to sustained release isosorbide mononitrate or placebo on day 3. Echocardiographic volumes after 6 weeks of treatment were similar in the two groups. CONCLUSIONS: No benefit was observed with administration of nitrates in the treatment groups as a whole for either acute or subacute infarction. There was, however, evidence of heterogeneity of effect in the different subgroups of acute infarction, and the possibility that nitrates may have differing actions in different groups of patients should be considered.

Aged↗
PubMedDate not supplied

Tolerance to the increase in coronary blood flow induced by KRN2391.

We examined whether KRN2391, isosorbide dinitrate and nitroglycerin induced tolerance in coronary arteries. Intracoronary arterial administration of KRN2391 (1 microgram), isosorbide dinitrate (30 micrograms) or nitroglycerin (3 micrograms) produced equipotent coronary vasodilatation. Development of tolerance was determined by whether the increase in coronary blood flow, caused by intracoronary arterial administration of these drugs, was attenuated by intravenous infusion of KRN2391, isosorbide dinitrate or nitroglycerin. The increase in coronary blood flow, caused by intracoronary arterial administration of KRN2391 was not affected by intravenous infusion of KRN2391 (0.3 or 1 micrograms/kg/min), isosorbide dinitrate (30 or 100 micrograms/kg/min) or nitroglycerin (1 or 3 micrograms/kg/min). The increase in coronary blood flow, caused by intracoronary arterial administration of isosorbide dinitrate or nitroglycerin, was significantly diminished by intravenous infusion of isosorbide dinitrate and nitroglycerin, but was unaffected by intravenous infusion of KRN2391. The present results suggest that KRN2391 does not induce acute tolerance by itself or cross-tolerance between KRN2391 and other nitrates.

Animals↗
PubMed1984

Nitrate tolerance.

These studies have shown the following: Tolerance to the hemodynamic and antianginal effects of isosorbide dinitrate. Tolerance develops quickly and can be demonstrated within 24 hours. Tolerance is rapidly reversed and the return of normal responsiveness is seen within 21 hours withdrawal of isosorbide dinitrate. Cross-tolerance occurs between the hemodynamic effects of isosorbide dinitrate and nitroglycerin. When tolerance is present, the next dose of isosorbide dinitrate does exert an effect, although somewhat less in magnitude and duration. Sublingual isosorbide dinitrate and nitroglycerin restores exercise performance despite tolerance to oral isosorbide dinitrate.

Angina Pectoris↗
PubMed1983

Drug interactions I: detection of inorganic nitrite in organic nitrate esters under acidic conditions simulating the human stomach.

Both unformulated (bulk) and formulated (drugs) organic nitrate esters (isosorbide dinitrate, nitroglycerin, and pentaerythritol tetranitrate) were studied in the presence and absence of hydrochloric acid to determine if they could be sources of nitrite (and therefore lead to nitrosamine formation) under acidic conditions similar to those found in the stomach. The presence and generation of nitrite ion was detected by a modification of the Griess reaction. Bulk isosorbide dinitrate and nitroglycerin were found to be contaminated with 13.8-121.4 mumoles of inorganic nitrite per mole of nitrate ester. In addition, in the presence of hydrochloric acid, these preparations generated 0.52-1.18 mumoles of inorganic nitrite/mole of nitrate ester/min. Unformulated nitroglycerin generated nitrite at a rate roughly twice that of isosorbide dinitrate. In contrast, no evidence for nitrite contamination or generation by pentaerythritol tetranitrate was found. Tablets and capsules of isosorbide dinitrate contained approximately 27-216 mumoles of nitrite/mole of nitrate ester and, in the presence of hydrochloric acid, generated an average of 0.55 mumole nitrite/min. For isosorbide dinitrate, this rate was similar for bulk and formulated drug. In comparison to isosorbide dinitrate, the amount of nitrite initially present in tablets and capsules of nitroglycerin varied more widely (approximately 25-2290 mumoles nitrite/mole of nitrate ester), and in this case nitrite was generated at higher rates than unformulated drug averaging approximately 4.7 mumoles nitrite/mole of nitrate ester/min. Contrary to a literature report, we found that nitrate ion is not reduced to nitrite by hydrochloric acid (pH 1-3).(ABSTRACT TRUNCATED AT 250 WORDS)

Chemistry, Pharmaceutical↗
PubMed1994

Spontaneous nitric oxide release accounts for the potent pharmacological actions of FK409.

(+-)-(E)-Ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409), which was isolated from microbial products, has been reported to show a vasorelaxant effect through a mechanism similar to that of the organic nitrates such as isosorbide dinitrate. In solution at pH 7.4, FK409 decomposed and released nitric oxide (NO) spontaneously, while isosorbide dinitrate did not. In in vitro biological tests, FK409 inhibited norepinephrine-induced contraction in rat isolated aorta more potently than did isosorbide dinitrate (ED50 = 1.0 and 310 nM, respectively) and ADP-induced human platelet aggregation (IC50 = 0.75 and > 100 microM, respectively). Nitrite/nitrate was recovered in urine accumulated for 24 h after collection from rats given FK409 or isosorbide dinitrate (10 mg/kg p.o.). FK409 (10 mg/kg p.o.) increased the plasma cyclic GMP level and at the same time decreased the mean blood pressure in conscious rats, while isosorbide dinitrate (10 mg/kg p.o.) did not change these parameters significantly. These results suggest that FK409 produces these pharmacological actions via spontaneously released NO, unlike isosorbide dinitrate, and has a possibility of becoming a unique orally active drug for cardiovascular diseases as a new NO donor.

Adenosine Diphosphate↗
PubMed1988

Coronary artery calibre after direct intra-arterial infusion of epoprostenol (prostacyclin).

Because epoprostenol (prostacyclin) is a prostaglandin that causes vasodilatation and inhibits platelet function it may be of benefit during coronary artery angioplasty. The safety and capacity of intracoronary epoprostenol to dilate coronary arteries were assessed in 16 patients undergoing routine coronary angiography. The view that best displayed the left epicardial coronary arteries was selected as a control for each patient. Intracoronary epoprostenol was then given and the angiogram was repeated in the chosen view. The procedure was repeated twice: once with a higher dose of epoprostenol and once after intracoronary isosorbide dinitrate. Angiograms were coded and analysed by an observer who was unaware of the treatment. The calibre of the arteries was measured from traced projections of the angiograms. The blood pressure, heart rate, and electrocardiogram were recorded throughout. The first two patients were given epoprostenol infusions of 2.5 and 5.0 ng/kg per minute to assess safety, and there were no untoward reactions. The next ten patients had epoprostenol infusions of 5.0 and 7.5 ng/kg per minute followed by intracoronary isosorbide dinitrate. No haemodynamic disturbances occurred and coronary luminal calibre did not change with epoprostenol (mean (SD) luminal diameter: 2.85 (0.62) mm control, 2.80 (0.61) mm at 5.0 ng/kg, and 2.80 (0.54) mm at 7.5 ng/kg), but it did increase significantly with isosorbide dinitrate (to 3.17 (0.36) mm). The last four patients had epoprostenol infusions of 7.5 and 10 ng/kg followed by intracoronary isosorbide dinitrate and two of them became hypotensive (one after epoprostenol and one after isosorbide dinitrate). Coronary luminal calibre did not change significantly (3.5 (0.45) mm control, 2.96 (0.81) mm at 7.5 ng/kg, 3.45 (0.96) mm at 10 ng/kg, and 3.20 (0.61) mm with isosorbide dinitrate). Eight patients developed tall T waves on the electrocardiogram during epoprostenol infusion but none had arrhythmias. The results indicate that clinically tolerable doses of intracoronary epoprostenol do not significantly dilate the epicardial coronary arteries. This route of administration is therefore unlikely to be of use during coronary angioplasty, although the antiplatelet action of intravenous epoprostenol might help to prevent restenosis.

Coronary Angiography↗
PubMed1987

Structure-activity relationship of organic nitrates for activation of guanylate cyclase.

The effect of different organic nitrates on the activity of soluble guanylate cyclase prepared from rat liver was investigated. We found a close correlation between the number of nitrate ester groups and the potency of guanylate cyclase activation. For erythrityl tetranitrate (ETN, EC50 = 14.5 microM), glyceryl trinitrate (GTN, EC50 = 60 microM), isoidide dinitrate (IIDN, EC50 = 0.24 mM) and isosorbide-5-nitrate (IS-5-N, EC50 = 1 mM), we were able to set up an equation by which the EC50 could be calculated from the number of nitrate groups per molecule. Compared to these results, the effect of sterical factors and lipophilicity on organic nitrate-induced activation of guanylate cyclase was small. However, there were still significant differences in the EC50 values for the cyclic mononitrates. Isosorbide-2-nitrate (IS-2-N, EC50 = 0.75 mM) was found to be more potent than the stereoisomeric isosorbide-5-nitrate. Similarly, the cyclic dinitrates isomannide dinitrate (IMDN, EC50 = 0.20 mM), isoidide dinitrate and isosorbide dinitrate (ISDN, EC50 = 0.28 mM) exhibited small but significant differences in their guanylate cyclase stimulatory potency. Two lipophilic ester derivatives of isosorbide-5-nitrate showed a 2-fold potency difference for vasodilation but were equipotent for activation of guanylate cyclase (EC50 = 0.85 mM). Also, the increase in lipophilicity due to esterification of the free hydroxylic group had no major influence on guanylate cyclase activation by isosorbide-5-nitrate. These results demonstrate that in a cell-free system, the potency of organic nitrates for guanylate cyclase activation is mainly determined by the number of nitrate groups. Since organic nitrate-induced activation of guanylate cyclase may involve the formation of nitric oxide free radicals, it is conceivable that the differences in potency reflect a varying degree of nitric oxide release from each compound tested.

Animals↗
PubMed1987

Induction and circumvention of nitrate tolerance applying different dosage intervals.

There is increasing evidence that constant nitrate plasma levels, as induced by at least three-times-daily ingestions of isosorbide dinitrate in sustained-release form, lead to an attenuation or even complete loss of the anti-ischemic effects (nitrate tolerance). Therefore, the dependence of tolerance development on dosage intervals according to once-daily and twice-daily ingestions was assessed. Tablets of isosorbide dinitrate (80 mg) in sustained-release form were administered once-daily at 8 A.M. (dosage interval 24 hours) or twice-daily at 8 A.M. and 8 P.M. (dosage interval 12 hours), as well as at 8 A.M. and 2 P.M., respectively (maximal dosage interval 18 hours). A total of 34 patients with angiographically proven coronary artery disease, a history of stable, exercise-dependent angina pectoris, and a reproducible, exercise-induced ST-segment depression of at least 0.15 mV (1.5 mm), who initially showed a response to 80 mg of isosorbide dinitrate, were enrolled. The anti-ischemic effects of isosorbide dinitrate on exercise-induced ischemia were objectively determined by the measurement of exercise-induced ST-segment depression before as well as two, six, and 12 hours after the ingestion at the first and the 15th day of the studies. Since the dosage interval of 12 hours resulted in constant plasma levels, the initially beneficial anti-ischemic effects of isosorbide dinitrate were considerably attenuated after two weeks of treatment. In contrast, the once-daily regimen with its intermittent peaks and valleys of nitrate plasma levels showed identical anti-ischemic effects at the 15th day as compared with the first day. Ingestions at 8 A.M. and 2 P.M. also circumvented the development of nitrate tolerance, however, combined with an even more pronounced anti-ischemic effect after 12 hours as compared with the once-daily regimen. Thus, the circumvention of nitrate tolerance requires a daily "nitrate-poor" interval. The best compromise between a maximal possible anti-ischemic effect and the circumvention of tolerance development was found for the "eccentric" dosage regimen in which the tablets were ingested in the morning and early afternoon.

Angina Pectoris↗
PubMed1995

Interaction of intravenous heparin and organic nitrates in acute ischemic syndromes.

We evaluated whether a drug interaction between intravenous nitroglycerin or isosorbide dinitrate and heparin exists. Ninety-six patients with a diagnosis of acute myocardial infarction, unstable angina, or other thromboembolic disorders were divided into 3 groups: group I (control group, n = 35) received intravenous heparin alone; group II (n = 31) received combined intravenous nitroglycerin and heparin; and group III (n = 30) received combined intravenous isosorbide dinitrate and heparin. We determined the mean of 2 separate measurements of heparin dosage requirement, antithrombin III activity, and the dose of intravenous nitroglycerin or isosorbide dinitrate at the time that the ratio of activated partial thromboplastin time (aPTT) to baseline aPTT was 1.5 to 2.0. The mean therapeutic heparin dose standardized to total body weight of each group was 13.8, 15.4, and 15.5 U/kg/hour, respectively. At that time, patients were receiving intravenous nitroglycerin at doses of 58.8 +/- 38.6 micrograms/min or intravenous isosorbide dinitrate at doses of 3.7 +/- 2.0 mg/hour. The mean antithrombin III activity of each group was 22.2, 22.8, and 21.3 mg/dl, respectively. The overall results for groups I, II, and III, and results for the subgroup of patients with acute ischemic syndromes in those groups, did not differ significantly. The heparin dose did not show a significant correlation to the dose of intravenous nitroglycerin (r = -0.26, p > 0.05) nor to that of isosorbide dinitrate (r = 0.30, p > 0.05).

Acute Disease↗
PubMed1984

"Maximal" drug therapy is not necessarily optimal in chronic angina pectoris.

Beta-adrenergic blocking agents, nitrates and calcium channel antagonists are effective in treating angina pectoris, but much remains unknown about how they act in combination. Consequently, treadmill exercise was used to assess the relative efficacy of nifedipine or isosorbide dinitrate, or both, in 19 patients with stable angina receiving propranolol. Propranolol therapy was continued and either placebo, nifedipine (20 mg), isosorbide dinitrate (20 mg) or both drugs were given randomly 1 1/2 hours before exercise in a double-blind trial. In 16 patients who completed the protocol, heart rate at rest during propranolol therapy was 53.7 +/- 1.9 beats/min (mean +/- standard error of the mean); it increased 4.6 +/- 1.2 beats/min with the addition of nifedipine (p less than 0.01), but was unchanged with isosorbide dinitrate or both combined. Compared with values during treatment with propranolol alone, systolic blood pressure at rest decreased with each vasodilator individually and when combined. Rate-pressure product at maximal exercise was the same with all combinations. Exercise duration was 467 +/- 50 seconds with propranolol, increased to 556 +/- 47 seconds with isosorbide dinitrate (p less than 0.05) and to 636 +/- 50 seconds with nifedipine (p less than 0.001). Exercise duration with all three drugs was 597 +/- 47 seconds (p less than 0.01 compared with propranolol alone). The improvement with nifedipine was greater than with isosorbide dinitrate (p less than 0.05) but exercise duration was not significantly different with the combination of these drugs than when either drug was used alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2002

A long-term transdermal nitric oxide donor improves uteroplacental circulation in women with preeclampsia.

OBJECTIVE: To determine the effects of long-term transdermal administration (range, 4-30 days; mean +/- SD, 11.1+/-7.2 days) of isosorbide dinitrate, a nitric oxide donor, in preeclamptic women. METHODS: We studied uterine and fetoplacental circulation of 12 preeclamptic women with oligohydramnios and an elevated pulsatility index in the uterine arteries. RESULTS: Transdermal isosorbide dinitrate significantly suppressed the blood pressure of patients. Pulsed Doppler ultrasonography revealed that the average pulsatility index in the uterine arteries was significantly reduced by treatment with isosorbide dinitrate (P < .003). The average pulsatility index in the umbilical artery was also significantly reduced (P < .004). Furthermore, the size of the amniotic fluid pocket increased approximately 4-fold by treatment with isosorbide dinitrate. CONCLUSIONS: Long-term transdermal administration of isosorbide dinitrate improves fetoplacental circulation and may be effective therapy for avoiding maternal hypertension and oligohydramnios in some preeclamptic women.

Administration, Cutaneous↗
PubMed2001

Nitric oxide and airway reactivity.

BACKGROUND: Nitric oxide is a neurotransmitter of the inhibitory nonadrenergic noncholinergic mediation in the respiratory system. Its participation in the regulation of airways functions is determined by its level in the organism. MAIN PURPOSE: We examined participation of nitric oxide in the changes of the airway reactivity evoked by toluene exposure as the source of the free radicals. The changes of nitric oxide level in the organism were evoked by administration of its indirect donor isosorbide dinitrate. Thiol groups were provided by administration of antioxidative mucolytic N-acetylcysteine. METHODS: Used drugs--isosorbide dinitrate (5 mg/kg b.w.) and N-acetylcysteine (300 mg/kg b.w.) were administered intraperitoneally or by inhalation 30 minutes before each exposure to the toluene vapours. The control group was not treated with drugs. After toluene exposure (2 hours in each of 3 consecutive days) tracheal and lung strips smooth muscle reactivity to histamine was observed under in "in vitro" conditions. RESULTS: The administration of isosorbide dinitrate decreased especially the lung strip smooth muscle reactivity to histamine. We revealed more expressive effect of the pretreatment with intraperitoneally administered isosorbide dinitrate in the comparison with inhalation. Simultaneous pretreatment with N-acetylcysteine intensified beneficial effect of isosorbide dinitrate probably by increasing of the intracellullary level of thiols. CONCLUSION: In our experimental conditions possible participation of nitric oxide in changes of airways smooth muscle reactivity after exposure to the toluene follows from results, as well as the importance of thiol groups for the activity of its indirect donors. (Fig. 6, Tab. 3, Ref. 35.)

Acetylcysteine↗