Isosorbide dinitrate-induced improvement in left ventricular ejection fraction during exercise in coronary arterial disease.
Explore the source record for details and available documents.
Adult↗
SEARCH · Search PubMed
Results for “Isosorbide Dinitrate”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Isosorbide 5-mononitrate: a review of a sustained-release formulation (Imdur) in stable angina pectoris.
UNLABELLED: Imdur (IMD) is a sustained-release isosorbide 5-mononitrate preparation for the treatment of chronic stable angina pectoris. Controlled medication release is achieved using the Durules principle of insoluble matrix embedding. Data from randomised double-blind trials show that IMD 60 mg once daily (the most widely studied dosage) has significant antianginal and anti-ischaemic effects compared with placebo after 2 weeks' treatment. Efficacy was generally observed approximately 1 to 12 hours after administration, indicating that once-daily administration in the morning will provide effective prophylaxis of symptoms throughout the day. Improvements from baseline are generally maintained during IMD repeated treatment. There was no evidence of classical tolerance to IMD 30 to 240 mg/day in a large well designed study. Although improvements from baseline were maintained over 6 weeks with IMD 30 or 60 mg/day, statistical significance versus placebo was eventually lost because of improved performance in the placebo group. IMD 120 or 240 mg/day were more effective than placebo after 6 weeks. Studies lasting up to 2 weeks found no evidence of tolerance to IMD 60 mg/day. In comparative trials lasting approximately 2 weeks, IMD 60 mg once daily was more effective than isosorbide dinitrate 30 mg 4 times daily and similar to or better than isosorbide dinitrate 20 mg 3 times daily. Preliminary data show that IMD 60 mg once daily has similar efficacy to diltiazem 60 mg 3 times daily and is at least as effective as certain other sustained-release isosorbide 5-mononitrate preparations. There is no evidence for rebound worsening of ischaemia 24 hours after IMD administration. Abrupt discontinuation during long term IMD treatment may exacerbate anginal symptoms. In general, IMD is well tolerated. The most frequently reported adverse event, headache, is usually mild to moderate, improves with long term therapy and rarely leads to treatment withdrawal. Patient compliance is better with once-daily administration of IMD than with twice-daily administration of conventional isosorbide 5-mononitrate. CONCLUSIONS: In patients with chronic stable angina, IMD provides effective antianginal prophylaxis for up to 12 hours and does not seem to be associated with rebound phenomena at the end of the dosage interval. Improvements from baseline are maintained during repeated administration, although loss of statistically significant superiority over placebo was evident during 6 weeks' treatment with IMD < or =60 mg/day in 1 study. Further evaluation of comparative efficacy (particularly with respect to other sustained-release preparations) and long term effects would be beneficial. Nevertheless, the available data suggest that IMD is a useful and convenient agent for the treatment of patients with chronic stable angina pectoris.
Adrenergic beta-Antagonists↗
[Use of peripheral vasodilators with different mechanisms of action in treating heart failure patients].
The efficacy of peripheral vasodilators with various mechanisms of action was studied in 26 patents with congestive heart failure, left ventricular dilatation and valvular regurgitation. An acute pharmacological test using prazosin was used in all the patients, 20 of them were given a 15-day course of prazosin therapy, 19 patients received a prolonged course of prazosin therapy (over 3 mos.), 15 patients were given a 15-day course with a combination of isosorbide dinitrate and hydralazine. ECG monitoring, catheterization of the right cardiac chambers, thermodilution, and tetrapolar impedance plethysmography were employed. Heart rate, arterial pressure, parameters of cardiac pre- and afterload and pulmonary hemodynamics were studied. Prazosin and isosorbide dinitrate in combination with hydralazine showed a high clinical efficacy in the treatment of patients with congestive heart failure. The improvement of clinical symptomatology was accompanied by considerable positive shifts of the central and peripheral hemodynamics. No considerable differences in the efficacy of prazosin and the combination of isosorbide dinitrate with hydralazine were revealed.
Adolescent↗
[Changes in left-ventricular function in chronic congestive heart failure treated with digoxin, furosemide and vasodilators].
48 patients (62.8 +/- 9.1 yrs) with III or IV NYHa class congestive heart failure after 2-week therapy with digoxin (D) and furosemide (F) underwent two-dimensional echocardiographic examination to assess left ventricular function. Then in 25 patients (group I) DF and nifedipine (N) were given within 2 weeks, D, F, N and captopril (C) within 4 weeks and again D, F, N within 2 weeks. In 23 patients (group II) isosorbide dinitrate (S) was administered instead of nifedipine. 2-DE examination had been performed at the end of the each study stage. Optimal daily drug dose were: D-0.34 +/- 0.07 mg, F-40.7 +/- 12.5 mg, S-44.3 +/- 10.4 mg and 75.8 +/- 26.4 mg. Nifedipine and isosorbide dinitrate administrated with digoxin and furosemide did not improve left ventricular function in comparison with a standard therapy (DF). The best positive changes were observed in both groups during treatment with captopril. Ejection fraction by Teichholz increased from 42.9 +/- 15.0% during DF stage to 45.2 +/- 11.5% (DFNK stage) in group I (p less than 0.001) and from 35.3 +/- 10.5% to 36.4 +/- 10.4% in group II respectively (p greater than 0.01). Left ventricular systolic and diastolic internal diameters significantly decreased (p less than 0.05) whereas stroke volume and cardiac indices nonsignificantly increased (p greater than 0.05). Captopril with digoxine, furosemide and nifedipine caused significant hemodynamic improvement. Effect of captopril with nifedipine was greater that of captopril with isosorbide dinitrate.
Adult↗
Active and passive effects of antihypertensive drugs on large artery diameter and elasticity in human essential hypertension.
The effects of antihypertensive drugs on the large arteries consist of two parts: the passive effect due to the change in pressure and the active effect, the drug action per se. This study proposes a method of dissociating the passive effect from the active effect. The diameter of the arterial artery was determined by the pulsed Doppler method and the pulse wave velocity of the brachioradial artery by mecanography. Arterial compliance was calculated by the Bramwell-Hill formula. Active and passive effects were determined by a logarithmic pressure-diameter model. This model was supported by in situ direct measurements of blood pressure and diameter in a segment of the femoral artery in dogs. Six drugs, cadralazine, ketanserin, medroxalol, nitrendipine, captopril, and isosorbide dinitrate, administered orally, were tested in 70 essential hypertensive patients. For all drugs, the pressure reduction induced a passive decrease in arterial diameter (p less than 0.02 to p less than 0.01). Cadralazine actively decreased arterial diameter (p less than 0.01), ketanserin had no active effect on diameter, and medroxalol, nitrendipine, captopril, and isosorbide dinitrate actively increased arterial diameter (p less than 0.05, p less than 0.01, p less than 0.01, and p less than 0.01, respectively). For all drugs, the pressure reduction also induced a passive increase in arterial compliance (p less than 0.05 to p less than 0.01). However, only nitrendipine, captopril, and isosorbide dinitrate actively increased arterial compliance (p less than 0.01, p less than 0.05, and p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Nitrates for angina pectoris. A critical review of therapeutic efficacy and tolerance.
Nitrates are effective in the management of exertional angina pectoris primarily due to their peripheral effects i.e. venodilation and arterial dilation, and thereby reduction in myocardial oxygen demand. These drugs also improve collateral blood flow in ischemic areas and in some patients may increase coronary blood flow by modifying tonus in the conductive or conduit coronary vessels. Sublingual nitroglycerin is the most effective antianginal agent but its prophylactic use is limited by its short duration of action. Until recently, the efficacy of long-acting oral nitrates was seriously questioned. However, recent data suggests that when given acutely in adequate doses, oral nitrates, transcutaneous and buccal preparations of nitroglycerin all exert prolonged hemodynamic and antianginal effects. Development of tolerance to the circulatory and antianginal effects during chronic therapy, however, remains a concern. Published literature suggests that tolerance to the circulatory effects and to headaches develops rapidly during sustained therapy with long-acting nitrates. However, reports regarding the development of tolerance to the antianginal effects and reduction of ST segment depression remain conflicting. Partial tolerance to the antianginal effects has been well-documented during chronic therapy with isosorbide dinitrate. Duration of improvement in exercise tolerance during four times daily therapy with isosorbide dinitrate has been shown to be shortened compared to prolonged effects following acute therapy. Recent data suggests that given in high doses, beneficial effects of ST segment depression during exercise may also diminish during chronic therapy with long acting nitrates. Tolerance to antianginal and circulatory effects can be reversed by withholding long-acting nitrates for 24 to 36 hours. Furthermore, initial studies suggest that tolerance to antianginal effects during sustained therapy can be avoided by giving smaller but effective doses of ISDN (20 to 40 mg) twice a day rather than prescribing larger doses more frequently.
Angina Pectoris↗
Generation of nitric oxide from nitrovasodilators modulates the release of histamine from mast cells.
The effect of organic and inorganic nitrovasodilators (sodium nitroprusside; 3-morpholinosydnonimine; glyceryl trinitrate; isosorbide dinitrate; sodium nitrite, was studied on the release of histamine evoked by compound 48/80 and calcium ionophore A 23187 in isolated purified rat serosal mast cells. All the compounds tested were capable of significantly reducing the release of histamine in a concentration-dependent fashion, at different levels of potency. This effect was reverted by oxyhaemoglobin. The inhibitory effect of glyceryl trinitrate on the release of histamine was potentiated in cells taken from animals pretreated with Escherichia coli lipopolysaccharide, and decreased by NG-nitro-L-arginine methyl ester. Glyceryl trinitrate and isosorbide dinitrate concentration-dependently increase the generation of nitric oxide by rat serosal mast cells. The inhibitory effect of glyceryl trinitrate and isosorbide dinitrate on the release of histamine from mast cells was potentiated by N-acetylcysteine, which significantly increases the generation of nitric oxide by mast cells. It is concluded that nitrovasodilators inhibit the release of mast cell histamine through the generation of nitric oxide. The effect may be relevant in considering the perivascular location of mast cells and the role played by these cells in cardiovascular pathophysiology.
Acetylcysteine↗
Nicorandil. A review of its pharmacology and therapeutic efficacy in angina pectoris.
Nicorandil belongs to the class of compounds known as potassium channel activators which are characterised by their arterial vasodilator properties. In addition, nicorandil has venodilating properties which are attributable to a nitrate group in its chemical structure. Therefore, by combining these two vasodilator mechanisms, nicorandil represents a novel type of compound for use in the treatment of angina pectoris. Furthermore, increasing experimental evidence suggests that potassium channel activation may also exert a direct cytoprotective effect by augmenting normal physiological processes which protect the heart against ischaemic events. Comparative studies of up to 3 months' duration suggest that nicorandil is equivalent in efficacy to isosorbide dinitrate, propranolol, atenolol, nifedipine or diltiazem in the treatment of stable angina. Preliminary evidence suggests that an improvement of anginal and ischaemic symptoms is maintained for up to 1 year. Whilst the efficacy of nicorandil in other types of angina has not been extensively studied, preliminary results indicate that intravenous nicorandil is as effective as isosorbide dinitrate in the treatment of unstable angina and is also effective in patients with variant angina. In addition, the limited data available indicate that nicorandil may be effective in patients with unstable and variant angina who are refractory to therapy with conventional antianginal agents, a potentially important area for further study. Headache, mostly of mild to moderate intensity was the most commonly reported adverse event, occurring in one-third of patients receiving the recommended therapeutic regimen of nicorandil 10 to 20mg twice daily. In comparative trials involving a total of 84 patients who received nicorandil, the incidence of headache was similar to that produced by isosorbide mononitrate and isosorbide dinitrate. Headache was most frequent on initiating therapy but declined with continued treatment. To date, approximately 5% of patients participating in European trials have withdrawn due to headache, although this rate may be reduced by using a lower starting dose of nicorandil (5 mg twice daily). In summary, clinical experience thus far indicates that nicorandil, with its novel combination of two distinct vasodilator mechanisms, offers an effective alternative to established vasodilator therapy with conventional nitrates and calcium antagonists in the long term treatment of stable angina pectoris. Further studies are warranted to establish whether the unique pharmacodynamic profile of nicorandil is advantageous for the treatment of other types of angina and/or the ischaemic myocardium.
Angina Pectoris↗
Historical aspects of nitrate therapy.
The exciting story of the development of nitrates as drugs in clinical medicine is briefly reviewed. Glyceryl trinitrate (nitroglycerin) was synthesised by Sombrero in 1847. Amyl nitrite was discovered a few years later and was used by Guthrie in 1859. The first report on the action of glyceryl trinitrate and amyl nitrite was published by Brunton in 1867, and further papers were published by Murell in 1879. Organic nitrates appeared in the 1930s. Krantz and co-workers synthesised and used mannide dinitrate, which was longer acting than the nitrates that had been used previously. Research on a similar drug, isosorbide dinitrate, was initiated by Porjé in Stockholm. The drug was first marketed in Sweden in 1946. Isosorbide dinitrate was independently synthesised in the United States by Harris and colleagues in the 1950s. The drug was used fairly extensively on both sides of the Atlantic. However, there was a temporary decrease in popularity around 1970 when Needleman and colleages reported oral nitrates to be of questionable value, as they underwent rapid biotransformation during first-pass metabolism in the liver. This opinion was later altered and today the drug enjoys worldwide acceptance in different formulations. Also, in recent years one of the active metabolites, isosorbide 5-mononitrate, has been marketed as an effective antianginal drug.
Cardiovascular Diseases↗
Medial elastic structure alterations in atherosclerotic arteries in minipigs: plaque proximity and arterial site specificity.
Using a model of atherosclerosis in minipigs, we analyzed changes in elastic structure within the medial sections of the abdominal aorta and left interventricular coronary artery both in the vicinity of and distal to atheromatous plaques. Twenty-four animals, divided into three groups, were fed either a control diet or a hypercholesterolemic and hyperhomocysteinic atherogenic diet, alone or in association with an antihypertensor, namely isosorbide dinitrate (Risordan). The atherogenic diet, administered for a period of four months, induced in the minipig advanced noncalcified atherosclerotic lesions that were histologically similar to those found in humans. A morphodensitometric analysis of the medial elastic structures was carried out on images obtained from specifically stained transverse arterial sections examined under a light microscope. The volume density of the elastic structures was diminished in the arterial media of the atherosclerotic animals due to opening and widening of the fenestrae in the elastic laminate and increased communication between the interlamellar spaces. Whereas this elastolytic process was uniform and independent of the proximity of atheromatous plaques in the left interventricular coronary artery, it was intensified in the vicinity of the plaques in the abdominal aorta. Overall elastolytic activity was increased in the walls of atheromatous artery in both arterial sites, and metalloproteinases were implied in this increase of activity. We previously reported that treatment with isosorbide dinitrate significantly reduced the moderate systolic hypertension and the increase in transparietal stress observed in the abdominal aorta of atheromatous animals. We report here that isosorbide dinitrate prevented the atherogenic-diet-induced deterioration of the elastic structure in these arteries; complete inhibition of changes to the elastic laminae was evident in areas remote from plaque formation, but only partial inhibition in the vicinity of such plaques. It did not, however, prevent structural damage in the left interventricular coronary artery or modify the increase in parietal elastolytic activity in either of the two arteries. This suggests that damage to the elastic structure in atheromatous arteries is dependent not only on overall elastolytic activity but also on localized factors, possibly related to parietal stresses, affected by the presence of atheromatous plaques.
Amino Acids↗
[The tourniquet test in evaluating the analgesic action of antianginal preparations].
Twenty-two patients with coronary heart disease (CHD) were examined for pain threshold and pain tolerance by a tourniquet test. The relationships between pain and ST segment depression were studied simultaneously during bicycle exercise. Pain sensitivity was measured in response to action of various antianginal drugs (isosorbide dinitrate, verapamil, nifedipine, diltiazem, propranolol, atenolol) and placebo. Reproducibility of the tourniquet test proved satisfactory. There were significant correlations between tourniquet test evidence and clinical patterns of ischemic myocardial episodes: significant differences in the values of pain threshold and pain tolerance in patients with painful myocardial ischemia, in combination of angina of effort with painless myocardial ischemia (p < 0.0001). Significant were also correlations between tourniquet test findings at bicycle exercise and value describing the proportion of ST depression to pain. As for the drugs, verapamil appeared most active in the tourniquet test (p < 0.02 and p < 0.05 for pain threshold and pain tolerance, respectively). Pain tolerance changes due to isosorbide dinitrate were somewhat greater than for placebo (p = 0.06). The study provided evidence in support of the adequacy of the tourniquet test for assessment of general pain sensitivity and pain sensitivity to myocardial ischemia as well as of analgetic effects of the drugs. Verapamil and isosorbide dinitrate are suggested to have analgetic activity.
Aged↗
Treatment of esophageal varices.
The pathophysiology and treatment of esophageal varices are reviewed. The cause of esophageal varices is generally thought to be portal hypertension. The most common cause of portal hypertension in the United States is alcoholic liver disease. Other etiologies of portal hypertension include portal vein thrombosis, schistosomiasis, and inferior vena caval obstruction by tumor or thrombus. Although short-term balloon tamponade and vasopressin infusion will control acute variceal hemorrhage, they do not affect the underlying problem and are not indicated for long-term treatment of esophageal varices. Surgical procedures either ablate varices or lower portal vein pressure. Portal-systemic shunts have emerged as the preferred surgical technique, but the superiority of total versus selective shunts is unclear. Pharmacological management can include administration of vasopressin, somatostatin, verapamil, or isosorbide dinitrate for short-term treatment or verapamil, isosorbide dinitrate, or propranolol for prolonged treatment. Use of sclerotherapy for treatment and prevention of hemorrhage from esophageal varices has grown recently. Because there are several sclerosing agents and combinations of agents available for use, assessing their relative safety and efficacy is difficult. Innovative approaches to management of varices include a shunt procedure involving the left lung, use of a tissue adhesive, and laser treatment. Because of its effectiveness and ease of administration, sclerotherapy appears to be a rational method of treatment for acute hemorrhage from esophageal varices.
Balloon Occlusion↗
[Coronary vasoconstriction induced by digoxin in normal subjects and in patients with coronary atherosclerosis].
This study evaluated the effects of digoxin infusion (0.014 mg/kg in 10 min i.v.) on large coronary arteries measured by quantitative digital angiography. Twenty-two patients (aged 47 +/- 12), divided in 3 groups were studied. The effects of digoxin infusion (after 10 and 20 min) and sublingual administration of isosorbide dinitrate were investigated in Group I (patients with angiographically normal coronary arteries, n = 9) and in Group II (patients with atherosclerotic coronary arteries, n = 8). In Group III (n = 5) to determine whether or not the effects of digoxin were mediated by activation of alpha-adrenergic receptors, coronary angiographies were performed after alpha-adrenoceptor blockade (phentolamine 0.11 mg/kg, i.v.). In Group I, 10 min after the end of digoxin infusion, cross-sectional area decreased from 7.7 +/- 4.1 mm2 to 6.0 +/- 2.2 mm2, and after 20 min to 5.6 +/- 2.6 mm2 (p < 0.05). Isosorbide dinitrate reverted digoxin-induced vasoconstriction as cross-sectional area increased to 8.5 +/- 3.4 mm2 (NS versus baseline). By 20 min after digoxin infusion heart rate was significantly reduced from 79 +/- 16 to 74 +/- 13 b/min (p < 0.01). Peripheral vascular resistances increased significantly 10 min after digoxin infusion (from 1396 +/- 693 to 1693 +/- 984 dyne*s*cm-5, p < 0.05), whereas cardiac output did not change. In Group II, minimal stenosis diameter decreased significantly 20 min after digoxin infusion from 1.6 +/- 0.5 mm to 1.4 +/- 0.5 mm (p < 0.05). Again, isosorbide dinitrate reverted digoxin-induced vasoconstriction as minimal stenosis diameter increased (NS versus control).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Evaluation of nitric oxide formation from nitrates in pig coronary arteries.
To clarify the hypothesis that organic nitrates are converted to nitric oxide (NO) via nitrite ion (NO2-) by glutathione S-transferase, the metabolic conversion of four nitrates was examined in pig coronary arteries and compared with that in rat liver. Nitrates caused the relaxation of the artery muscles with the order of nitroglycerin > isosorbide dinitrate > nicorandil > or = nipradilol, whereas the order of NO formation in the arteries was nitroglycerin > isosorbide dinitrate > nipradilol > nicorandil. The same order of NO formation from the nitrates was also observed in liver cytosol. Nicorandil may cause more relaxation than nipradilol by both NO releasing and other (unknown) actions. Although the order of the potency in NO2- formation from the nitrates in liver cytosol was the same as that seen in NO formation, NO2- was not detected in pig coronary arteries. Thus NO2- formation from the nitrates correlated with NO formation in liver cytosol but not in pig arteries. When nonenzymatic and enzymatic NO formations from nitroglycerin were examined in the arteries, the enzymatic NO formation, which was not inhibited by glutathione S-transferase inhibitors, was 13% of the total NO. These results indicate that in pig coronary arteries, nitrates release NO mostly through a nonenzymatic manner, although there is a slight amount of enzymatically produced NO, and glutathione S-transferase may not contribute to the enzymatic NO formation.
Animals↗
Effects of 8:00 a.m. and 2:00 p.m. doses of isosorbide-5-mononitrate during twice-daily therapy in stable angina pectoris.
"Trough" plasma concentrations of isosorbide-5-mononitrate (IS-5-MN), an active metabolite of isosorbide dinitrate, of less than 95 ng/ml are considered necessary to prevent development of tolerance to isosorbide dinitrate and IS-5-MN. In a double-blind, crossover, placebo-controlled study, the effects of IS-5-MN during twice daily eccentric therapy were evaluated in 18 patients with reproducible exercise-induced angina who were nitrate responders. In a random order, patients received either placebo or IS-5-MN (20 mg) at 8 a.m. and 2 p.m. for 1 week each. Average trough plasma IS-5-MN concentrations before the 8 a.m. and 2 p.m. doses were 67 and 226 ng/ml, respectively, and increased to 382 and 488 ng/ml 2 hours after the 8 a.m. and 2 p.m. doses, respectively. Despite a more than threefold higher trough plasma IS-5-MN concentration before the 2 p.m. dose than before the 8 a.m. dose, the increase in exercise duration 2 hours after the doses was similar (1.21 minutes [21%] after 8 a.m. dose, and 1.08 minutes [19%] after 2 p.m. dose). These increases in exercise duration after IS-5-MN were significantly (p less than 0.01) greater than those observed after placebo (0.17 minutes [3%] after 8 a.m. dose, and -0.05 minute [-0.5%] after 2 p.m. dose). Reduction in standing systolic blood pressure at 2 hours after the doses was also nearly identical after the 8 a.m. and 2 p.m. doses of IS-5-MN (21 [15%] and 19 [14%] mm Hg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms.
BACKGROUND: A group of patients has been described who have chest pain resembling angina and positive exercise tests, but normal coronary angiograms and no coronary-artery spasm. This constellation of features has sometimes been called syndrome X or microvascular angina. We attempted to determine whether endothelium-dependent vasodilatation of the coronary vasculature was impaired in patients with this syndrome. METHODS: We infused the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilators papaverine and isosorbide dinitrate into the left coronary artery of 9 patients and 10 control subjects. The diameter of the left anterior descending coronary artery was assessed by quantitative angiography, and changes in coronary blood flow were estimated with the use of an intracoronary Doppler catheter. RESULTS: Acetylcholine, given in doses of 1, 3, 10, and 30 micrograms per minute, increased coronary blood flow in a dose-dependent manner in both groups. However, the mean (+/- SD) acetylcholine-induced increases in coronary blood flow were significantly less (P < 0.001) in the patient (8 +/- 14, 37 +/- 37, 59 +/- 67, and 103 +/- 77 percent, respectively) than in the controls (62 +/- 52, 186 +/- 93, 341 +/- 128, and 345 +/- 78 percent, respectively). The changes in coronary blood flow in response to 2 mg of isosorbide dinitrate (236 +/- 66 percent vs. 280 +/- 56 percent) and 10 mg of papaverine (366 +/- 168 percent vs. 411 +/- 92 percent) did not differ significantly between the patients and controls. The administration of papaverine resulted in myocardial lactate production in the patients but not in the controls. The three lower doses of acetylcholine caused a similar degree of dilatation of the left anterior descending coronary artery in the two groups, and the highest dose caused a similar degree of constriction in the two groups. Isosorbide dinitrate and papaverine caused a similar degree of dilatation in both groups. CONCLUSIONS: These findings suggest that endothelium-dependent dilatation of the resistance coronary arteries is defective in patients with anginal chest pain and normal coronary arteries, which may contribute to the altered regulation of myocardial perfusion in these patients.
Acetylcholine↗
Effect of prolonged nitrate therapy on left ventricular remodeling after canine acute myocardial infarction.
BACKGROUND: Prolonged nitrate therapy during healing between 2 days and 6 weeks after anterior myocardial infarction has the potential for limiting further left ventricular remodeling (or changes in topography) and preserving function. Longterm therapy throughout healing over 6 weeks might be more beneficial than short-term therapy over the first 2 weeks after infarction. METHODS AND RESULTS: The effect of prolonged nitrate therapy between 2 days and 6 weeks during healing after infarction on serial parameters of ventricular remodeling (scar expansion, scar thinning, ventricular dilation, and hypertrophy) and function (asynergy or akinesis plus dyskinesis and ejection fraction) by serial two-dimensional echocardiography, hemodynamics, postmortem topography (computerized planimetry, geometric maps, and radiographs), and collagen content (hydroxyproline) was studied in 64 instrumented dogs randomized 2 days after left anterior descending coronary artery ligation to various nitrate regimens (n = 32) over the first 2 weeks (subgroup 1: 2% transdermal nitroglycerin at 8 AM and 4 PM, n = 6; subgroup 2: 2% transdermal nitroglycerin plus 2.6 mg of sustained-release oral nitroglycerin at 8 AM, 3 PM, and 10 PM, n = 5; subgroup 3: oral isosorbide dinitrate, 30 mg at 8 AM and 4 PM, n = 11) or 6 weeks (subgroup 4: isosorbide dinitrate, n = 10) and in matching controls (n = 32). Nitrate therapy reduced left atrial pressure, mean arterial pressure, and the rate-pressure product compared with controls over the 6 weeks. Postmortem scar mass and hydroxyproline were similar in control and nitrate groups. However, scar stretching and thinning, cavity dilation, noninfarct wall hypertrophy, and apical bulging were less with nitrates, especially in the long-term subgroup 4. In vivo remodeling parameters between 2 days and 6 weeks after ligation showed that, compared with controls, nitrate therapy prevented further stretching of the asynergic segment, decreased the expansion index, decreased further scar thinning, prevented the increase in ventricular volumes, reduced the frequency of ventricular aneurysm, prevented the increase in ventricular mass, reduced the extent of asynergy, and improved ejection fraction. Although the beneficial effect on topography and function was seen in all nitrate subgroups, the overall benefit was greater with long-term therapy over 6 weeks (subgroup 4) than short-term therapy confined to the first 2 weeks (subgroups 1, 2, and 3). CONCLUSIONS: Prolonged nitrate therapy, in various regimens during healing after infarction, effectively reduced left ventricular loading and prevented infarct thinning, further infarct expansion, progressive ventricular dilation, and the increase in mass. These effects were associated with decreased asynergy and improved ejection fraction. The beneficial effects were greater with long-term therapy over 6 weeks than short-term therapy over the first 2 weeks.
Animals↗
Effect of caffeine on ergotamine absorption from rat small intestine.
The effect of caffeine on the absorption of ergotamine from the rat small intestine was studied. The results of a series of experiments showed that caffeine significantly enhanced absorption of ergotamine from solutions of pH 5.0 when both substances were in solution and when an intact blood supply was either absent (in vitro everted sac experiments) or present (in situ experiments). Caffeine did not appear to influence the absorption rate of ergotamine in situ experiments when the solution pH was 3.0. Isosorbide dinitrate, a vasodilator, enhanced ergotamine absorption when both substances were administered simultaneously into intestinal loops in situ. Isosorbide dinitrate probably exerts its effect by increasing blood flow to the intestine. The results are consistent with an hypothesis that the rate-determining step in ergotamine absorption is the transport of the drug from a lipid phase (GI membrane) into an aqueous phase (blood). Caffeine is thought to exert its rate-accelerating effect by increasing the water solubility of ergotamine neutral molecules.
Animals↗