Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002962 (angina)
 21,142 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent discovery of endothelium-derived relaxation factor (EDRF) has altered the traditional classification of vasodilators used in angina pectoris and heart failure. If a vasodilator induces release of EDRF from the epithelium it is classified as endothelium-dependent, if not it is independent. Sodium nitroprusside and SIN-1 (active metabolite of molsidomine) are the main independent vasodilators since the endothelium relaxation factor appears to be principally a nitric oxide radical in these synthetic vasodilators. In contrast, calcium-channel blockers and a good number of endogenous chemical mediators (acetylcholine, bradykinin, serotonin, etc.) are endothelium-dependent. Furthermore, simple increase in blood flow through the large vessels can result in endothelium-dependent vasodilation (flow rate-dependence) the extent of which depends on the drug examined. The fact that the pharmacologic response of a vasodilator can be altered under certain pathologic conditions (atherosclerosis, hypertension, diabetes, etc.) further increases the importance of the role of the vascular endothelium in the action of vasodilators since endothelial modulation may then be completely diverted to secretion of endothelium-derived contracting factors (EDCFS).
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PMID:[Vasodilator agents and the vascular endothelium]. 262 13

To investigate the mechanism of action of nitrovasodilators in exercise-induced angina, 15 patients with chronic stable angina underwent a symptom-limited supine exercise test (exercise 1). After recovery, in 10 patients (group I) a coronary vasodilator, SIN-1 (the active metabolite of molsidomine) was injected into the most diseased coronary artery (80 micrograms in 4 min). In the remaining 5, a placebo was injected (group II). Immediately thereafter, the same exercise (exercise 2, identical workloads and exercise duration) was repeated. In group I, after intracoronary injection of SIN-1, the control values at rest (including pulmonary wedge pressure) did not significantly change. Heart rate, blood pressure and cardiac index rose in a similar way during exercises 1 and 2 (61, 20, 26 and 62, 21, 35%, respectively). However, 3 patients were angina-free without ST-changes during exercise 2. In the remaining 7, the ST/heart rate slope was reduced (60%; p less than 0.02), the increase in pulmonary wedge pressure was less pronounced (p less than 0.01) and ST-depression at end-exercise 2 was smaller: 1.3 +/- 0.3 versus 2.1 +/- 0.3 mm (p less than 0.01) for identical work loads and double products. In group II, exercise 2 was identical to exercise 1 and the ST/heart rate slopes were quite reproducible. Therefore, these results argue for an improvement in coronary blood supply after intracoronary SIN-1 and suggest that the beneficial action of nitrovasodilators could be related to direct effects on the coronary circulation. However, the magnitude of this mechanism seems variable from one patient to another.
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PMID:Exercise-induced angina alleviated by intracoronary SIN-1. 343 6

We studied the effects of intracoronary injections of SIN-1 (0.8 mg), the active metabolite of molsidomine, on coronary artery diameters and coronary stenoses. In nine patients with abnormal angiograms measurements were made 4 and 8 minutes after SIN-1 administration. There was a statistically significant increase in coronary luminal diameter in proximal, medial, and distal segments as well as at the level of the stenoses. At 4 minutes after administration distal segments showed a mean increase in diameter of 50%, compared to a mean increase of 26% in proximal segments. In six patients with normal angiograms SIN-1 abolished three of four coronary spasms induced by ergonovine maleate. A protective effect of SIN-1 against the vasoconstrictor effects of ergonovine was still present at 8 minutes after administration. Heart rate and blood pressure remained unchanged throughout the study. We conclude that the vasodilation induced by SIN-1 in normal and stenotic coronary arteries is probably an important contribution to the antianginal efficacy of molsidomine and suggests that molsidomine may be effective in the prophylaxis of variant angina.
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PMID:The new long-acting coronary artery dilator molsidomine and its metabolite SIN-1. 383 7

Prostacyclin belongs to the family of prostaglandins, which are derived from arachidonic acid. It is secreted by vascular endothelium and possesses vasodilator and platelet anti-aggregant properties. This paper shows that molsidomine, a new anti-angina agent with vasodilator effects, is able to induce the secretion of prostacyclin by vascular endothelial cells in the aorta of the piglet. Molsidomine, via its stable metabolite SIN 1, induces very rapid and early secretion of prostacyclin followed by a refractory effect on vascular endothelium. At the same time, SIN 1 inhibits the platelet synthesis of thromboxane A2, which suggests that part of the action of molsidomine is related to an improvement in the prostacyclin/thromboxane A2 equilibrium, which has been shown to be disturbed in the course of certain cardiovascular diseases.
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PMID:[Cellular mechanism of action of molsidomine. Bioinduction of prostacyclin]. 642 Dec 23

N-Carboxy-3-morpholinosydnone imine ethyl ester (molsidomine) and its main metabolite 3-morpholinosydnone imine (SIN-1) were investigated in rabbit platelet-rich plasma (PRP) for antiaggregatory activity and inhibition of thromboxane A2 (TXA2) generation (arachidonic acid (AA)-induced) as well as in human PRP regarding prostaglandin endoperoxide analogue (U-46 619)- and AA-induced aggregation and TXB2 formation. The results were compared with the effects of nictindole. In rabbit PRP the inhibitory effects of molsidomine on aggregation and TXA2 generation were 20fold lower than that of SIN-1. The IC50-values of SIN-1, which is the pharmacologically active biotransformation product of molsidomine, were about 1 mumol/l in the experimental models used. The inhibitory effects of nictindole were about 50 times higher than those of SIN-1. In human PRP the inhibitory potency of SIN-1 decreased in the following sequence: U-46 619-induced aggregation (IC50 = 0.9 mumol/l) greater than AA-induced aggregation (IC50 = 1.4 mumol/l) greater than TXB2 formation (IC50 = 2.9 mumol/l). Molsidomine was nearly without effect in human PRP. Our own preliminary results and findings obtained by other authors seem to exclude a direct effect of SIN-1 on cyclooxygenase and thromboxane synthetase. The possible clinical significance of our findings in different types of angina pectoris and for myocardial infarction is discussed.
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PMID:SIN-1, the main metabolite of molsidomine, inhibits prostaglandin endoperoxide analogue- and arachidonic acid-induced platelet aggregation as well as platelet thromboxane A2 formation. 689 78

Anti-ischemic drugs may develop their cardiac activity via peripheral (reduction in preload and/or afterload) or cardiac (coronary vasculature, myocardial cell metabolism) effects. The aim of the study was to investigate whether SIN-1, the active metabolite of molsidomine, develops a direct myocardial anti-ischemic property. Three groups of seven patients each were treated with 0.4 mg SIN-1 administered via either the intracoronary (IC) or intravenous (IV) route, or with placebo in a double-blind randomized investigation. SIN-1 had no influence on either the ischemic parameters in the surface electrocardiogram (ECG) or the intracoronary ECG. There was also no change in peripheral or central hemodynamics or in the severity of angina following this low IC or IV dosage. There is no evidence of a direct myocardial anti-ischemic response of SIN-1. The well known anti-ischemic activity of SIN-1 or molsidomine has to be attributed to the proven peripheral and cardiac vascular responses.
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PMID:SIN-1 has no direct myocardial anti-ischemic action. 822 84

Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with counterclockwise hysteresis, i.e. a greater effect associated with the decrease of plasma concentrations than during their increase, which may be at least partly due to the metabolic delay in the formation of NO from SIN-1. Accordingly, the duration of action of molsidomine is longer than would be expected on the basis of the elimination half-life. The pharmacokinetics of molsidomine support the recommended dosages for use in angina pectoris.
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PMID:Clinical pharmacokinetics of molsidomine. 874 36

Generalized atherosclerosis and coronary artery disease (CAD) are associated with endothelial dysfunction and during acute myocardial ischemia platelet activation has been reported. Activated platelets exert activated fibrinogen receptors (GP IIb/IIIa) and express CD 62p being regarded as reliable marker for platelet activation. Patients with angiographically proven CAD performed a bicycle exercise test until the onset of angina or ST-segment depression. We studied the ischemia-induced alterations in fibrinogen binding to activated platelet GP IIb/IIIa receptors and CD 62p expression. Therefore, the basal fibrinogen binding to GP IIb/IIIa and CD 62p expression and the thrombin-concentration for half-maximal platelet activation before and after exercise testing were determined. Additionally, inhibition of thrombin-induced platelet activation by increasing concentrations of the prostacyclin-analog iloprost and the NO-donor SIN-1 was examined. In patients with CAD, a significantly reduced basal activation and a highly significant reduction in sensitivity towards thrombin was measured. The thrombin-induced expression of GP IIb/IIIa and CD 62p was significantly diminished in patients with CAD after physical exercise and their platelets were significantly more sensitive towards the inhibitory effects of iloprost and SIN-1. These data demonstrate a significant reduction in platelet activation in response to physical exercise in patients with CAD and advanced atherosclerosis. Despite exercise induced myocardial ischemia as evidenced by angina and ECG-changes, the platelets are not generally activated, as it could be expected. Thus, patients with myocardial ischemia experienced a reduced platelet activity and enhanced sensitivity towards prostacyclin (PGI2) and nitric oxide, probably due to an augmented release of endogenous platelet inhibitory mediators.
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PMID:Increased platelet sensitivity toward platelet inhibitors during physical exercise in patients with coronary artery disease. 995 Feb 58

The antiviral effect of nitric oxide (NO)-releasing compounds was investigated. Using bacterially expressed and purified proteinases 2A and 3C of coxsackievirus B3, in vitro assays demonstrated the inhibition of the 2A proteinase activity in the presence of S-nitroso- N-acetyl-penicillamine (SNAP), 3-morpholinosydnonimine (SIN-1), 4-phenyl-3-furoxancarbonitrile (PFC), glyceryl trinitrate (GTN), and isosorbide dinitrate (ISDN). Sodium nitroprusside (SNP), which releases NO after metabolization, had no effect. The 3C proteinase was inactivated by SNAP, GTN, and ISDN. The vasodilators GTN and ISDN, widely used in the treatment of angina pectoris, exhibited antiviral activity in CVB3-infected GMK cells. CVB3-infected NMRI outbred mice showed significantly reduced signs of myocarditis after treatment with GTN or ISDN. Inhibitors of the cellular inducible NO synthase (iNOS) such as N(G)-nitro-L-arginine methyl ester (L-NAME), N(G)-nitro-L-arginine (L-NNA), and S-methyl-isothiourea (SMT), had no deleterious effect on CVB3-infected NMRI mice, indicating that endogenous NO synthesis is unlikely to be a major defense mechanism after enterovirus infection of outbred mice.
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PMID:Nitric oxide donors inhibit the coxsackievirus B3 proteinases 2A and 3C in vitro, virus production in cells, and signs of myocarditis in virus-infected mice. 1451 74