Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The selective serotonin reuptake inhibitor, paroxetine, has been reported to inhibit cytochrome P450 activity. Nitric oxide synthase (NOS) is structurally homologous to cytochrome P450. Accordingly, in our study, we observed the effects of paroxetine on NOS activity. Seventeen ischemic heart disease (IHD) patients received paroxetine and fourteen received nortriptyline for treatment of clinical depression defined by a score of 17 or higher on the Hamilton Rating Scale for Depression (HAM-D). Serum nitrite and nitrate levels were significantly decreased following paroxetine treatment but not nortriptyline treatment. Paroxetine was also a more potent inhibitor of NOS enzyme activity than nortriptyline, as measured by the conversion of [14C] arginine to [14C] citrulline by hamster brain cytosols. In addition, paroxetine reversed the force-frequency relationship in isolated hamster papillary muscles in a manner analogous to that of known NOS inhibitors. Thus, paroxetine appears to be a novel NOS inhibitor in vitro and in vivo.
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PMID:Paroxetine is a novel nitric oxide synthase inhibitor. 899 87

Nitrite and nitrate (NO2 and NO3), the oxidative products of nitric oxide (NO), were elevated in the plasma of rabbits on the third day following ligation of a coronary artery. This elevation coincided with increased activity of the inducible form of nitric oxide synthase (iNOS) in infarcted heart muscle. Data are reported which relate the elevated plasma concentrations of NO2+NO3 (NO(x)) to the increased induction of iNOS in an infarcted heart. NO2 and NO3 in plasma were measured by chemiluminescence. Nitrate was converted to nitrite by nitrate reductase. Plasma from the ear vein, right and left ventricle, and coronary sinus were analyzed for NO(x), and iNOS activity was enzymatically determined in infarcted, risk, and normal areas of the heart. The production equivalent of NO(x) by the heart and lung was also calculated. In addition, the effect of a specific inhibitor of iNOS, S-methylisothiourea sulfate (SMT) on plasma concentration and myocardial production of NO(x) was determined. It was concluded that the elevation of plasma NO(x) following onset of myocardial ischemia was directly related to increased induction of iNOS in the heart. This conclusion was based on a proportional and simultaneous increase in NO(x) plasma concentration with myocardial iNOS activation. The inhibitory effect of SMT furnished additional confirmation of the relationship between myocardial iNOS activation and NO(x) plasma levels in experimental myocardial infarction.
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PMID:Oxidation products of nitric oxide, NO2 and NO3, in plasma after experimental myocardial infarction. 904 16

The aim of the study was to evaluate feasibility of emergence of nitrate withdrawal syndrome consequently to discontinuation of short-term nitrate administration for coronary heart disease. 12 males with stable effort angina functional class III were subjected to 24-h Holter ECG monitoring. In a randomized cross-over trial each patient received for 3 days isosorbide dinitrate (10-30 mg 4 times a day) followed by 3-day course of placebo. The monitoring was performed on day 3 of the drug or placebo administration and on the first day of their withdrawal. Isosorbide dinitrate discontinuation had no negative effects on the patients' condition though significantly increased the number and duration of episodes of asymptomatic myocardial ischemia. 4 patients developed episodes of asymptomatic myocardial ischemia at rest which were not observed in placebo application. It is believed that much caution should be used in planning interrupted regimes of nitrates therapy in patients with severe angina pectoris.
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PMID:[The emergence of silent myocardial ischemia as the manifestation of the nitrate withdrawal syndrome in patients with ischemic heart disease]. 908 1

Vascular tolerance develops rapidly in isolated vascular strips exposed to millimolar concentrations of nitroglycerin. Several mechanisms, including depletion of sulfhydryl groups, reduced biotransformation of nitrates to NO or nitrosothiols, oxygen free radical injury, and downregulation of a membrane-bound enzyme or a nitrate receptor, have been proposed, but the exact mechanism responsible for in-vitro tolerance remains unknown. In-vivo tolerance of the beneficial effects of nitrates on hemodynamics, myocardial ischemia, and exercise performance develops rapidly. It has been suggested, but remains to be proven, that development of venous tolerance and not arterial tolerance is responsible for the attenuation of nitrate effects during long-term nitrate therapy. Several mechanisms, including neurohormonal activation, depletion of sulfhdryl groups, and the shift of fluid from the extravascular to intravascular compartment have been implicated. However, the use of agents to counteract these mechanisms (ACE inhibitors, sulfhydryl donors, diuretics) has produced conflicting results. Thus, at present the mechanism responsible for in vivo tolerance to nitrates remains unknown. Both in vitro and in vivo vascular tolerance to nitrates can be prevented or minimized by providing nitrate-free or low-nitrate intervals. However, during nitrate-free periods, rebound phenomena (rest angina in patients with ischemic heart disease or a deterioration in exercise performance prior to the renewal of the morning dose in patients with stable angina) remain a clinical concern. When treating patients with stable angina pectoris, it must be recognized that none of the nitrate preparations or formulations can provide round-the-clock antianginal or antiischemic prophylaxis. In these patients, beneficial antianginal and antiischemic effects of nitrates for 10-14 hours during the daytime can be maintained by using formulations and dosing regimens that avoid or minimize the development of tolerance (standard formulation of isosorbide-5-mononitrate, 20 mg in the morning and 7 hours later; slow-release formulation of isosorbide-5-mononitrate, 120-240 mg once a day; or nitroglycerin patch delivering 0.6 nitroglycerin per hour for 10-12 hours each day). Only the patch on and off treatment is associated with nitrate rebound. Although intermittent nitrate therapy is not associated with the development of tolerance, this strategy cannot be recommended for treating unstable angina because rebound angina during nitrate-free periods complicates clinical decision making. In the acute phase of unstable angina, continuous treatment with intravenous nitroglycerin is recommended because it permits rapid up- or down-titration. Tolerance towards antianginal and antiischemic effects does develop in a substantial number of patients with 24 hours, but this can be overridden by dose escalation and restoration of the therapeutic effectiveness of nitroglycerin. Tolerance towards the beneficial effects of nitrates on hemodynamics and on exercise performance also develops rapidly during continuous or long-term nitrate therapy, and for these reasons nitrates are not used as first-line therapy to treat chronic heart failure. In combination with hydralazine, high-dose isosorbide dinitrate (30-40 mg four times a day) improves survival, but this combination therapy is inferior to ACE inhibitors.
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PMID:Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure. 911 Jan 17

A randomized, double-blind, crossover study tested the antiischemic and antianginal efficacy of felodipine, extended-release 5-10 mg, versus amlodipine, 5-10 mg once daily. Fifty-two patients with documented exercise-induced angina pectoris and myocardial ischemia during 24-h electrocardiographic monitoring were included in the study. Forty-seven patients completed the 8-week treatment period, whereas five patients withdrew from the study. The mean number of ischemic episodes/24 h was reduced from 19.9 at baseline to 2.3 during amlodipine and to 2.4 during felodipine; the total duration of ischemic episodes decreased from 69.8 min/24 h to 15.2 min and 15.5 min during amlodipine and felodipine, respectively (for both variables, p = 0.83 and p = 0.53 between treatments, and for both treatments, p < 0.001 compared with baseline). Eighteen (38%) patients receiving amlodipine and 19 (40%) patients receiving felodipine showed no ST-segment depression during treatment. Maximal ST-depression was reduced from an average of 2.1 mm to 1.1 and 1.2 mm on amlodipine and felodipine, respectively (p = 0.68 between treatments and p < 0.001 compared with baseline). Mean heart rate remained unchanged compared with baseline. Anginal attacks were reduced from 16.4/week at baseline to 4.7/week with amlodipine and to 4.3/week with felodipine (p = 0.26 between treatments, and p < 0.001 vs. baseline). Accordingly, nitrate consumption was reduced from 14.7 capsules per week to 4.0 and 3.8 with amlodipine and felodipine, respectively (p = 0.40 between treatments, and p < 0.001 compared with baseline). Adverse reactions were infrequent and distributed similarly between the two treatments. It is concluded that both drugs effectively reduced ischemic episodes and anginal attacks and were well tolerated in patients with stable angina pectoris. There was no evidence that the two regimens were different in their antiischemic and antianginal properties.
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PMID:Felodipine and amlodipine in stable angina pectoris: results of a randomized double-blind crossover trial. 915 63

The underlying mechanisms of myocardial ischemia in microvascular angina may include endothelial dysfunction, abnormal smooth muscle tone, and abnormal autonomic control of coronary microvasculatures. This randomized, double-blind, placebo-controlled, crossover study was conducted to evaluate the effect of nicorandil (a nitrate-potassium channel opener) therapy on exercise-induced myocardial ischemia and cardiac autonomic activity in 13 patients with microvascular angina. After a 2-week placebo run-in period, patients were randomly assigned to the first 2-week treatment with nicorandil 5 mg tid or placebo, then crossed over to the second 2-week treatment after a 2-week washout period. Treadmill exercise tests and 24-hour ambulatory electrocardiogram monitoring were performed at the end of each treatment phase. The results showed that both time to 1-mm ST depression and total exercise duration were significantly prolonged with nicorandil treatment compared with placebo (p = 0.026 and 0.036, respectively). Maximum exercise ST depression also tended to be less with nicorandil treatment than with placebo (p = 0.083). Compared with 10 healthy control subjects, study patients had significantly reduced heart rate variability in both low- and high-frequency bands while receiving placebo. Nicorandil treatment did not change the altered heart rate variability in either time domain or spectral analysis. Systemic hemodynamics were also unchanged with nicorandil treatment. Thus, 2-week oral nicorandil therapy moderately improved exercise-induced myocardial ischemia without modifying the already altered cardiac autonomic activity, suggesting that nicorandil might have a direct vasodilatory effect on coronary microvasculatures in patients with microvascular angina.
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PMID:Effects of short-term treatment of nicorandil on exercise-induced myocardial ischemia and abnormal cardiac autonomic activity in microvascular angina. 920 16

The predominant venodilator properties of the nitrates and their augmentation of collateral coronary blood flow to the ischemic myocardium endows them with some ideal characteristics for treating myocardial ischemic syndromes. Additional efficacy stems from the ability of the nitrates to replenish the deficient endothelium-derived relaxing factor (EDRF), nitric oxide (NO), in patients with coronary heart disease and also to inhibit platelet aggregation. In stable angina pectoris, the antianginal and antiischemic effects of oral nitrates are well established. Continuous administration of nitrates may lead to tolerance of their clinical efficacy. Recent studies, however, have demonstrated that when used in recommended doses, tolerance can be avoided during long-term treatment with oral nitrates without provocation of anginal attacks during periods of low nitrate levels at night and early hours of the morning. Thus, prolonged treatment with an asymmetric twice-daily regimen of immediate-release isosorbide-5-mononitrate in patients with stable angina pectoris does not give rise to clinical tolerance, prolongs exercise duration, and delays the onset of myocardial ischemia. In unstable angina pectoris, nitrates rapidly relieve chest pain and ameliorate the electrocardiographic signs of myocardial ischemia. In patients with acute myocardial infarction, early treatment with nitrates prevents left ventricular dilatation, improves pumping function, and reduces the risk of ventricular arrhythmias. In patients with chronic heart failure, oral nitrates improve exercise tolerance and, when given in combination with the systemic arterial dilator hydralazine, extend survival. Meta-analysis of published studies has demonstrated that both intravenous and oral nitrates reduced infarct size and morbidity and mortality in patients with acute myocardial infarction. In the ISIS 4 post-infarction study, isosorbide-5-mononitrate 60 mg once daily was not superior to placebo in reducing mortality risk. However, in the GISSI 3 study, the combination of nitrates with an angiotensin-converting enzyme (ACE) inhibitor reduced mortality risks by 17% in patients with acute myocardial infarction. In both the ISIS 4 and GISSI 3 studies, 62% and 57% of the patients in the placebo and control groups, respectively, were treated with nitrates for control of rest angina, myocardial ischemia, and or left ventricular failure symptoms, and this widespread use of open-label nitrates in the control groups may have diluted the true beneficial effects of nitrates in both studies. Taken together, these many studies with oral nitrate treatment in coronary heart disease and heart failure clearly emphasize that these drugs are safe and play more than a symptomatic role in the management of patients with acute and chronic ischemic syndromes due to coronary artery disease.
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PMID:Oral nitrates: more than symptomatic therapy in coronary artery disease? 921 Oct 13

The efficacy of antianginal agents in the treatment of patients with chronic stable angina has traditionally been evaluated by performance measures, such as the exercise treadmill test (ETT). Although reliable and reproducible, ETT is not a sensitive measure of changes in myocardial ischemia. The effects of antianginal agents on coronary blood flow and myocardial perfusion have been less frequently studied. Angiographic studies have demonstrated that nitrates may operate by preferentially directing blood flow to ischemic regions of the myocardium. These investigations have been limited, however, by the invasive nature of the evaluation. Measurements of regional myocardial perfusion may also be made with noninvasive tests. Both quantitative single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have been employed, but few studies have used these techniques to assess the effects of antianginal drugs (in general) and nitrates (in particular) on changes in reversible myocardial perfusion defects. Studies that have evaluated the direct effects of nitrate treatment on coronary blood flow and myocardial perfusion defects in patients with chronic stable angina are reviewed, and preliminary data from a study of the effects of long-term nitrate treatment on myocardial perfusion are discussed.
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PMID:Achieving sustained improvement in myocardial perfusion: role of isosorbide mononitrate. 922 55

Angina pectoris due to coronary artery disease is a common manifestation of myocardial ischemia. Reduction of oxygen demand (beta-blockers) and relief of coronary vasoconstriction (calcium blocker or nitrate) are additive approaches to controlling ischemia. Risk factor reduction may improve coronary vascular physiology, and ASA reduces the likelihood of thrombosis and myocardial infarction. It is still unclear whether reduction of angina reduces cardiac morbidity and/or mortality. In the Asymptomatic Cardiac Ischemia Pilot Study (ACIP) and Total Ischemic Burden Bisoprolol Study (TIBBS) trials, data suggest benefit from reducing myocardial ischemia. Thus control of angina pectoris is a major goal of the treatment of coronary artery disease.
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PMID:Optimal treatment of stable angina. 939 90

Pravastatin, a hydrophilic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, has been reported to beneficially affect atherogenesis, plaque stability, and transient myocardial ischemia in significant coronary artery disease by influencing lipid metabolism and by intracellular signaling via mevalonate pathway products other than cholesterol. Leukocytes are implicated to play a pathophysiological role in these events. We were interested in finding out whether pravastatin could affect transendothelial migration (TEM), chemotaxis, and respiratory burst activity of the neutrophil ex vivo. In addition, effects on monocyte and T-lymphocyte chemotaxis were tested. For TEM assays, monolayers of human umbilical vein endothelial cells (HUVECs) were grown to confluence on polycarbonate filters bearing 5-microns pores in Transwell (Costar) culture plate inserts. Chemotaxis experiments were performed using modified Boyden chambers with cellulose nitrate micropore filters. Respiratory burst activity was measured fluorometrically. Treatment of neutrophils and monocytes with pravastatin at 2 to 200 mumol/L and 10 to 1000 mumol/L, respectively, significantly decreased chemotaxis triggered by fMet-Leu-Phe. This effect was abolished in the presence of mevalonic acid (500 mumol/L); no effect of pravastatin was seen on T-lymphocyte chemotaxis triggered by interleukin-8. Preincubation of neutrophils with pravastatin (200 mumol/L) also resulted in a significant reduction in the number of neutrophils that transmigrated a tumor necrosis factor-stimulated or lipopolysaccharide-stimulated HUVEC monolayer. At none of the concentrations tested (2 pmol/L to 200 mumol/L) did pravastatin affect neutrophil respiratory burst activity. We conclude that pravastatin may alter monocyte chemotaxis and neutrophil-endothelial interactions in migratory responses at concentrations obtained in vivo with cholesterol-lowering doses.
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PMID:Mevalonate-dependent inhibition of transendothelial migration and chemotaxis of human peripheral blood neutrophils by pravastatin. 940 Mar 76


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