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)

Nicorandil is an antianginal drug that exerts both a conventional nitrate effect and an independent ATP-dependent potassium channel-opening effect. The present study examined the effects of nicorandil on left ventricular regional work (RW) during coronary angioplasty in 22 patients with angina pectoris who were scheduled for angioplasty to the left anterior descending artery. The patients were randomly assigned to receive either nitroglycerin (group NG, n=12, 0.5 microg x kg(-1) min(-1)) or nicorandil (group NR, n = 10, 1.5 microg x kg(-1) min(-1)). Inflation was performed for 60 s and the data were collected every 10 s. The RW was derived from the relation between mean wall stress and area strain. The RW of the interventricular septum decreased after balloon inflation and was at its minimum after the 60s inflation (group NR: 1.24 +/- 0.72mJ/cm3, group NG: 0.63 +/- 0.25mJ/cm3). After balloon deflation, the septal RW of both groups increased, and recovered to the baseline condition at about 30s. At 20 s after deflation, the septal RW in group NR (3.58 +/- 1.17 mJ/cm3) was significantly higher than that in group NG (2.25 +/- 0.59mJ/cm3) (p < 0.05). An intravenous infusion of nicorandil led to good recovery of RW from ischemia compared with that obtained with nitroglycerin.
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PMID:Nicorandil infusion leads to good recovery from ischemia of left ventricular regional work in comparison with nitroglycerin. 1238 Oct 90

The disturbances in coronary vasomotor tone have been extensively analyzed, but the exact molecular mechanisms underlying abnormal coronary vasomotion remain to be elucidated. It has been suggested that impaired coronary vasoreactivity can be the expression of a defect in vascular smooth muscle cells. A mouse model of human variant (vasospastic) angina has been recently obtained by disruption of Kir6.1/Kcnj8, a gene coding for a small pore-forming inward rectifier potassium channel. A phenotype resembling variant angina was also reported in mice lacking Sur2, the partner protein of Kir6.1. To better define the role of the smooth muscular ATP-sensitive potassium channels in the pathogenesis of abnormal coronary vasomotion, a complete mutational analysis of Kir6.1/KCNJ8 gene was performed in a series of 18 Italian patients with impaired coronary vasomotility. Polymerase chain reaction and direct sequencing of PCR products were done. No mutations were detected in the sample analyzed, thus suggesting that Kir6.1/KCNJ8 aberrations are not a common cause of abnormal coronary vasomotion in Italians. To the best of our knowledge, this study represents the first mutational analysis of Kir6.1/KCNJ8 gene in humans. Since major racial differences in the prevalence of abnormal coronary vasomotion have been described, further mutation screenings of Kir6.1/KCNJ8 gene are required to assess its role in the pathogenesis of impaired coronary vasomotility among various ethnic groups.
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PMID:Absence of Kir6.1/KCNJ8 mutations in Italian patients with abnormal coronary vasomotion. 1296 27

The basis for life is the ability of the cell to maintain ion gradients across biological membranes. Such gradients are created by specific membrane-bound ion pumps [adenosine triphosphatases (ATPases)]. According to physicochemical rules passive forces equilibrate (dissipate) ion gradients. The cholesterol/phospholipid ratio of the membrane and the degree of saturation of phospholipid fatty acids are important factors for membrane molecular order and herewith a determinant of the degree of non-specific membrane leakiness. Other operative principles, i.e. specific ion channels can be opened and closed according to mechanisms that are specific to the cell. Certain compounds called ionophores can be integrated in the plasma membrane and permit specific inorganic ions to pass. Irrespective of which mechanism ions leak across the plasma membrane the homeostasis may be kept by increasing ion pumping (ATPase activity) in an attempt to restore the physiological ion gradient. The energy source for this work seems to be glycolytically derived ATP formation. Thus an increase in ion pumping is reflected by increased ATP hydrolysis and rate of glycolysis. This can be measured as an accumulation of breakdown products of ATP and end-products of anaerobic glycolysis (lactate). In certain disease entities, the balance between ATP formation and ion pumping may be disordered resulting in a decrease in inter alia (i.a.) cellular energy charge, and an increase in lactate formation and catabolites of adenylates. Cardiac syndrome X is proposed to be due to an excessive leakage of potassium ions, leading to electrocardiographic (ECG) changes, abnormal Tl-scintigraphy of the heart and anginal pain (induced by adenosine). Cocksackie B3 infections, a common agent in myocarditis might also induce an ionophore-like effect. Moreover, Alzheimer's disease is characterized by the formation of extracellular amyloid deposits in the brain of patients. Perturbation of cellular membranes by the amyloid peptide during the development of Alzheimer's disease is one of several mechanisms proposed to account for the toxicity of this peptide on neuronal membranes. We have studied the effects of the peptide and fragments thereof on 45Ca2+-uptake in human erythrocytes and the energetic consequences. Treatment of erythrocytes with the beta 1-40 peptide, results in qualitatively similar nucleotide pattern and decrease of energy charge as the treatment with Ca2+-ionophore A23187. Finally, in recent studies we have revealed and published in this journal that a rare condition, Tarui's disease or glycogenosis type VII, primarily associated with a defect M-subunit of phosphofructokinase, demonstrates as a cophenomenon an increased leak of Ca2+ into erythrocytes.
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PMID:Imbalance of plasma membrane ion leak and pump relationship as a new aetiological basis of certain disease states. 1464 92

A new category of anti-anginal drug - exemplified by ranolazine - is believed to work by partially inhibiting cardiac oxidation of fatty acids; oxidation of glucose requires less oxygen per mol of ATP generated, and thus is preferable to fat oxidation when oxygen availability is limiting in underperfused cardiac tissue. Unfortunately, there is no reason to believe that these drugs inhibit fat oxidation selectively in the heart; thus, chronic use of these drugs can be expected to increase body fat stores until the original rate of fat oxidation is restored by mass action - presumably negating the therapeutic benefit in angina, while exacerbating the manifold adverse effects of insulin resistance syndrome. The rational way to decrease cardiac metabolic reliance on fatty acids is to consume a very-low-fat quasi-vegan diet (i.e., 10% fat calories). Indeed, such diets are known to have a rapid and substantial therapeutic impact on anginal symptoms, while concurrently benefiting insulin sensitivity, markedly improving serum lipid profile, promoting leanness, and lessening coronary risk. A reduction in diurnal insulin secretion might also be achieved, which would be expected to decrease sympathetic activity. While reduced myocardial demand for oxygen doubtless contributes to the beneficial impact of such diets on angina, it is likely that improved cardiac perfusion consequent to improved endothelium-dependent vasodilation also plays a role in this regard. Supplemental carnitine, also beneficial in angina, appears to improve utilization of glucose in the ischemic myocardium by lowering elevated acetyl-coA levels and thereby disinhibiting pyruvate dehydrogenase. Certain other nutraceuticals may aid control of angina by improving endothelial function. In the longer term, these measures have the potential to slow or reverse the progression of stenotic lesions that underlie most cases of angina. These safe and relatively inexpensive nutritional strategies for coping with angina deserve far more attention than orthodox medical practice has thus far accorded them.
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PMID:A shift in myocardial substrate, improved endothelial function, and diminished sympathetic activity may contribute to the anti-anginal impact of very-low-fat diets. 1528 86

Ranolazine was shown to improve exercise parameters in patients with chronic angina. It works by switching myocardial energy metabolism from fatty acids to glucose, thus increasing the efficiency of ATP production under hypoxic conditions. Tumors are hypoxic and may also respond to ranolazine. We found that ranolazine caused a dose-dependent increase in tumor number in APC(Min/+) mice, a model of spontaneous intestinal tumorigenesis. Tumors from drug-treated mice were also more dysplastic and invasive than those from untreated mice. These findings have implications for the use of ranolazine in patients with a history of malignant neoplasms or adenomatous polyps.
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PMID:The anti-ischemia agent ranolazine promotes the development of intestinal tumors in APC(Min/+) mice. 1515 18

Nicorandil, ATP sensitive potassium channel opener, is shown to reduce coronary events for patients with stable angina. The present study was designed to examine the protective potential of nicorandil for patients undergoing off-pump coronary artery bypass grafting. Twenty-four patients undergoing off-pump coronary artery bypass grafting were randomly assigned to two groups, one receiving continuous infusion of nicorandil (1.0 microg.kg(-1).min(-1)) (n = 12) through anesthesia to next day and the other receiving no nicorandil for control (n = 12). For assessing myocardial injury, heart type fatty acid binding protein, troponin T, and creatine kinase MB isoform were determined during the first 15 hours after reperfusion. The concentration of heart type fatty acid binding protein in the nicorandil group was significantly lower than that in the control group. On the other hand, the concentrations of troponin T and creatine kinase MB isoform in the nicorandil group were lower than those in the control group, but the differences did not reach statistical significance. Furthermore, nicorandil did not affect the patients' hemodynamic variables. Our data suggest that the infusion of nicorandil provides small myocardial protection without affecting hemodynamic parameters during perioperative treatment of patients undergoing off-pump coronary artery bypass grafting.
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PMID:Prophylactic effect of intravenous nicorandil on perioperative myocardial damage in patients undergoing off-pump coronary artery bypass surgery. 1545 60

Since Mg(2+)-ATP is the controlling factor for the rate-limiting enzyme in the cholesterol biosynthesis sequence that is targeted by the statin pharmaceutical drugs, comparison of the effects of Mg(2+) on lipoproteins with those of the statin drugs is warranted. Formation of cholesterol in blood, as well as of cholesterol required in hormone synthesis, and membrane maintenance, is achieved in a series of enzymatic reactions that convert HMG-CoA to cholesterol. The rate-limiting reaction of this pathway is the enzymatic conversion of HMG CoA to mevalonate via HMG CoA. The statins and Mg inhibit that enzyme. Large trials have consistently shown that statins, taken by subjects with high LDL-cholesterol (LDL-C) values, lower its blood levels 35 to 65%. They also reduce the incidence of heart attacks, angina and other nonfatal cardiac events, as well as cardiac, stroke, and total mortality. These effects of statins derive less from their lowering of LDL-C than from their reduction of mevalonate formation which improves endothelial function, inhibits proliferation and migration of vascular smooth muscle cells and macrophages, promotes plaque stabilization and regression, and reduces inflammation, Mg has effects that parallel those of statins. For example, the enzyme that deactivates HMG-CoA Reductase requires Mg, making Mg a Reductase controller rather than inhibitor. Mg is also necessary for the activity of lecithin cholesterol acyl transferase (LCAT), which lowers LDL-C and triglyceride levels and raises HDL-C levels. Desaturase is another Mg-dependent enzyme involved in lipid metabolism which statins do not directly affect. Desaturase catalyzes the first step in conversion of essential fatty acids (omega-3 linoleic acid and omega-6 linolenic acid) into prostaglandins, important in cardiovascular and overall health. Mg at optimal cellular concentration is well accepted as a natural calcium channel blocker. More recent work shows that Mg also acts as a statin.
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PMID:Comparison of mechanism and functional effects of magnesium and statin pharmaceuticals. 1546 51

The heart is a pump, but also a furnace able to produce at each moment a large amount of energy and to adapt fast enough to face the changes in both fuel supply and energy demand. The pharmacological treatment of angina has been largely focused on the "pump" through hemodynamic agents aimed at decreasing cardiac effort to decrease energy demand. A new concept arose focusing the "furnace" through metabolic agents aimed at decreasing the oxygen cost of ATP production. This goal can be achieved by shifting energy production from fatty acid beta-oxidation to glucose oxidation. CPT1 inhibitors were developed to prevent the fatty acid entry into mitochondria but induced cardiac hypertrophy. Regulation of carnitine biology either by carnitine supply or by gamma-butyrobetaine hydroxylase inhibitors have led to controversial data both in pharmacological and clinical concerns. Trimetazidine and ranolazine increase the glucose/fatty acid oxidation balance and exhibit beneficial effects in animal studies as well as in clinical trials, both in monotherapy and in association with a traditional hemodynamic drug. The association of metabolic and hemodynamic agents brings additive benefits in angina, whereas associations of hemodynamics do not. The mechanism of these drugs has not been fully understood in terms of specific target. In animal studies, dietary docosahexaenoic acid allowed similar protection, through a mechanism related to membrane conformation without specific enzymic target. From the mechanistic research published in this field, enough has now been understood to foresee some future possible targets, mainly related to the cardiomyocyte fatty acid metabolism.
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PMID:Effectors of fatty acid oxidation reduction: promising new anti-ischaemic agents. 1572 67

The aim of this study was to examine the effect of pharmacological modulation of the ATP-sensitive potassium channels in the development of warm-up angina pectoris. Thirty-one patients with stable angina pectoris, a positive exercise test and angiographically documented coronary artery disease underwent three exercise tests 90 min after receiving either glibenclamide 10.5 mg (an ATP-sensitive potassium channel blocker), pinacidil 25 mg (an ATP-sensitive potassium channel opener) or placebo in a blinded fashion. There was a 30-min recovery period between the first and the second test and 60 min between the second and the third test. The rate-pressure product at 1-mm ST-segment depression (ischemic threshold) and the maximum ST-segment depression (STD) adjusted to the highest rate-pressure product common to the three tests were analyzed. In the placebo group, there was a significant increase in the ischemic threshold during the second and third test and a significant decrease in the maximum adjusted STD during the second test which was lost during the third test. This apparent adaptation to exercise-induced ischemia was not seen in the glibenclamide-treated patients. In the pinacidil-treated patients, there was a paradoxical decrease in ischemic threshold during the second test with no change in maximum adjusted STD which tended to be lower than in the placebo-treated patients on each exercise test. This study confirms that the warm-up phenomenon can be induced during repeated exercise testing. The blockade of this phenomenon by glibenclamide suggests that the ATP-sensitive potassium channels may be involved in this potential protective mechanism. At the same time, the paradoxical response in the pinacidil-treated patients flags a warning that drugs acting on the sarcolemmal ATP-sensitive potassium channels may have a direct effect on the ST-segment that may interfere with the interpretation of the electrocardiogram.
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PMID:Effects of pharmacological modulation of the ATP-sensitive potassium channels on the development of warm-up angina pectoris. 1616 74

Myocardial ischemia is a metabolic problem involving reduced delivery of oxygen to cardiac mitochondria, resulting in less ATP formation, acceleration of glycolysis and production of lactate and H+ by the cell. Traditional therapies for ischemia aim at restoring the balance between mitochondrial ATP production and breakdown by reducing the need for ATP via suppression of heart rate, blood pressure and cardiac contractility, or by increasing oxygen delivery via increased myocardial blood flow. Despite optimal treatment with traditional hemodynamically oriented drugs (beta-adrenergic receptor antagonist, Ca2+ channel antagonist and nitrates), many patients continue to suffer from angina. Thus, there is a need for anti-anginal drugs that act directly on cardiomyocytes to lessen the metabolic abnormalities induced by ischemia and reduce the symptoms (chest pain and exercise intolerance). Ranolazine has been demonstrated to improve exercise time to angina or 1 mm of ST-segment depression in a manner similar to currently approved drugs, but without any significant effects on heart rate or blood pressure at rest or during exercise. In two Phase III trials, ranolazine improved exercise tolerance and reduced the frequency of angina attacks in chronic severe angina patients when administered either as monotherapy or on a background of atenolol, amlodinine or diltiazem. At present, ranolazine is under review for US Food and Drug Administration approval and, if approved, it will represent the first drug of its class in the USA.
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PMID:Ranolazine: new approach for the treatment of stable angina pectoris. 1618 Oct 27


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