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Query: KEGG:D01849 (Cardiovasc)
 199,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the role of platelet-activating factor (1-O-hexa-decyl-2-acetyl-sn-glyceryl-phosphoryl-choline, PAF) in myocardial ischemic and reperfusion-induced injury, the effects of a PAF receptor antagonist (WEB 2086) were studied in an anesthetized canine model of ischemia (90 min) and reperfusion (6 h). Thirty minutes after onset of ischemia, WEB 2086 was administered as a bolus (20 mg/kg intravenously, i.v.) followed by a continuous 6-h infusion (10 mg/kg/h i.v.). Controls received vehicle alone (0.9% saline). Platelet aggregation was studied at baseline and at 1, 2, 4, and 6 h of drug administration and at the end of the reperfusion period. WEB 2086 treatment did not significantly affect platelet aggregation stimulated by ADP or arachidonic acid (AA). After 1 h of drug infusion, the ex vivo aggregatory response to exogenous (200 nM) PAF was ablated in WEB 2086-treated animals. WEB 2086 administration did not affect heart rate (HR) or mean arterial blood pressure (MAP) during the occlusion or reperfusion phases. During reperfusion of the ischemic tissue, left circumflex coronary artery (LCX) blood flow of WEB 2086-treated animals increased (p < 0.05) above control value. The area of the left ventricle at risk of infarct was not different between control and WEB 2086-treated groups. Infarct size was not significantly reduced in WEB 2086-treated animals. The results of our investigation using a 90-min ischemic period followed by 6-h reperfusion show that pharmacologic antagonism of PAF by WEB 2086 does not protect the heart against ischemia and reperfusion-induced injury.
J Cardiovasc Pharmacol 1992 Dec
PMID:Inhibition of platelet-activating factor fails to limit ischemia and reperfusion-induced myocardial damage. 128 5

The beneficial effects of calcium-channel blockers against myocardial stunning have been tested in experimental studies, showing that, when added before or during ischemia, a protective effect against postischemia stunning is achieved. The present study was undertaken to test and compare the protective effect of calcium antagonists [nisoldipine (NIS) and nifedipine (NIF)] and nitrates (NIT) against myocardial stunning in patients with coronary artery disease undergoing percutaneous transluminal coronary angioplasty (PTCA) with prolonged inflation as PTCA represents a model of induced acute and severe ischemia for a brief period and might cause myocardial stunning. The study included 30 patients between the ages of 42 and 67 years, all with exercise-induced angina and single-vessel disease, with severe stenosis (80% to subtotal occlusion) localized on the left anterior descending artery and with the absence of collaterals on the coronary angiograms. Moreover, all patients had normal left ventricular (LV) overall function, as well as normal systolic thickening of the anterior wall, supplied by the diseased artery. Patients were randomized to a pre-PTCA treatment with NIT, 80-120 mg/day (10 patients), NIF, 40-60 mg/day (10 patients), and NIS, 10-20 mg/day (10 patients). Pre-PTCA treatment was initiated 7 days before the procedure and continued after. During the PTCA, at the first balloon inflation, an additional dose of 300 micrograms of NIT was injected into the left anterior descending artery through the balloon catheter in the patients in the NIT group, as well as 0.2 mg of NIF in NIF group patients and 0.05 mg of NIS in NIS group patients.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1992
PMID:Myocardial stunning following coronary angioplasty: protective effects of calcium-channel blockers. 128 9

In the initial seconds after a sudden reduction in coronary blood flow, a temporary mismatch between myocardial energy demand and supply exists. The mechanisms underlying the rapidly ensuing reduction in contractile function in the ischemic myocardium are still unknown. In the presence of some residual blood flow, a state of "perfusion-contraction matching" develops. The metabolic status of such hypoperfused myocardium improves, since myocardial lactate production is attenuated and creatine phosphate (CP), after an initial reduction, returns toward control values. The hypoperfused myocardium responds to inotropic stimulation by dobutamine. The recruitment of an inotropic reserve implies increased energy utilization. During inotropic stimulation, after partial normalization, lactate production is again increased, and CP is decreased again. Thus, a supply-demand imbalance that had been at least partially corrected by the ischemia-induced decrease in regional contractile function is precipitated again. A situation of chronic contractile failure in viable myocardium that normalizes upon reperfusion has been termed myocardial "hibernation." Myocardial "stunning" is characterized by a reversible postischemic contractile dysfunction despite full restoration of blood flow. The details of the underlying mechanisms are not clear. An inadequate energy supply and impaired sympathetic neurotransmission have been excluded. Potential mechanisms, which are not mutually exclusive, may include (a) damage of membranes by free radicals, (b) an increase in free cytosolic calcium during ischemia and reperfusion, and (c) a decrease in the calcium sensitivity of the myofibrils. The equally pronounced increases in regional contractility in normal and "stunned" myocardium during postextrasystolic potentiation and the infusion of calcium or the calcium-sensitizing agent AR-L-57, however, suggest an unchanged calcium sensitivity of reperfused myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1992
PMID:Characterization of "hibernating" and "stunned" myocardium with focus on the use of calcium antagonists in "stunned" myocardium. 128 10

Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([CA2+]i). The present study was designed to determine the effects of the calcium antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with buffer containing 10(-8) M nisoldipine. From the left ventricular developed pressure, the time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i from 0.35 to 0.81 microM and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function (Fig. 1). Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM and in systolic [Ca2+]i to 0.77 microM and lessened the decrease in contractile function. Nisoldipine significantly accelerated the decline in [Ca2+]i during reperfusion and improved recovery of contractility and relaxation. These effects were associated with a significant diminution in ischemic lactate production. Taken together, our results provide direct quantitative evidence on a beat-to-beat basis that the calcium antagonist nisoldipine can ameliorate ischemia-induced abnormalities in [Ca2+]i handling, an effect that was associated with improved myocardial function during early reperfusion.
J Cardiovasc Pharmacol 1992
PMID:Ventricular function and calcium handling during ischemia. 128 12

There are several potential outcomes of myocardial ischemia. When ischemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. When myocardial ischemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function. Under these conditions, reperfusion restores complete contractile performance. This type of ischemia, leading to a reversible, chronic left ventricular dysfunction, has been termed hibernating myocardium. The difference between this condition and that described before, i.e., prolonged ischemia, which results in further damage on reperfusion, is, most likely, related to residual coronary flow. In the hibernating myocardium, which is always supplied by a narrow coronary artery, blood flow is not low enough to cause progression toward tissue necrosis, but it is low enough to cause pH changes that, in turn, are responsible for the downregulation of myocardial contractility. The level of underperfusion is sufficient to maintain aerobic metabolism of the quiescient myocardium as demonstrated by the absence of lactate and creatine phosphokinase release. There are no doubts that revascularization is essential for hibernated myocardium, and the clinical goal to achieve is the possibility of accurately distinguishing viable from infarcted tissue. A third possible outcome of myocardial ischemia is a postischemic ventricular dysfunction or myocardial stunning. This term describes a transient mechanical dysfunction that persists on reperfusion after a short period of ischemia, despite the absence of irreversible damage. There are numerous clinical conditions in which stunning might manifest.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1992
PMID:Stunned and hibernating myocardium: possibility of intervention. 128 14

Endothelium-dependent vasodilation is reduced in essential hypertensive subjects. To evaluate whether this abnormality is a primary defect or is a consequence of blood pressure increment, in offspring of essential hypertensive and normotensive subjects (n = 13 subjects for each group) matched for age, sex, body weight, and blood pressure, we studied the response of forearm vasculature to acetylcholine (ACh) (an endothelium-dependent vasodilator), sodium nitroprusside (a direct vasodilator of vascular smooth muscle), and forearm ischemia (13 min plus 1 min of exercise) to induce maximal vasodilation. Drugs were infused into the brachial artery at cumulative doses (ACh: 0.15, 0.45, 1.5, 4.5, and 15 micrograms/100 ml of forearm tissue/min; sodium nitroprusside: 1, 3, and 10 micrograms/100 ml of forearm tissue/min) while forearm blood flow was measured by strain-gauge venous plethysmography. The intra-arterial blood pressure and heart rate were continuously monitored. Despite a comparable forearm vascular response to sodium nitroprusside and to forearm ischemia, the effect of ACh was significantly (p < 0.001) reduced in offspring of hypertensive subjects compared to the offspring of normotensive subjects. These data indicate that ACh-mediated forearm vasodilation is reduced in normotensive subjects with a familial history of essential hypertension, a finding that suggests that endothelium dysfunction can precede the appearance of hypertension and that this abnormality might play a role in the pathogenesis of essential hypertension.
J Cardiovasc Pharmacol 1992
PMID:Endothelium-dependent forearm vasodilation is reduced in normotensive subjects with familial history of hypertension. 128 67

Immunoreactivity for vasoactive peptides [endothelin (ET); calcitonin gene-related peptide (CGRP); atrial natriuretic peptide (ANP); neuropeptide Y (NPY)] was investigated in nervous tissue of Mongolian gerbils in which the common carotid artery (CCA) was temporarily occluded (30 min-4 h) on one side, provoking transient unilateral ischemia at the forebrain level. Observations were carried out in a group of animals that were perfused promptly after CCA reopening, and in a group of animals that were perfused 12 h later. In animals of the first group, darker immunostaining was usually observed for most peptides in the forebrain ipsilateral to the CCA occlusion. Computer-assisted densitometric analysis showed that the asymmetry was relevant for ET, CGRP, and ANP, and almost undetectable for NPY. In animals of the second group, areas of tissue degeneration were observed. In these areas, ET immunoreactivity was markedly denser, whereas immunoreactivity for the remaining peptides was about at the background level. It is concluded that ischemia induces an increase in both vasoconstrictor and vasodilator peptides that in areas of moderate ischemia might maintain a residual tissue perfusion. In areas of severe hypoxia, a predominant ET-induced vasoconstriction would contribute to tissue damage.
J Cardiovasc Pharmacol 1992
PMID:Ischemia-induced changes in the immunoreactivity for endothelin and other vasoactive peptides in the brain of the Mongolian gerbil. 128 82

Coronary heart disease is the most frequent cause of death in Western, industrialized countries. Coronary risk factors are prevalent in such countries and sometimes combine to constitute the so-called syndrome X--hypertension, central obesity, serum lipid and clotting disturbances, and insulin resistance. beta-Blockers, unlike calcium antagonists, have proved highly effective in secondary prevention of myocardial infarction. If present at the time of the myocardial infarction, beta-blockers (unlike calcium antagonists and diuretics) probably decrease mortality 1 month later. Early intervention (within 12 h) of chest pain with intravenous beta-blockers results in a 15% reduction in cardiovascular mortality at 1 week. Later intervention (3-28 days) with oral non-ISA beta-blockers results in a 30% reduction in mortality after 1 year; ISA-containing beta-blockers are probably less effective (less decrease in heart rate). Hydrophilicity/lipophilicity of beta-blockers is unimportant in terms of decreased mortality. Primary prevention of myocardial infarction, unlike stroke, in hypertensive patients has been disappointing, possibly due to treatment-induced biochemical/lipid changes or inappropriate lowering of diastolic blood pressure in high-risk subjects (J-curve effect). beta-Blockers should be first-line therapy for hypertensive patients up to the age of 65 years, particularly men (and nonsmokers) as Q-wave myocardial infarction is significantly decreased by beta-blockers and significantly increased by diuretics. However, in elderly hypertensive subjects, beta-blockers have not significantly decreased myocardial infarction (unlike stroke), whereas diuretics have. The effects of beta-blockers and diuretics on heart size (and thus coronary flow reserve) in the elderly may be important. Thus, beta-blockers should be second-line therapy for the elderly hypertensive individual but first-line if overt ischemia (e.g., angina or recent myocardial infarction) also is present. In patients with angina but normal blood pressure, beta-blockers tend to decrease and calcium antagonists increase cardiovascular events. Thus, beta-blockers are highly effective agents in the secondary prevention of myocardial infarction and are moderately effective in primary prevention of myocardial infarction in hypertensive patients (particularly men) under the age of 65 years.
J Cardiovasc Pharmacol 1992
PMID:Beta-blockers: primary and secondary prevention. 128 45

In myocardial infarction, adrenergic stimulation of the heart is thought to cause cell damage and malignant arrhythmias. In rat hearts as well as in human cardiac tissue, ischemia induces norepinephrine (NE) release, which results in micromolar catecholamine concentrations in the interstitial space of the ischemic myocardium. It has been found that local metabolic, rather than centrally evoked NE release, plays the crucial role in excess adrenergic activation of the ischemic myocardium. NE release in ischemia is nonexocytotic and has been characterized as a two-step process. (a) Induced by energy deficiency, NE escapes from its storage vesicles and accumulates in the axoplasm. (b) NE is transported across the plasma membrane into the extracellular space via the neuronal NE carrier (uptake1), which has reversed its normal transport direction because of increased intracellular sodium concentration. NE release induced by ischemia is independent of the presence of calcium in the extracellular space and is not altered by blockade of N-type (neuronal) calcium channels. Furthermore, modulation of protein kinase C does not interfere with NE liberation in the ischemic myocardium. This independence of extracellular calcium, calcium entry into the neuron, and protein kinase C activity is in contrast to the strong calcium dependence of exocytotic transmitter release, which is found under physiological conditions. On the basis of these findings, it was unexpected that calcium antagonists such as gallopamil, verapamil, diltiazem, felodipine, and nifedipine suppress ischemia-induced NE release. The most potent effect was found for gallopamil with a concentration of 50% inhibition (IC50) of 300 nmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1992
PMID:Calcium antagonism and norepinephrine release in myocardial ischemia. 128 51

A number of previous studies have reported that administration of calcium antagonists reduces acute ischemic injury in a variety of experimental models. More recently, however, it has been suggested that the beneficial effects of reperfusing the ischemic myocardium might be blunted by the paradoxical occurrence of a specific form of reperfusion-mediated injury. Although the ultimate mechanisms responsible for this phenomenon have not been completely elucidated, it has been suggested that oxygen radical generation, neutrophil activation, and calcium overload, may all contribute to the development of myocardial damage in postischemic hearts. Several experimental studies suggest that, in addition to their well-known effects on ischemic injury, calcium antagonists may variably affect these mechanisms of reperfusion-mediated cell damage. In particular, evidence has been provided that suggests these drugs may inhibit oxygen radical-mediated peroxidation of membrane lipids and may also reduce activation of stimulated neutrophils. Furthermore, calcium-channel blockers might also prevent calcium overload in reperfused hearts, and they might interfere with reperfusion injury indirectly, secondary to a reduction in the severity of ischemia. From the experimental data available it can be speculated that calcium antagonists might contribute to reducing oxygen radical damage following reflow. At the same time, these drugs may allow the extension of the time window of reperfusion therapy, thus further expanding the benefits of thrombolysis.
J Cardiovasc Pharmacol 1992
PMID:Calcium antagonists and experimental myocardial ischemia reperfusion injury. 128 53


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