Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the United States, there may be as many as two million totally asymptomatic men with silent myocardial ischemia due to coronary artery disease. Because detection of such patients is often fortuitous, a rigorous screening protocol has been suggested for high-risk subgroups (i.e., persons with multiple coronary risk factors and/or family histories of premature coronary artery disease). At present, the initial procedure of choice for a screening protocol is the exercise test, followed by radionuclide procedures to differentiate true-positive from false-positive responses if coronary angiography is being considered. Holter monitoring is useful in documenting out-of-hospital ischemic events in asymptomatic patients with documented coronary artery disease. Prognostic studies in patients with and without coronary angiographic data indicate that asymptomatic patients with an ischemic ST-segment depression on exercise tests comprise a high-risk subgroup that has a well-defined morbidity and mortality due to future cardiac events. The angiographic surveys show that the greatest risk is in those individuals with more extensive disease. Treatment in asymptomatic persons requires the use of objective measurements as end points. Several reports have demonstrated the efficacy of beta-blockers, calcium channel blockers, and coronary angioplasty in this population, at least so far as reducing total ischemic activity is concerned. How nonsurgical therapy will affect ultimate prognosis is still unclear. However, surgical therapy in asymptomatic patients with left main coronary artery disease and triple-vessel disease has been reported to improve long-term survival.
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PMID:Should silent ischemia be treated in asymptomatic individuals? 220 61

1. The effects of the phorbol ester, phorbol myristate acetate (PMA) were examined on function and energy metabolism in the isolated working heart of the rat. 2. At a concentration of 10(-9) M PMA produced a rapid loss in cardiac function in terms of aortic flow rate (AFR) and coronary flow rates (CFR) whereas a similar concentration of 4 alpha-phorbol 12,13-didecanoate was ineffective. At a concentration of 10(-10) M, the PMA-induced depression was more gradual but nevertheless very pronounced with an almost total loss in AFR after 30 min perfusion. The reduction in CFR was more moderate than that observed with respect to AFR. 3. The protein kinase C (PKC) inhibitor (+/-)-1-O-hexadecyl-2-O-acylglycerol significantly attenuated the loss in AFR and CFR following addition of PMA. 4. Two inhibitors of Na+/H+ exchange, amiloride and quinacrine, totally prevented the reduction in AFR. Although the PMA-induced depression in CFR was also attenuated by both amiloride and quinacrine, these effects were not significant, probably reflecting the less pronounced effect of PMA on this parameter. 5. Nifedipine, a dihydropyridine calcium channel blocker reduced PMA toxicity to a similar degree as Na+/N+ exchange inhibition whereas the calcium channel agonist Bay K 8644 was without effect. 6. Tissue content of energy metabolites including high energy phosphates, total adenine nucleotides or lactate were not significantly affected by PMA perfusion. 7. We conclude that PKC activation is necessary for phorbol ester-induced cardiac dysfunction. The consequence of PKC stimulation includes (1) Na+/H+ exchange activation and a subsequent elevation in intracellular calcium [Ca2+]i via Na+/Ca2+ exchange and (2) PKC-dependent phosphorylation of the calcium channel, both of which would produce toxicity by elevation of [Ca21]i. Pharmacological manipulation of any of these steps prevents PMA toxicity by virtue of a reduction in the accumulation of [Ca21]i. PMA effects or their prevention are unrelated to any changes in energy metabolism.
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PMID:Mechanisms for cardiac depression induced by phorbol myristate acetate in working rat hearts. 220 2

The programmed onset of myocardial dysfunction and its progression to congestive heart failure in the cardiomyopathic Syrian hamster is hallmarked by alterations in myocellular calcium regulation. To determine whether calcium channel blockade is effective in halting the progressive depression of myocardial contractile performance in this animal model of congestive heart failure, oral verapamil therapy was instituted at 50 days of age, and treatment continued for various durations until the time of study at either 150 or 250 days of age. Left ventricular papillary muscle isometric and isotonic performance, as well as transmembrane electrical characteristics, was depressed in diseased hamsters at 150 days of age and deteriorated further by 250 days of age. These changes were evidenced by prolongation of contraction duration, a marked depression in the load-velocity relation, and a significant prolongation in the repolarization phase of the transmembrane action potential. Myocardial functional and electrical alterations associated with the progression of life in myopathic hamsters were completely halted by verapamil therapy that was continuous from 50 days after birth until death by diastolic arrest, at 150 or 250 days of age. However, premature termination of verapamil treatment before death resulted in a progressive renewal of the functional and electrical alterations for the duration of drug termination. It is concluded that the pathological changes seen during the lifetime of the cardiomyopathic hamster can be prevented by continuous calcium channel blockade and that intermediate prevention can be attained by protracted verapamil therapy. Thus, chronic verapamil therapy may be a useful adjunct in the prevention of human congestive heart failure of similar etiology.
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PMID:Chronic calcium channel blockade prevents the progression of myocardial contractile and electrical dysfunction in the cardiomyopathic Syrian hamster. 224

The effect of two calcium channel inhibitors, diltiazem and nifedipine in animal models of depression: a) behavioral despair test and b) behavioral deficit produced by uncontrollable footshock was investigated. Additionally, the influence of both drugs on mouse killing (muricide) behavior induced by chronic isolation was studied. Both drugs given in single doses increased the active behavior of rats in behavioral despair test. Nifedipine but not diltiazem was partially effective in the test when administered chronically (14 days). Both drugs also attenuated stress-induced behavioral depression in the open field and forced swim test. Diltiazem was markedly more active in the former whereas nifedipine in the latter test. Neither compound influenced killing behavior in muricidal rats. Our data support the notion that calcium channel inhibitors may possess antidepressant activity, although there appear to exist certain differences in their scope of action depending on the model applied.
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PMID:Activity of diltiazem and nifedipine in some animal models of depression. 227 70

We have used a resting (5 mM K+) or depolarizing (60 mM K+) choline-based medium, and a nondepolarizing sodium-based or choline-based medium, to characterize the inhibitory potential of tricyclic antidepressants against the voltage-dependent calcium channels or the Na(+)-Ca2+ exchange process, respectively, in synaptosomes from rat brain cortex. Imipramine, desipramine, amitriptyline, and clomipramine inhibited net K(+)-induced 45Ca uptake with similar IC50 values (26-31 microM), and this uptake was also inhibited by diltiazem with an IC50 of 36 microM; these results indicate an inhibition of voltage-dependent calcium channels by tricyclic antidepressants. The net uptake of 45Ca induced by Na(+)-Ca2+ exchange was also inhibited by the four tricyclic antidepressants tested, but not by diltiazem; imipramine (IC50 = 94 microM) was a more potent inhibitor of this process than desipramine (IC50 = 151 microM), and the IC50 values of amitriptyline (107 microM) and clomipramine (97 microM) were similar to that of imipramine. Some degree (approximately 25%) of brain calcium channel blockade could be present at the steady-state concentrations of tricyclic antidepressants expected to occur therapeutic use of these compounds to treat depression or panic disorder.
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PMID:Tricyclic antidepressants inhibit voltage-dependent calcium channels and Na(+)-Ca2+ exchange in rat brain cortex synaptosomes. 228 85

Prolonged depression of segmental systolic thickening after brief coronary artery occlusion may result principally from events during reperfusion rather than during the ischemic interval. Thus, cellular calcium overload at reperfusion may be a mediator of contractile dysfunction after brief ischemia, and reduction of calcium entry by diltiazem, a calcium channel antagonist, may enhance recovery of systolic thickening after brief periods of ischemia. Thirteen awake unsedated dogs instrumented with hemodynamic catheters, left anterior descending coronary artery occluders and five to six pairs of intramyocardial sonomicrometers underwent two 15 min coronary artery occlusions with 24 h reperfusion. The order of infusion of diltiazem (15 micrograms/kg per min) or saline solution was alternated. Systolic thickening, hemodynamic variables and regional myocardial blood flow were measured serially over 24 h. Despite equally severe ischemic dysfunction during coronary occlusion, diltiazem-treated segments with systolic thinning during ischemia recovered control segmental thickening significantly earlier than saline solution-treated segments (at 30 versus 180 min of reperfusion). Blood pressure was mildly decreased during diltiazem treatment; therefore, a second group of 10 dogs underwent a similar occlusion and reflow period during infusion of nitroprusside to lower mean arterial pressure equivalently. Decreases in blood pressure in this group resulted in some improvement in segmental systolic function; however, this did not reach statistical significance at any time. Regional myocardial blood flows were similar in the saline solution- and diltiazem-treated groups during ischemia and reflow. Thus, it is concluded that 1) diltiazem infusion significantly enhanced recovery of segmental systolic thickening after 15 min of ischemia and 24 h of reperfusion; 2) the enhancement in segmental systolic function could not entirely be attributed to decreased mean arterial pressure; 3) improvement in postischemic segmental ventricular function was seen only in those segments with systolic thinning during ischemia; thus, segments with the most severe ischemic dysfunction benefited most; and 4) there were no important differences in regional myocardial blood flow during ischemia and reperfusion between saline- and diltiazem-treated animals.
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PMID:Differential enhancement of postischemic segmental systolic thickening by diltiazem. 230 44

Moderate alcohol intoxication in man, a ubiqitious social event, causes acute but reversible myocardial depression, the mechanism of which is unknown. We investigated whether this depression could be due to a direct effect of ethanol on the process of electromechanical coupling by simultaneously measuring the transmembrane action potential and contraction, or the cytosolic calcium transient (via aequorin photoluminescence) and contraction in isolated ferret right ventricular papillary muscle. Ethanol, in concentrations that are similar to plasma levels in man during intoxication (0.15 vol %), depressed the force of contraction approximately 10%. The step in the electromechanical process that was affected appeared to be the calcium-myofilament interaction, as there was no change in the transmembrane action potential or cytosolic calcium transient. This inhibition was quickly reversed by removal of the ethanol from the perfusate. On the other hand, higher concentrations of ethanol produced changes in contraction, the calcium transient, and the action potential, suggesting multiple levels of inhibition of electromechanical coupling. Increasing the perfusate calcium or use of the calcium channel agonist, BAY-K 8644, increased cytosolic calcium to near maximum but had little effect on contractility, confirming that the relationship between calcium and the myofilaments had been altered. These data suggest that the acute depression in ventricular function seen with alcohol consumption may be due to a direct effect on electromechanical coupling through inhibition of the calcium myofilament interaction.
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PMID:Mechanism of myocardial contractile depression by clinical concentrations of ethanol. A study in ferret papillary muscles. 233 1

To investigate the mechanism of antianginal action of the calcium channel blocker nisoldipine and to determine the reproducibility of the clinical and hemodynamic events induced by supine leg exercise, 30 patients with stable effort angina pectoris were studied. They were divided into two groups; one group of 19 patients received a single 10-mg dose of nisoldipine orally, and the other group of 11 patients received a single dose of placebo orally. Chest pain was induced in all of 30 patients during the control exercise test. After nisoldipine administration, chest pain was not induced in 13 of 19 patients and was of lessened severity in five patients with the same work load as those performing control exercise. ST segment at peak exercise showed less severe depression after nisoldipine. Systemic vascular resistance was reduced by 38% (p less than 0.001) at rest and 22% (p less than 0.001) at peak exercise, and coronary vascular resistance was reduced by 31% (p less than 0.01) at rest and 18% (p less than 0.01) at peak exercise. Pulmonary artery wedge pressure fell from 6 +/- 1 to 3 +/- 1 mm Hg (p less than 0.001) at rest and from 28 +/- 3 to 11 +/- 2 mm Hg (p less than 0.001) at peak exercise. Coronary sinus flow at rest and myocardial oxygen uptake both at rest and during exercise was not modified by nisoldipine. However, coronary sinus flow at peak exercise increased significantly from 219 +/- 24 to 249 +/- 31 ml/min (p less than 0.01) after nisoldipine, and myocardial oxygen uptake was not significantly changed despite decreased coronary vascular resistance. The clinical and hemodynamic events induced by the exercise during invasive studies (except pulmonary artery wedge pressure at rest) were reproducible after placebo administration. Our data demonstrate that increased coronary blood flow could be the major mechanism of the antianginal action of nisoldipine in supine leg exercise-induced angina.
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PMID:Hemodynamic mechanisms of antianginal action of calcium channel blocker nisoldipine in dynamic exercise-induced angina. 234 82

We have studied the effects of the calcium channel blockers verapamil, diltiazem and nifedipine and the volatile anaesthetics halothane, enflurane and isoflurane on myocardial metabolism after postischaemic reperfusion in the rat isolated heart-lung preparation. In the presence of the volatile anaesthetics, the preparations were perfused for 10 min, made globally ischaemic for 8 min, and then reperfused for 10 min. Each of the calcium blockers was administered 5 min before ischaemia. Three hearts in the halothane-verapamil group (n = 10) failed to recover from the ischaemia and the recovery time in the same group was significantly longer than in the enflurane-verapamil or isoflurane-verapamil groups. Although there was no significant difference in myocardial lactate concentrations among the groups, ATP and glycogen contents in the halothane-verapamil group were significantly less than those in the other groups. The results suggest that the combination of halothane and verapamil causes significant myocardial depression during recovery from ischaemia and subsequent metabolic deterioration.
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PMID:Interaction between calcium channel blockers and volatile anaesthetics in the rat heart-lung preparation. 235 99

In the experiments on Wistar rats with pain syndrome of spinal origin (PSSO) caused by the generator of pathologically enhanced excitation (GPEE) in dorsal horns of the spinal cord lumbosacral segments, it was shown that the intravenous verapamil injection (1.25 mg/kg) undoubtedly decreased behaviour response and improves the state of microcirculation. The compound of 10-fold decreased dose does not affect the behaviour response and microcirculation. When PSSO exists, the intravenous injection of analgin (150 mg/kg) produced an effect on the behaviour response and does not produce any action on microcirculation. When verapamil reaches the dorsal surface of the spinal cord (GPEE area) it decreases the behaviour response and microcirculation disorders created in PSSO. The obtained data make it clear that the GPEE depression caused by the verapamil calcium channel blocker weakens PSSO and normalizes the microcirculation.
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PMID:[Effects of verapamil on behavioral and microcirculatory disorders in pain syndrome of spinal etiology]. 237 46


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