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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of verapamil and nifedipine on cellular mechanisms of arrhythmia were examined in isolated canine Purkinje fiber-papillary muscles. Microelectrode recordings were made simultaneously from both tissues. Preparations were superfused with Tyrode's solution modified to mimic specific conditions of ischemia for 40 min with or without calcium channel blockers. Verapamil or nifedipine resulted in significantly greater depolarization of Purkinje tissue in response to ischemic conditions and increased the incidence of inexcitability or conduction block in Purkinje and muscle tissues. These calcium channel blockers caused only minor changes in ischemia-induced depolarization of muscle. In Purkinje tissue, return to nonischemic conditions in the absence of drugs caused, in sequence, oscillatory afterpotentials, temporary depolarization to inexcitability, and a phase of automaticity at low membrane potential. These events did not occur in muscle. Verapamil or nifedipine abolished oscillatory afterpotentials and low membrane potential automaticity in Purkinje tissue. However, reperfusion-induced depolarization and inexcitability of Purkinje tissue was delayed but not attenuated. This study demonstrates that verapamil or nifedipine exacerbate depolarization and depression of conduction in Purkinje tissue exposed to ischemic conditions. However, verapamil and nifedipine suppress some but not all potential mechanisms of arrhythmia induced by reperfusion.
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PMID:Effects of verapamil and nifedipine on mechanisms of arrhythmia in an in vitro model of ischemia and reperfusion. 170 59

The effects of L-type calcium channel blockers and stimulants on naloxone-precipitated withdrawal in mice acutely dependent on morphine were evaluated. Verapamil (10-80 mg/kg), diltiazem (20-120 mg/kg) and nicardipine (20-160 mg/kg), when administered subcutaneously, produced a dose-dependent reduction in forepaw tremor and weight loss during the abstinence reaction; jumping was also reduced by all three drugs, although the effect was not statistically significant in the case of nicardipine. By contrast, the calcium agonist Bay K 8644 (0.5-2 mg/kg, SC) increased forepaw tremor and weight loss, although this latter effect did not reach statistical significance. The effects of the calcium channel active drugs on the rotarod test were also explored, no correlation appearing with the results observed in abstinence (except for the jumping response), which suggests that the withdrawal results are not influenced by motor incoordination or unspecific CNS depression. These findings suggest that L-type calcium channels probably play an important role in withdrawal after acute morphine dependence. Taken together with other observations in chronic models, these results show that calcium channels are similarly involved in morphine abstinence after acute and chronic dependence, in contrast to the differences in the content and uptake of neuronal calcium induced by morphine under both conditions.
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PMID:Differential effects of L-type calcium channel blockers and stimulants on naloxone-precipitated withdrawal in mice acutely dependent on morphine. 171 13

Direct cardiac effects of KT-362 (5-[3 [[-2-(3,4-dimethoxyphenyl)-ethyl]amino]-1-oxopropyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate), a drug that may inhibit intracellular calcium mobilization as well as extracellular calcium influx was compared to verapamil. Guinea pig hearts (n = 19) were used to examine the changes in atrial rate, atrioventricular conduction time (AVCT), coronary flow, myocardial oxygen consumption (MVO2), and isovolumetric left ventricular pressure (LVP). Both drugs concentration-dependently and reversibly decreased atrial rate, contractility, and MVO2; AVCT increased during spontaneous rhythm. The increases in AVCT and the incidence of AV dissociation were accentuated during cardiac pacing. Verapamil significantly increased coronary flow, while KT-362 did not. Median effective concentration (EC50) was about 25 times lower for verapamil in depressing LVP and about three times lower in depressing atrial rate and AV conduction. The changes in calcium channel current in voltage-clamped single canine Purkinje cells (n = 6) were also examined. Verapamil (0.3 microM) and KT-362 (7 microM) decreased peak Ca2+ channel current at maximum activation (+10 mV) by 38.1 +/- 8% and 28.6 +/- 6%, respectively, without shifting the current-voltage relationship. This study indicates that verapamil is more potent than KT-362 in depressing contractile function, heart rate, and AV conduction in isolated hearts and calcium current in isolated cardiac Purkinje cells. Moreover, there was a much greater difference between the EC50 for verapamil and that for KT-362 for the depression of indices of contractility (23-30-fold) than for the depression of sinoatrial and atrioventricular nodal function (2.5-4-fold).
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PMID:Comparative cardiac effects of KT-362 and verapamil in isolated heart--correlation to calcium channel current depression. 172 38

The calcium antagonists are a heterogeneous class of drugs which block the inward movement of calcium into cells through 'slow channels' from extracellular sites. By inhibiting phase 0 depolarisation in cardiac pacemaker cells and phase 2 plateau in myocardium, and by depressing calcium ion flux in smooth muscle cells of blood vessels, these agents may exert profound effects on the cardiovascular system, particularly in susceptible individuals or in overdose. Sinus node depression, impaired atrioventricular (AV) conduction, depressed myocardial contractility, and peripheral vasodilatation may result. Pharmacokinetic features of calcium antagonists include rapid and complete absorption from the gastrointestinal tract, with extensive first-pass hepatic metabolism yielding generally low bioavailability. The volume of distribution is generally large and protein binding is high. Elimination is almost entirely by the liver. Impaired renal function does not affect pharmacokinetics. Verapamil is the most potent inhibitor of cardiac conduction and contractility, with diltiazem also showing such effects. Nifedipine is the most potent vasodilator, but only occasionally impairs the sinus node or AV conduction. Significant pharmacodynamic effects are common during combination therapy with calcium antagonists, especially verapamil and beta-blockers. Verapamil may significantly elevate serum digoxin concentrations and may exert additive negative effects on chronotropism and dromotropism when this combination is used. Overdoses of calcium entry blockers are becoming more frequent and reflect an extension of the known pharmacodynamic profile of these agents. Typical features include confusion or lethargy, hypotension, sinus node depression and cardiac conduction defects. Onset of symptoms may be delayed if a sustained release preparation is ingested. Management of calcium antagonist overdose includes gut decontamination with lavage and activated charcoal. All symptomatic patients and patients with a history of ingesting a sustained release preparation should be admitted for ECG monitoring. If bradycardia and/or conduction defects contribute to hypotension, atropine or isoprenaline (isoproterenol) may accelerate the ventricular rate. Transvenous pacing may be required. Depressed myocardial contractility usually responds well to calcium chloride or calcium gluconate administration, but further inotropic support may be required. Peripheral vasodilation should be managed with intravenous fluids and a pressor agent such as dopamine or norepinephrine (noradrenaline).
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PMID:Poisoning due to calcium antagonists. Experience with verapamil, diltiazem and nifedipine. 179 22

The efficacy and tolerability of sustained release verapamil (Securon SR) was investigated in twenty-four patients with chronic stable angina. Patients entered four randomised, double-blind treatment periods, each lasting one week of verapamil-SR 240 mg once daily, 360 mg once daily, 240 mg twice daily, and matching placebo. Four patients were withdrawn, but in one instance this was attributable to side effects from verapamil. Among the remaining twenty patients, mean frequency of angina fell from 4.25 episodes during the last five days of placebo to 2.35, 2.6 and 1.3 episodes during respective active treatments (all P less than 0.001). Compared with placebo the median percentage increase in time to 1 mV ST depression during treadmill exercise (12 hours post dose) was significant only with the regimen of verapamil-SR 240 mg given twice daily at +11% (P = 0.04). Total duration of exercise was also significantly longer and maximum ST depression significantly less only with the twice daily treatment (704 + 186 sec vs 648 + 203 sec; P = 0.03, and 1.75 + 0.73 mm vs 2.15 +/- 0.62 mm; P = 0.02). Side effects, predominantly constipation, breathlessness, and swollen ankles, occurred most frequently with verapamil-SR 360 mg. Thus, sustained release verapamil is well tolerated and effective in the treatment of angina. A regimen of 240 mg given twice daily emerges as superior to once daily treatments for 24-hour prophylaxis of angina.
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PMID:Double-blind randomised placebo-controlled dose-efficacy study of sustained release verapamil in chronic stable angina. 187 77

Verapamil elimination kinetics and pharmacodynamic effects were studied in 29 healthy individuals (23-81 years of age) after single i.v. doses (0.15-0.22 mg/kg) and during infusions to reach stable plasma verapamil concentrations of 28 +/- 11, 57 +/- 19 and 112 +/- 26 ng/ml (mean +/- S.D.). Aging prolonged verapamil elimination (P less than .008): elimination half-life of 218 +/- 91 min in young (ages 20-39), 280 +/- 78 min in middle-aged (40-59) and 288 +/- 73 min in elderly (greater than 60). After single verapamil doses. 1) heart rate increased with lesser increases in elderly subjects; 2) blood pressure decreased (P = .006) with greater decreases in elderly subjects; 3) spontaneous P-R intervals increased with lesser increases in elderly subjects but, 4) atrioventricular conduction times increased during transesophageal pacing without detectable age differences in responses. During steady-state infusions, 1) heart rate during sinus rhythm was unchanged but atrioventricular dissociation with junctional rhythms developed in elderly subjects (3/9); 2) blood pressure decreased with greater decreases in the elderly; 3) spontaneous P-R intervals increased with lesser increases in the elderly but no age differences in paced P-R interval changes were detected at equivalent verapamil concentrations; 4) heart rate variation (during sinus rhythm) decreased in an age-independent manner as measured by decreases in the S.D. of R-R intervals and decreased power spectral content with greatest changes seen in high frequency (respiratory) content; and 5) heart rate and blood pressure responses to cold pressor and handgrip testing were not attenuated by verapamil. In conclusion, aging prolongs verapamil elimination and alters dynamic responses to verapamil with greater sinus node depression and hypotensive effects in elderly vs. younger subjects. Although less spontaneous P-R interval prolongation was seen on ECG of the elderly vs. young, underlying atrioventricular conduction was prolonged by verapamil independent of age as shown by results when pacing was used to eliminate frequency-dependent effects caused by differing heart rate responses.
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PMID:Aging alters verapamil elimination and dynamics: single dose and steady-state responses. 221 68

Rodent muscles were exposed to several organic calcium antagonists, and mechanical responses to direct electrical stimulation were recorded. Verapamil and D600, at 25 microM, depressed twitch and tetanus tension and caused fading of the tetanus plateau. These effects increased with frequency of stimulation, and were not reversed by doubled extracellular calcium. Depression of tension progressed to complete paralysis after 60-90 min exposure to verapamil. Bepridil and diltiazem both caused depression of tension and tetanus fade. Nifedipine caused marked, and nitrendipine caused slight, potentiation of twitch tension but did not alter tetanic tension. The magnitude of the observed effects on tension (either depression or potentiation) correlated with neither the relative calcium antagonist potencies of the drugs in other tissues nor with the ability of the drugs to cross the cell membrane. The continued decline in tension observed on prolonged exposure indicates that chronic exposure to low levels in vivo might lead to significant muscle weakness.
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PMID:Effects of calcium antagonists on mechanical responses of mammalian skeletal muscles. 241 76

Ventricular action potentials and longitudinal conduction times over short distances of epicardium were recorded in isolated rabbit hearts. Global ischemia produced a progressive decrease of resting membrane potential, depression of action potentials, and conduction slowing to approximately 50% of control values over 8 to 10 min. Verapamil (2 X 10(-6) M) markedly attenuated ischemia-induced conduction slowing in association with less depression of maximum upstroke velocity (Vmax) and slightly less change in resting membrane potential. In contrast, Bay K 8644 (10(-7) M), a calcium-channel agonist, exacerbated ischemia-induced conduction slowing and depression of Vmax but did not significantly affect resting membrane potential. Regression analysis of Vmax vs resting membrane potential and the square of conduction velocity vs Vmax demonstrated that verapamil and Bay K 8644 shifted these relationships in opposite directions. The results indicate that the calcium-channel activation state can modulate slowing of conduction during early ischemia. This is most likely due to alterations in calcium influx before and/or during ischemia. There appear to be three possible components to this effect: (1) a small alteration in the magnitude of ischemia-induced depolarization, (2) alterations of membrane responsiveness at depolarized values of resting membrane potential, and (3) alterations in "nonactive" components of conduction during ischemia, such as changes in excitability or cell-to-cell coupling.
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PMID:Modulation of conduction slowing in ischemic rabbit myocardium by calcium-channel activation and blockade. 245 5

Ro 40-5967 is a structurally novel calcium antagonist that binds to the verapamil binding site but has very weak negative inotropic effects compared to verapamil. The goals of the present study were to assess the effects of Ro 40-5967 on myocardial function during ischemia, and to compare them to those of verapamil. For this purpose, in anesthetized dogs where the circumflex coronary artery was cannulated and perfused at controlled pressure, myocardial function was measured using piezo electric crystals implanted into the endocardium. Myocardial distribution of coronary blood flow was assessed using radioactive microspheres. Ischemia was produced by lowering perfusion pressure from 100 to 15 mm Hg in steps. During ischemia, Ro 40-5967 partially prevented the decrease of segmental shortening (p less than 0.01) and increased coronary flow, especially in the endocardium (p less than 0.01). In contrast, verapamil did not improve myocardial function during ischemia. The protective effect of Ro 40-5967 could be partially explained by the decrease of arterial pressure and heart rate induced by Ro 40-5967. However, Ro 40-5967 injected directly inside the coronary artery did not induce systemic effects, but still had protective effects (p less than 0.05). Verapamil injected intracoronary produced severe cardiac depression. We conclude that in the present model during ischemia Ro 40-5967 has no negative inotropic effects, and in contrast to verapamil can improve the myocardial function.
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PMID:Effects of Ro 40-5967, a novel calcium antagonist, on myocardial function during ischemia induced by lowering coronary perfusion pressure in dogs: comparison with verapamil. 248 Nov 85

The hemodynamic effects of intravenous class I and class IV antiarrhythmic drugs were investigated at different doses in comparison. In open-chest rats hemodynamic measurements in the intact circulation and isovolumic registrations 5 min after infusion of flecainide (2, 4, 8 mg/kg), disopyramide (1, 2, 4, 8 mg/kg), quinidine (5 and 10 mg/kg) and verapamil (0.35, 0.7, 1.5 mg/kg) were compared to saline controls. After clinically usual doses all investigated drugs had no effects on stroke volume, cardiac output, dp/dtmax and systemic resistance. The isovolumic pressure generating capacity of the left ventricle was not decreased at these doses. High intravenous doses of the drugs, however, caused a significant depression of myocardial performance (pressure generating capacity). Furthermore, flecainide decreased mean aortic pressure and heart rate, while disopyramide had no significant effect on the peripheral circulation. Blocking of the autonomic system (1 mg/kg propranolol and 0.1 mg/kg atropine) did not change significantly the action of disopyramide. Quinidine lowered heart rate and pressures. Verapamil reduced the heart rate and tended to decrease the mean aortic pressure. Besides the negative inotropic action of high doses the different hemodynamic profiles of class I and class IV antiarrhythmic drugs might be of importance for intravenous application in patients with left ventricular dysfunction.
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PMID:Circulatory and myocardial effects of different sodium antagonistic drugs in comparison to the calcium antagonist verapamil. 251 61


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