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)

Four patients without symptoms of episodic hyperkalemic weakness from two families with paramyotonia congenita (Eulenburg) are described. 1. Maximum voluntary muscle contraction of the upper and lower arm was studied under isometric conditions at different temperatures. If the temperature was lowered stepwise, distinct paresis occured at 32--31 degrees C which increased with the amount of muscular effort. The upper arm muscles, however, developed weakness gradually after cooling. 2. During cooling of the resting muscle, the EMG showed dense spontaneous activity of the fibrillary type, which decreased again at about 30 degrees C. It can be assumed that in paramyotonia congenita cooling produces muscle cell membrane depolarization which at a critical level causes the firing of action potentials and finally muscular paresis. 3. Increasing muscular stiffness can be interpreted as abnormally slow muscular relaxation after isometric contraction. In the forearm muscles the time to 3/4 relaxation after cooling was about six times normal, in the upper arm muscles only two times normal. As an additional parameter the mechanical resistance to passive stretching of a muscle has been studied. This passive muscular tension increased simultaneously with the onset of weakness. 4. The close relation between weakness and stiffness suggest that both symptoms are caused by the same basic defect which is probably located in the sarcolemma. It is suggested that a defect of the sodium channel causes a cooling-dependent increase in sodium conductance. Raised intracellular sodium causes in the first place membrane depolarization, and in the second place depression of calcium reuptake through competition by sodium for calcium binding sites. This would explain muscle stiffness and delayed relaxation as well.
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PMID:Influence of temperature on isometric contraction and passive muscular tension in paramyotonia congenita (Eulenburg). 9 68

Reentrant ventricular arrhythmias (RVA) were analyzed in dogs 3--7 days after ligation of the anterior descending coronary artery using averaged "composite" recordings of electrical activity of reentrant pathways (RP) from the epicardial surface of the infarction zone (IZ). Verapamil (V) and D-600 (D) (0.2--0.5 mg/kg i.v.) resulted in slight-to-moderate improvement of conduction in RP with abolition of spontaneous RVA and RVA initiated by premature depolarizations. The effect of V was not blocked by pretreatment with propranolol (0.5 mg/kg i.v.). Using a standard microelectrode technique and strips of epicardial muscle from the IZ, D (0.5--1 X 10(-6) g/ml) slightly improved the upstroke velocity and membrane responses of depressed ischemic cells. In contrast, tetrodotoxin (5 X 10(-7) g/ml) further depressed or abolished action potentials of ischemic cells. We conclude: 1) the moderate antiarrhythmic effect of V and D on RVA is the result of improved conduction in RP; 2) this action is partly explained by improvement of a depressed sodium channel and is not related to catecholamine release; 3) slow-response action potentials play no significant role in the genesis of ischemia-related RVA, which probably results from depression of the fast response.
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PMID:Reentrant ventricular arrhythmias in the late myocardial infarction period. 7. Effect of verapamil and D-600 and the role of the "slow channel". 45 24

In contrast to mammalian brain, which exhibits rapid degeneration during anoxia, the brains of certain species of turtles show an extraordinary capacity to survive prolonged anoxia. The decrease in energy expenditure shown by the anoxic turtle brain is likely to be a key factor for anoxic survival. The "channel arrest" hypothesis proposes that ion channels, which regulate brain electrical activity in normoxia, may be altered during anoxia in the turtle brain as a mechanism to spare energy. Goals of present research were to test this hypothesis and to determine whether down-regulation of sodium channels is a possible explanation for spike threshold shifts seen during anoxia in isolated turtle cerebellum. We report here that anoxia induced a significant (42%) decline in voltage-gated sodium channel density as determined by studies of the binding of a sodium channel ligand, [3H]brevetoxin. This study demonstrates that sodium channel densities in brain may be regulated by tissue oxygenation or by physiological events associated with anoxia. Moreover, it also suggests that downregulation of sodium channels may be a basis for changes in action potential thresholds, the electrical depression and energy conservation that provide the unique anoxic tolerance of turtle brain.
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PMID:Downregulation of sodium channels during anoxia: a putative survival strategy of turtle brain. 131 18

Propafenone is an antiarrhythmic agent with fast sodium channel, calcium channel, and beta-adrenergic receptor blocking properties. The effects of propafenone on arrhythmias, free intracellular calcium and left ventricular performance were studied using perfused rat hearts during (i) pacing-induced ventricular fibrillation and (ii) infusion with 2.65 x 10(-6) M, 5.3 x 10(-6) M and 7.9 x 10(-6) M propafenone hydrochloride (corresponding to approximately 1, 2 and 3 mg kg-1 body weight). A bolus of 1 mg kg-1 propafenone during ventricular fibrillation resulted in a decrease in intracellular calcium, with subsequent conversion to sinus rhythm. In perfused hearts with sinus rhythm propafenone produced a dose-dependent decrease in heart rate and myocardial oxygen consumption together with a rise in left ventricular diastolic pressure, and diastolic [Ca2+]i, indicative of depression of left ventricular function. We conclude that a bolus of propafenone during ventricular fibrillation leads to a decrease in [Ca2+]i preceding conversion to sinus rhythm. In rat hearts with sinus rhythm the depressive effects of propafenone on [Ca2+]i are dose dependent.
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PMID:Effects of propafenone on pacing-induced ventricular fibrillation and intracellular calcium in rat hearts. 133 67

Many investigations using the microdialysis technique have been performed in anesthetized animals, both in this laboratory and elsewhere. Concern arises with this preparation that the anesthetic may compromise neuronal function, or that it may interact with test drugs affecting neurotransmitter overflow. In addition, in these studies the microdialysis probe typically is introduced into the brain on the day of testing, and data collection commences within an hour or two following probe insertion. It has been suggested that transmitter recovered in the perfusate probably represents leakage due to tissue damage as well as exocytotic release, and may not accurately reflect neuronal responses to the manipulations of interest. Such potential confounds present important implications for the interpretation of data from these studies. The present investigation examined the effects of chloral hydrate anesthetic on (1) basal dopamine (DA) overflow in the anterior striatum, and (2) DA responses to systemically delivered drugs of two different classes known to influence DA activity. Three putative indices of impulse-dependent release were measured: (a) the time course and stability of basal DA overflow over several hours; (b) sodium channel involvement by adding tetrodotoxin (TTX) to the artificial CSF; and (c) calcium channel involvement using magnesium (Mg) in a calcium-free perfusate. Basal DA levels became stable in both conscious and anesthetized preparations by the second hour after probe insertion. Levels of recovered DA overflow in the anterior striata of conscious rats were approximately double those in chloral hydrate-anesthetized rats. Consistent with other findings, this suggests a general depression of CNS function by chloral hydrate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Striatal extracellular dopamine in conscious vs. anesthetized rats: effects of chloral hydrate anesthetic on responses to drugs of different classes. 147 24

Local anaesthetics are responsible for 5 to 10% of all reported adverse reactions to anaesthetic drugs. Adverse effects may be classified as: (a) those associated directly with blocking ion channels in cell membranes, such as cardiovascular and CNS toxicity; (b) those due to other effects of drug or vehicle (mainly peripheral nerve complications); (c) allergic reactions (often a mistaken diagnosis); and (d) mechanical or other effects of technique, such as needle trauma or introduction of infection. Signs and symptoms of CNS toxicity include convulsions, followed by coma and respiratory depression. Convulsions are due to disinhibition of nervous conduction, probably by an action at the gamma-aminobutyric acid (GABA) receptor complex, while depressant effects, which predominate at higher doses, are due to blockade of sodium channels. CNS toxicity is potentiated by hypoxia and hypercapnia, so acute management must minimise these. Cardiovascular toxicity also involves sodium channel blockade, reducing contractility and interfering with conduction. Bupivacaine differs from lidocaine (lignocaine) in the sudden occurrence of dangerous ventricular arrhythmias including fibrillation at subconvulsant doses. Ropivacaine is a newer amide local anaesthetic with toxicity intermediate between these but potency similar to bupivacaine. Neurotoxic complications leading to prolonged deficit after intraspinal administration are uncommon. Causes are multifactorial, and include pH of and additives to preparations. Allergic reactions account for only 1% of untoward reactions, but anaphylactoid collapse can be lifeth-reatening and requires rapid and effective management.
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PMID:Adverse effects of local anaesthetics. 150 66

Effects of three class I antiarrhythmic drugs (quinidine, lidocaine, and prajmaline) on transmembrane resting (RMP) and action potentials (AP) of isolated rabbit atrial and ventricular myocardium were studied at different stimulation rates. The frequency-dependent depression of the maximal upstroke velocity (Vmax) of the AP (sodium channel block) was analyzed according to the "guarded receptor" hypothesis. The resting block (Vmax depression after a resting period) induced by prajmaline (10(-6) M), quinidine (2.2 x 10(-5) M), and lidocaine (4.3 x 10(-5) M) was more expressed in the atrium (44, 28, and 19%, respectively) than in the ventricle (32, 9, and 0%, respectively). There were also significant (p less than 0.05) atrioventricular differences in the frequency-dependent extra block (Vmax reduction on stimulation at 3.3 Hz) for quinidine (39 vs. 26%) and lidocaine (4 vs. 25%). From the analysis, according to the guarded receptor hypothesis, it follows that the three compounds bind preferentially to inactivated sodium channels with about the same affinity to the atrium and ventricle, except for quinidine which shows a significantly smaller dissociation constant in the atrium (5 x 10(-6) M vs. 2.7 x 10(-5) M; p less than 0.001). We conclude that the atrioventricular differences in the resting block are mainly due to atrioventricular differences in the RMP, whereas the differences in the frequency-dependent extra block are based on the shorter atrial AP duration (lidocaine) or are due to higher affinity to atrial sodium channels (quinidine).
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PMID:Comparative analysis of the action of class I antiarrhythmic drugs (lidocaine, quinidine, and prajmaline) in rabbit atrial and ventricular myocardium. 168 32

Amiodarone and its pharmacologically active metabolite desethylamiodarone have a sodium channel blocking action that explains some of their antiarrhythmic efficacy. However, the well-documented depression of the calcium channel-dependent sinus node and atrioventricular node function that occurs with amiodarone therapy suggests that amiodarone also blocks calcium influx through voltage-dependent calcium channels. Recent electrophysiologic data support the notion that amiodarone, but not desethylamiodarone, acts as a calcium channel antagonist. In this study, the effects of amiodarone and desethylamiodarone on calcium antagonist receptors associated with the voltage-dependent calcium channels were characterized. Amiodarone, but not its active metabolite desethylamiodarone, was a potent competitor at dihydropyridine and phenylalkylamine (verapamil-like) calcium antagonist binding sites in rat heart, brain, and skeletal and smooth muscles. Substantial inhibition of calcium antagonist binding was retained even after extensive washing of membranes and 2 days after in vivo treatment of rats with amiodarone. The pattern of inhibition of calcium antagonist binding suggests that amiodarone acts at phenylalkylamine binding sites. It is suggested that the acute effects of amiodarone--sinus and atrioventricular node inhibition, vasodilatation, and negative inotropic actions--may reflect calcium antagonist influences of amiodarone itself. Chronic effects of drug therapy, such as inhibition of ventricular conduction by sodium channel blockade, may selectively involve desethylamiodarone.
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PMID:Differential effects of amiodarone and desethylamiodarone on calcium antagonist receptors. 169 76

Despite its widespread clinical use, the precise mechanism of action of amiodarone (AMI) has not been completely defined. We examined the effects of AMI (20 micrograms/ml) on Vmax and on conduction velocity (theta) during longitudinal (LP) and transverse (TP) propagation with respect to fiber orientation, in 10 strips of uniform anisotropic epicardial muscle obtained from the left ventricle of adult canine hearts. Mean values +/- SEM (standard error of the mean) were calculated as normalized values (beat 50/beat 1) after 4 h of AMI superfusion at five different basic cycle lengths (BCL). Vmax decreased from 0.99 +/- 0.01 at a BCL of 5,000 ms to 0.43 +/- 0.03 at a BCL of 300 ms during LP. During TP, Vmax decreased from 0.99 +/- 0.01 at a BCL of 5,000 ms to 0.54 +/- 0.05 at a BCL of 300 ms. The differences in the relative changes between both directions at a BCL of 300 ms, as well as at intermediate values of 1,000, 500, and 400, were significant (p less than 0.01). theta during LP (theta L) was depressed from 0.99 +/- 0.01 at a BCL of 5,000 ms to 0.80 +/- 0.04 at a BCL of 300 ms. In contrast, theta during TP (theta T) did not change as the BCL was decreased. In consequence, theta L was significantly more depressed than theta T at BCLs shorter than 1,000 ms (p less than 0.05). Moreover, theta T after AMI was not statistically different from control at any BCL studied. The lack of depression of theta T associated with a marked depression of Vmax during either LP or TP suggests that in addition to its sodium channel blocking properties, AMI could produce a decrease in the effective axial resistivity.
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PMID:Differential effects of amiodarone on Vmax and conduction velocity in anisotropic myocardium. 169 14

Classifications of antiarrhythmic drugs have developed because of a need to organize the large number of agents available according to pharmacological properties of clinical relevance. The current classification is a hybrid of classification systems developed in the early 1970s. It subdivides drugs according to 4 major pharmacological actions: (a) depression of phase 0 sodium current; (b) antagonism of adrenergic effects on the heart; (c) prolongation of of action potential duration; and (d) calcium channel blockade. Further subdivision of sodium channel blockers is based on the kinetics of sodium channel blockade and drug effects on action potential duration. A critical analysis of selected aspects of the clinical actions of antiarrhythmic drugs indicates the value of the current classification, as well as some limitations in its ability to separate drugs into distinct groups with characteristic clinical properties. The strengths of the current classification are due to the clinical importance of the pharmacological properties on which it is based. These results in electrophysiological actions, indications, and adverse effects that are typical for each group of drugs. The limitations of the current system relate to the propensity of individual drugs to have actions of more than one class simultaneously, the way that the various actions of a given drug are dependent on concentration, rate, and tissue type, and to problems in subclass definition. Some of these shortcomings could be alleviated by returning to the concept, originally put forward by Singh and Vaughan Williams, of classes of drug action rather than classes of drug per se. This approach would be pharmacologically more realistic than trying to assign each antiarrhythmic agent to a single unique class, would be better able to incorporate the complexities of drug action, and would potentially be more flexible. The wide use of antiarrhythmic drug classifications attests to their value, and suggests that they are likely to continue to be important in the future.
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PMID:Antiarrhythmic drug classifications. A critical appraisal of their history, present status, and clinical relevance. 171 4


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