Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present work, the effect of tedisamil on gap junctional conductance (gj) and conduction velocity was investigated in the failing heart of cardiomyopathic hamsters (TO-2 strain). It was found that tedisamil (10(-7) M) increased gj by 53.8+/-1% (n = 23) in cell pairs isolated from 2 months old cardiomyopathic hamsters. The effect of tedisamil was suppressed by intracellular dialysis of an inhibitor of protein kinase A and also by adenosine indicating that the drug increases gj through the activation of adenylcyclase. Tedisamil also increased the conduction velocity and cardiac refractoriness of ventricular muscle from young cardiomyopathic hamsters. At an advanced stage of the disease, however, when the beta-adrenoceptor, adenylcyclase signaling system is impaired, tedisamil was unable to increase gj. The present results indicate that the antiarrhythmic action of tedisamil is in part related to an increase in junctional conductance and conduction velocity.
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PMID:Effect of tedisamil on cell communication, impulse propagation, and excitability of the failing heart. 1039 18

Decreasing heart rate is potentially useful in ischaemic heart disease. Tedisamil is a bradycardic agent resulting from its ability to inhibit transient outward current (I(to)) in atria. Tedisamil inhibits I(to), potassium current (IK), K(ATP) and the protein kinase A-activated chloride channel in ventricles as well as vascular IK and Ca(2+)-activated IK (IK((Ca))). Tedisamil prolongs cardiac action potentials and the corrected QT (QTc) of the ECG and also increases cardiac refractoriness. Tedisamil is anti-arrhythmic in animal models of ventricular arrhythmias and atrial flutter. The bradycardic effect of tedisamil is associated with a reduction in myocardial oxygen demand. On isolated rat ventricle, tedisamil is a positive inotrope and on isolated rabbit atria, tedisamil reverses the negative inotropic effect of pinacidil. Tedisamil contracts the isolated rat portal vein and aorta, reduces cromakalim-induced relaxations of contracted rat aorta and increases blood pressure in animals and humans. Tedisamil is 96% bound to plasma proteins, has a plasma half-life of about 10 h and is cleared from the kidney unchanged. Clinical trials have shown that the electrophysiology of tedisamil is that of a class III anti-arrhythmic. In coronary artery disease, tedisamil has no effect on inotropism and increases the threshold for angina. Potassium channel blockade with tedisamil may have advantages over calcium channel blockers or K(ATP) channel openers as an anti-ischaemic mechanism in coronary artery disease. In exercise-induced myocardial ischaemia, beta-blockers are probably favourable to tedisamil, as they will limit the increase in heart rate, contractility and blood pressure caused by sympathetic stimulation, whereas tedisamil will not. In heart failure patients, tedisamil reduces heart rate, but increases blood pressure. The usefulness of tedisamil as a bradycardic agent is limited by the increase in blood pressure. A drug that is bradycardic without increasing blood pressure would be an improvement on tedisamil as the master switch of nature for ischaemic heart disease.
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PMID:Tedisamil: master switch of nature? 1111 86