Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tedisamil is a new bradycardic agent with an inhibitory action on K+ channels in cardiac muscle, and secondary beneficial effects in experimentally induced cardiac ischemia. In whole-cell clamp studies in enzymatically dispersed, single smooth muscle cells from the guinea-pig portal vein, tedisamil inhibited the delayed rectifier K+ current (determined as the charge transferred through the cell membrane), the mean concentration for half-maximal inhibition being 2.9 microM. In contrast to controls in the absence of drugs or in the presence of the classical K+ channel blockers barium, tetraethylammonium or 4-aminopyridine, the time course of the delayed rectifier K+ current in the presence of tedisamil could no longer be fitted by a single exponential, and signs of an accelerated inactivation by tedisamil were obtained. The slow onset of the response to tedisamil applied to the outside of the vascular myocytes, and the finding that tedisamil applied directly to the cytosol via the pipette was highly effective, suggest an intracellular site of action.
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PMID:Tedisamil inhibits the delayed rectifier K+ current in single smooth muscle cells of the guinea-pig portal vein. 163 Aug 81

We examined the effects of tedisamil on ventricular fibrillation (VF) elicited by regional ischemia and by reperfusion in isolated rat hearts (n = 12/group). During 30 min of ischemia, 0.1, 0.55, and 3 microM tedisamil had no influence on the incidence of VF (an index of VF initiation). However, sustained VF (SVF, defined as that lasting greater than 120 s, an index of VF maintenance) was reduced in a concentration-dependent manner from 73 to 54, 17 (p less than 0.05), and 0% (p less than 0.05), respectively. Tedisamil caused sinus bradycardia but this was not the basis for tedisamil's antiarrhythmic activity since SVF was also inhibited in separate groups of hearts that were paced throughout the study. Tedisamil had no effect on reperfusion-induced VF initiation. However, VF maintenance was, again, inhibited, with SVF incidence reduced from 75% to 40, 20, and 0% (p less than 0.05), respectively, by increasing concentrations of tedisamil. A similar effect was, again, observed in paced hearts. The average cycle length of the electrogram during VF correlated with preceding width of the ventricular complex; both of these variables were concentration-dependently increased by tedisamil and mean values of each correlated inversely with the incidence of SVF. The ratio of SVF cycle length to ventricular tachycardia cycle length was 1:3, and this ratio was conserved in the presence and absence of drug. The data are consistent with a drug-induced increase in the probability of spontaneous termination of multiple wave-front re-entry.
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PMID:Influence of tedisamil on the initiation and maintenance of ventricular fibrillation: chemical defibrillation by Ito blockade? 172 Aug 45

The electrophysiologic and antifibrillatory properties of tedisamil (KC-8857) were studied in vivo in a conscious canine model of sudden cardiac death. Male mongrel dogs were anesthetized, and surgical anterior myocardial infarction was induced by a 2-h occlusion, with reperfusion of the left anterior descending coronary artery. Three to five days after infarction, dogs were subjected to programmed electrical stimulation (PES) to identify those at risk for ischemia-induced ventricular fibrillation. Previous studies documented that dogs with a significant anterior-wall infarction develop ventricular tachycardia in response to PES and are at an increased risk for sudden cardiac death on imposition of a transient ischemic event in a region remote from the infarct-related artery. PES-inducible animals were randomized to either oral placebo or oral tedisamil treatment (3 mg/kg, b.i.d for 4 days, Group 1, n = 8). Control animals received empty gelatin capsules (Group 2, n = 8). The effective refractory period and QTc interval were unchanged after 3 days of oral placebo or tedisamil dosing. Arrhythmic activity after drug administration was not observed in dogs treated with tedisamil. PES induction of ventricular tachycardia was reduced significantly in the tedisamil-treated group (100% inducible before drug vs. 9% inducible after drug; p < 0.05). In the sudden-cardiac-death protocol, tedisamil reduced the incidence of lethal ischemic arrhythmias developing in response to acute posterolateral myocardial ischemia. Tedisamil-treated animals exhibited a 100% compared with a 25% survival rate in the control group (p < 0.05). Anterior-wall infarct size, expressed as a percentage of the left ventricle, did not differ between groups: Group 1 = 20 +/- 1%; Group 2 = 22 +/- 1%. Our findings suggest that tedisamil might be useful in the prevention of malignant ventricular arrhythmias in myocardial ischemic injury.
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PMID:Antifibrillatory efficacy of long-term tedisamil administration in a postinfarcted canine model of ischemic ventricular fibrillation. 945 78

BACKGROUND: The electrophysiologic and antifibrillatory properties of tedisamil (KC-8857;3,7-di-(cyclopropylmethyl)-9,9-tetramethylene-3,7-diazabicyclo[3.3.1]-nonane dihydrochloride) were studied in a conscious canine model of sudden cardiac death. METHODS AND RESULTS: Three to five days after surgically induced myocardial infarction (2-hour occlusion of the left anterior descending coronary artery), animals were subjected to programmed electrical stimulation to identify those at risk for ischemia-induced ventricular fibrillation. Sixty minutes after tedisamil (10 mg/kg, administered orally) PES was repeated. Tedisamil increased the ventricular effective refractory period from 106 +/- 6 to 134 +/- 7 ms (P <.05) compared to placebo treatment, which did not alter the ERP (123 +/- 6 to 116 +/- 5 ms). Tedisamil prolonged the QTc interval, from a predrug value of 308 +/- 14 to 327 +/- 14 ms, postdrug. The extent of the surgically induced anterior wall myocardial infarct did not differ between groups, tedisamil, 29 +/- 2%, and placebo, 28 +/- 2% of the left ventricle. CONCLUSIONS: Tedisamil conferred protection against ischemia induced ventricular fibrillation; 7 of 10 tedisamil-treated dogs survived, compared to 4 of 14 surviving in the vehicle treated group (P <.05). Although we observed instances of vomiting and/or diarrhea in several dogs after a single oral administration of tedisamil, the data indicate that oral administration of tedisamil provides protection from ischemia-induced ventricular fibrillation in the postinfarcted conscious canine. The mechanism by which tedisamil achieves its antifibrillatory effect may be related to its ability to prolong the ERP of the ventricular myocardium without altering ventricular conduction velocity.
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PMID:Tedisamil Attenuates Ventricular Fibrillation in a Conscious Canine Model of Sudden Cardiac Death. 1068 32

Potassium channel openers and blockers, which belong to a novel class of vasodilator drugs and to the class of specific bradycardic substances, are potential new antianginal drugs. Experimental findings in vivo suggest that bimakalim is a new substance characterized as ATP-sensitive K+ channel openers, since it exerts preferential vasodilation of the collateral circulation of the coronary vasculature and both leads to increase blood flow to ischemic areas and to attenuate the ST segment elevation caused by regional ischemia in the canine heart. Opening of KATP increases the conductivity of potassium ions which results in hyperpolarization of smooth muscle membranes, thus producing vasodilation. Tedisamil is a new bradycardic agent proven to exert antiischemic and antiarrhythmic effects by blockade of the cellular cardiac repolarization K+ currents as well as of multiple neuronal and vascular K+ currents (Ito, Ik, and K+ATP). Using right heart catheterization and exercise tolerance tests, we investigated the hemodynamic, antiischemic and neurohumoral effects of bimakalim and tedisamil in patients with angiographically proven coronary artery disease, stable angina pectoris and reproducible ST segment depression during exercise. In 50 patients with coronary artery disease, the hemodynamic and antiischemic effects of a single oral dose bimakalim of 0.1 mg, 0.3 mg and 0.6 mg were compared to placebo. In a dose-finding baseline-controlled study, a comparable collective was examined for the effects of acute i.v. administration of tedisamil 0.1, 0.2, 0.3 and 0.4 mg/kg bw. A subgroup of 8 patients receiving 0.3 mg/kg bw tedisamil i.v. was compared with a similar group of 14 patients who had received esmolol (i.v. bolus of 500 micrograms/kg, maintenance dose 200 micrograms/kg/min) and gallopamil (initial dose 0.025 mg/kg, maintenance dose 0.0005 mg/kg/h) in a second intra-individual comparison. Furthermore, in 48 patients, short-term (6 days) effects of tedisamil, 2 times 100 mg orally, were compared to 2 times 50 mg atenolol treatment. With a single oral dose of bimakalim antianginal and/or antiischemic effects were lacking, increased doses, however, induced changes in hemodynamics typical of vasodilation, i.e., a significant decrease in systolic blood pressure and a secondary chronotropic response. In contrast to bimakalim, tedisamil produced antiischemic effects and was found to have favorable hemodynamic, neurohumoral and antiischemic effects in comparison to the betablocker esmolol and atenolol in patients with coronary artery disease. Tedisamil induced a dose-dependent decrease in both heart rate and the index of myocardial oxygen consumption associated with an improvement in ST segment depression. Tedisamil as well as esmolol and atenolol showed almost equipotent antiischemic effects at the doses administered. Compared with gallopamil, both tedisamil and esmolol were superior in their effects on myocardial oxygen consumption and ST segment depression, whereas plasma lactate concentrations were more reduced by tedisamil and gallopamil.
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PMID:Potassium channel openers and blockers in coronary artery disease. Comparison to betablockers and calcium antagonists. 1082 53

Tedisamil is antiarrhythmic class III drug with antifibrillating/defibrillating potency linked to enhancement of intermyocyte gap junctional electrical coupling most likely via its sympathomimetic cAMP-related mechanisms. This study was designed to examine the effect of tedisamil on cAMP level in guinea pig hearts in vivo and in vitro in Langendorff preparation. The drug was administered either as a bolus into vena jugularis in dosage 1.0 and 1.5 mg/kg or into the perfusion solution at a concentration of 1.5 x 10(-6) mol/l. In additional experiments, this period was followed by brief 10 min global ischemia, induced by clamping of the aorta or perfusion. After 10 min from the onset of tedisamil administration as well as after 10 min of ischemia the ventricular tissue was immediately frozen for cAMP immunoassay. Tedisamil caused in normal heart small but significant dose-dependent increase of myocardial cAMP (pmol/mg) level in vivo 1.8 and 2.5 vs. 1.4 as well as in vitro 1.1 vs. 0.8 (p < 0.05) conditions. Ischemia itself induced accumulation of cAMP in both, in vivo and in vitro experiments, 2.6 vs. 1.4 and 1.3 vs. 0.8, respectively. The preischemic elevation of cAMP by tedisamil was not potentiated by following ischemia, on the contrary, decline of the cyclic nucleotide was detected comparing to ischemia itself. In conclusion, tedisamil increased cAMP level in normal heart and prevented additional ischemia-related elevation of this nucleotide. The results indicate modulation of myocardial cAMP level by tedisamil, which may account for its protective effect on gap junctional electrical coupling.
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PMID:Modulation of cAMP level by tedisamil in guinea pig heart. 1097 60

Atrial fibrillation has recently come into clinical and research focus. In particular, ventricular rate control has been carefully compared with atrial rhythm control. Additionally, the recent discovery of atrial stunning has initiated clinical and research interest in atrial remodeling. Atrial fibrillation is more likely to occur when the atria are damaged by increased fibrosis. The ideal way to prevent atrial fibrillation and the risk of repetition is by tackling the root causes, such as ischemic heart disease, heart failure, and left ventricular hypertrophy. Tedisamil is an unusual antifibrillatory compound that has a novel mechanism of action by inhibiting the transient outward current (Ito) and the repolarizing potassium currents in the sinoatrial node. Tedisamil works acutely against atrial fibrillation. Importantly, atrial fibrillation is often caused by or related to cardiac ischemia, and conversely, ischemia is caused by the increased oxygen demand of atrial fibrillation. Hence, the double properties of tedisamil as a drug that both inhibits atrial fibrillation and acts in an anti-ischemic mode are an attractive basis for future clinical research.
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PMID:Tedisamil in coronary disease: additional benefits in the therapy of atrial fibrillation? 1274 50