aconitine and Myocardial-Ischemia

Screening active constituents of traditional Chinese medicines (TCMs) is vital for lead compound discovery. Sini decoction (SND) is a well-known TCM formula for relieving myocardial ischemia (MI) in clinic. Due to complex nature, the effective compounds of SND are still unknown. In this study, a novel "system to system" strategy based on the correlation of drug-related and drug-induced ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOFMS) serum metabolomic profiles was developed to discover bioactive compounds of SND against isoproterenol-induced MI. Thirteen SND-induced metabolites and 19 SND-related metabolites were identified by UHPLC-Q-TOFMS coupled with S-plot and SUS-plot of orthogonal projection to latent structure-discriminant analysis (OPLS-DA) models, respectively. Canonical correlation analysis between the SND-induced and SND-related metabolites revealed that 12 compounds had strongly correlated relationship with the protective effect of SND on MI, and these compounds include isotalatizidine, songorine, fuziline, neoline, talatizamine, 14-acetyltalatizamine, liquiritigenin, benzoylmesaconitine, isoliquiritin, benzoylaconitne, benzoylhypaconitine and 6-gingerol. Combination functional enrichment analysis and network topology analysis revealed that the targeted metabolic pathways of these correlated compounds were involved in valine, leucine and isoleucine biosyntheses, tryptophan metabolism, glycerophospholipid metabolism and sphingolipid metabolism. The results demonstrated that the "system to system" strategy may be a high-throughput method to discover potentially effective compounds from TCMs.

Topics: Aconitine; Alkaloids; Animals; Aspartate Aminotransferases; Catechols; Chalcone; Chromatography, High Pressure Liquid; Creatine Kinase; Disease Models, Animal; Drugs, Chinese Herbal; Fatty Alcohols; Flavanones; Glucosides; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Malondialdehyde; Mass Spectrometry; Metabolome; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Vagal nerve stimulation (VNS) protects from myocardial and vascular injury following myocardial ischaemia and reperfusion (IR) via a mechanism involving activation of alpha-7 nicotinic acetylcholine receptor (α7 nAChR) and reduced inflammation. Arginase is involved in development of myocardial IR injury driven by inflammatory mediators. The aim of the study was to clarify whether VNS downregulates myocardial and vascular arginase via a mechanism involving activation of α7 nAChR following myocardial IR.. Anaesthetized rats were randomized to (i) sham-operated, (ii) control IR (30-min ischaemia and 2-h reperfusion, (iii) VNS throughout IR, (iv) the arginase inhibitor nor-NOHA+IR, (v) nor-NOHA+VNS+IR, (vi) selective α7 nAChR blockade by methyllycaconitine (MLA) followed by VNS throughout IR and (vii) MLA+IR.. Infarct size was reduced by VNS compared to control IR (41 ± 3% vs. 67 ± 2% of the myocardium at risk, P < 0.001). Myocardial IR increased myocardial and aortic arginase activity 1.7- and 3.1-fold respectively (P < 0.05). VNS attenuated the increase in arginase activity compared to control IR both in the myocardium and aorta (P < 0.05). MLA partially abolished the cardioprotective effect of VNS and completely abrogated the effect of VNS on arginase activity. Arginase inhibition combined with VNS did not further reduce infarct size.. Vagal nerve stimulation reduced infarct size and reversed the upregulation of arginase induced by IR both in the myocardium and aorta via a mechanism depending on α7 nAChR activation. The data suggest that the cardioprotective effect of VNS is mediated via reduction in arginase activity.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Arginase; Arginine; Down-Regulation; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nicotinic Antagonists; Random Allocation; Rats; Rats, Sprague-Dawley; Vagus Nerve Stimulation

The antiarrhythmic effects of 100; 150; and 300microg/kg i.p. oxygen/ozone mixture were tested on arrhythmias induced by i) ischemia; ii) ischemia/reperfusion; iii) aconitine (15microg/kg/i.v.); potassium chloride (1.5% i.v.) in rats. 25min of cardiac left descending coronary artery ischemia caused severe incidence of ventricular tachycardia, ventricular fibrillation and mortality. These were significantly reduced by pre-treatment of rats with oxygen/ozone mixture at doses of 150 and 300microg/kg. In separate experiments using a protocol of 5min ischemia followed by 8min reperfusion this caused arrhythmias starting within 6+/-1s. The incidence of ventricular tachycardia was 100%, while ventricular fibrillation occurred in 75% of the animals and lasted 85+/-14s. The mortality was 62.5%. These figures were significantly (P<0.01) reduced in animals treated with 150microg/kg oxygen/ozone and a substantial increase observed with 300microg/kg, whilst not affected by the lower dose of 100microg/kg. 150 and 300microg/kg oxygen/ozone prolonged the onset time for the appearance of arrhythmias induced by aconitine (300microg/kg oxygen/ozone, approximately 81% longer). Oxygen/ozone also reduced the ventricular tachycardia duration, ventricular fibrillation incidence, arrhythmia score, and increased the rat's survival rate. As for example, this latter was increased from 25% (aconitine) to 50% (aconitine+oxygen/ozone 150microg/kg). 100microg/kg oxygen/ozone was without effect. None of the oxygen/ozone doses affected the arrhythmias caused by potassium chloride 1.5% i.v. All the oxygen/ozone antiarrhythmic effects were similar to those observed with lidocaine (1.5mg/kg i.v.). In conclusion, oxygen/ozone has antiarrhythmic effects against arrhythmias caused by aconitine, myocardial ischemia and ischemia/reperfusion.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Male; Myocardial Ischemia; Oxygen; Ozone; Potassium Chloride; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Myocardial ischaemia is associated with perturbations of electrophysiological profile of cardiac myocytes. The persistent sodium current (I(Nap)) is one of the major contributors to ischaemic arrhythmias and appears as an attractive therapeutic target. We investigated the effects of F 15845, a new anti-anginal drug on I(Nap) and in integrative models of I(Nap)-induced arrhythmias.. Sodium current was investigated using patch clamp technique on wild-type and DeltaKPQ-mutated hNav1.5 channels transfected in HEK293 cells. Effects of F 15845 on action potentials (APs) were studied by the glass microelectrode technique and its anti-arrhythmic activities were investigated in ischaemia- and aconitine-induced arrhythmias in the rat.. We demonstrated that F 15845 is a potent blocker of I(Nap) acting from the extracellular side of the channel. Blockade of I(Nap) was voltage dependent and characterized by an almost pure tonic block. F 15845 shortened AP from rabbit Purkinje fibres, confirming its lack of pro-arrhythmic activity, and prevented AP lengthening induced by the I(Nap) activator veratridine. F 15845 did not affect APs from rabbit atria and guinea pig papillary muscle where I(Nap) is not functional, confirming its inability to affect other cardiac ionic currents. F 15845 was effective at preventing fatal ventricular fibrillation and ventricular tachycardia during coronary ligation without modifying heart rate and blood pressure, and dose dependently increased the dose threshold of aconitine required to induce ventricular arrhythmias.. F 15845, a novel anti-anginal drug targeting I(Nap), demonstrates new anti-arrhythmic properties which may be of therapeutic benefit against ischaemia-induced arrhythmias.

Topics: Aconitine; Action Potentials; Animals; Arrhythmias, Cardiac; Benzothiepins; Cell Line; Heart Atria; Humans; Male; Myocardial Ischemia; Patch-Clamp Techniques; Purkinje Fibers; Rabbits; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Sodium Channels; Swine; Veratridine

Topics: Aconitine; Alkanesulfonic Acids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Chloride; Cardiotonic Agents; Male; Myocardial Ischemia; Rats; Rats, Wistar

It has been found that intravenous administration of nociceptin (0.4 mg/kg) prevents development of aconitine-induced arrhythmias but has no effect on the incidence of occlusion, reperfusion, CaCl2-induced arrhythmias, and exacerbates epinephrine-evoked dysrhythmias. Pretreatment with hexamethonium, atropine, guanethidine and naloxone did not abolish the arrhythmic effect of nociceptin. Intracerebroventricular infusion of orphanin FQ was shown to increase cardiac tolerance of arrhythmogenic influence of aconitine, but this effect is completely abolished by hexamethonium administration. It has been suggested that stimulation of both central and peripheral ORL1 receptors increases cardiac resistance against arrhythmogenic effect of aconitine via different mechanisms.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Disease Models, Animal; Electrocardiography; Epinephrine; Heart; Heart Rate; Injections, Intravenous; Injections, Intraventricular; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Rats; Rats, Wistar; Receptors, Opioid

Antiarrhythmic activity of oral allapinin was studied in 64 patients with ischemic heart disease. 27 of the patients had undergone coronary artery bypass grafting 2 to 12 months before, 19 patients had postinfarction cardiosclerosis, 38--arterial hypertension, 30--circulation insufficiency stage I. Arrhythmia presented as ventricular extrasystole (n = 28), paroxysmal atrial fibrillation (n = 18), paroxysmal atrial tachycardia (n = 11), frequent supraventricular extrasystole (n = 7). Arrhythmia continued from 6 months to 8 years. An effective single dose was defined with acute pharmacological test. The treatment course lasted for 21 days. Allapinin proved to be highly effective: ventricular ectopic activity was suppressed in 71.4% patients, atrial tachycardia paroxysms were prevented in 72.7%, paroxysms of atrial fibrillation--in 77.8%. Allapinin tolerance was good. Extracardiac side effects occurred most frequently, but dose lowering was necessary only in 6.2%. The drug was discontinued because of cardiac side effects in 4.7% cases. ECG monitoring is a highly informative method of the treatment efficacy control.

Topics: Aconitine; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Artery Bypass; Drug Tolerance; Electrocardiography; Humans; Hypertension; Male; Middle Aged; Monitoring, Physiologic; Myocardial Ischemia; Time Factors

The effects of 6,7,8, 9-tetrahydro-2-methyl-5H-cyclohepta[b]pyridine-3-carbonylguanidine maleate (TY-12533) on myocardial ischemia/reperfusion injury were evaluated in rats. Inhibitory effects of TY-12533, TY-50893 (the 9-chloro derivative of TY-12533) and cariporide on the platelet Na(+)/H(+) exchanger in vitro were almost equal at pH 6.2 and decreased at pH 6.7; but TY-12533 was four times more potent than TY-50893 and cariporide at pH 6.7. TY-12533, TY-50893 and cariporide administered before ischemia (0.01-1 mg/kg, i.v.) suppressed the ischemia/reperfusion-induced arrhythmias to the same extent in vivo; but TY-12533 was more effective than cariporide and TY-50893 when they were administered during ischemia (0.1-1 mg/kg). Similar results were obtained for the inhibitory effects of these drugs administered before ischemia (0.03-0.1 mg/kg, i.v.) and during ischemia (0.1-1 mg/kg) on the ischemia/reperfusion-induced myocardial infarction. These differences between TY-12533 and the other drugs in vitro and in vivo may be ascribed to the pK(a) values of the guanidinium moiety of TY-12533 (6.93), TY-50893 (6.35) and cariporide (6.28).

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiotonic Agents; Disease Models, Animal; Guanidines; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Pyridines; Rats; Rats, Wistar; Sodium-Hydrogen Exchangers; Sulfones

To compare the effects of oxysophoridine (Oxy) and sophoridine (Sop) on experimental arrhythmias and myocardial physiologic properties.. Arrhythmias were induced by drugs and myocardial ischemia. Physiologic properties were determined on isolated heart atria.. Oxy 500 mg.kg-1 (1/6 LD50) decreased the incidence of ventricular arrhythmias induced by aconitine (P < 0.01), increased the threshold dose of ouabain-induced ventricular premature (VP, P < 0.05), ventricular tachycardia (VT, P < 0.05), ventricular fibrillation (VF, P < 0.01), and cardiac arrest, (P < 0.01). After i.v. Oxy 500 mg.kg-1 into the rats with ligation of left anterior descending coronary artery, the total numbers of ectopic beats were decreased (P < 0.05), the incidence of VF was lowered, and the duration of VT was shortened (P < 0.01). Oxy 250 mg.kg-1 (1/13 LD50) i.v. shortened the duration of arrhythmias induced by BaCl2 (P < 0.01) and delayed the onset of arrhythmias induced by chloroform-epinephrine (P < 0.05). Oxy produced dose-dependent positive inotropic effects in the isolated left atrial of guinea pigs, increased the concentration of epinephrine to elicit automaticity in left atria, decreased slightly the excitability, and prolonged the functional refractory period. Sop produced the similar effects on arrhythmias as Oxy.. Oxy produced the similar anti-arrhythmic effects as Sop did at the equivalent effective dose.

Topics: Aconitine; Alkaloids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium Compounds; Chlorides; Female; Guinea Pigs; Heart Arrest; Male; Matrines; Mice; Myocardial Contraction; Myocardial Ischemia; Ouabain; Quinolizines; Rabbits; Rats; Rats, Wistar; Refractory Period, Electrophysiological