Effects of cycloprotobuxine-A on atrial fibrillation.

AIM: To study the effects of cycloprotobuxine-A (Cyc-A) on atrial fibrillation. METHODS: Atrial fibrillations in vivo and in vitro were induced by arrhythmogenic drugs. Action potentials were measured by the standard microelectrode technique. RESULTS: Cyc-A, similar to or slightly stronger than amiodarone (Ami), decreased incidences of atrial fibrillation elicited by CaCl2-acetylcholine in mice and increased doses of aconitine, ouabain, or adrenaline to elicit atrial fibrillation in isolated guinea pig atria. Cyc-A 0.3-100 mumol.L-1 decreased the normal automaticity and 0.3-30 mumol.L-1 attenuated or almost abolished the isoprenaline-induced abnormal increase in automaticity in sinus nodal cells. In isolated left atria, Cyc-A 0.3-30 mumol.L-1 inhibited the abnormal rhythmic activity elicited by adrenaline, prolonged action potential duration (APD) and effective refractory period, and reduced excitability. At 3-30 mumol.L-1, Cyc-A also decreased the maximal velocity of depolarization (Vmax). Cyc-A antagonized the acetylcholine-induced shortening of APD. These electrophysiologic effects were similar to those of amiodarone, but Ami did not affect the Vmax. CONCLUSION: Cyc-A produces a protective effect against experimental atrial fibrillation via a prolongation of repolarization, a decease of automaticity, and an inhibition of excitability.

[Anti-atrial fibrillation effects of cyclovirobuxine-D and its electrophysiological mechanism studied on guinea pig atria].

Cyclovirobuxine-D (CVB-D) was shown to produce significant and dose-dependent protective effects against atrial fibrillation induced by CaCl2-Ach in mice. On atrial fibrillation induced by aconitine, ouabain or adrenaline in isolated guinea pig atria, the effects of CVB-D were similar to those of amiodarone. CVB-D 0.3-100 mumol.L-1 was shown to depress the automaticity of the isolated guinea pig right atria. In isolated left atria, CVB-D 0.3 mumol.L-1 was found to inhibit the abnormal automaticity elicited by adrenaline, to prolong the duration of action potential and effective refractory period and to reduce excitability. At high concentration (30 mumol.L-1), CVB-D was also found to decrease the maximal velocity of depolarization (Vmax) and to elongate the conduction time of initiation. Amiodarone 0.3-30 mumol.L-1 was shown to closely resemble CVB-D in electrophysiology without effect on Vmax.

Protective effects of 3,6-dimethylamino-dibenzopyriodonium edetate on global ischemia reperfused isolated rat hearts.

The effects of 3,6-dimethylamino-dibenzopyriodonium edetate (IHC-72) on global ischemia reperfused rat hearts were investigated. In the isolated working rat heart, 40-min global ischemia followed by 30-min reperfusion resulted in increases of ventricular tachycardia (VT) and ventricular fibrillation (VF), increases of creatine kinase (CK) release and malondialdehyde (MDA) contents, but decreased superoxide dismutase (SOD) activity. Following ischemia and reperfusion, the accumulation of myocardial calcium increased. IHC-72 50 mumol.L-1 given 10 min before ischemia and during reperfusion decreased the cardiac CK release, VT, and VF, reduced the MDA contents, prevented the reduction of SOD activity and attenuated the accumulation of myocardial calcium and sodium vs control. These results indicated that IHC-72 protected myocardial reperfused injury.

Effects of 3,6-dimethylamino-dibenzopyriodonium edetate on action potentials in guinea pig papillary muscles.

The effects of 3,6-dimethylamino-dibenzopyriodonium edetate (IHC-72) on action potentials (AP) and slow response action potentials of guinea pig papillary muscles were studied with intracellular microelectrodes. IHC-72 12.7, 25.4, and 50.8 mumol.L-1 decreased the maximal upstroke velocity (Vmax), amplitude of action potential (APA), over shot (OS), and resting potential (RP) while prolonged the action potential duration at 30%, 50%, 90%, and 100% repolarization (APD30, APD50, APD90, and APD100). IHC-72 25.4 and 50.8 mumol.L-1 decreased the APA, Vmax, and prolonged APD50 and APD90 under high K+ superfusion. IHC-72 25.4 and 50.8 mumol.L-1 depressed the automaticity, APA, and maximal diastolic potential (MDP) of the slow response action potentials induced by BaCl2. The results indicated that IHC-72 might nonspecifically inhibit the transmembrane movement of Ca2+, Na+, and K+.

[Effects of furyl-dihydropyridine on action potential ventricular myocardium of rabbit in vivo and isolated guinea pig left atrium in vitro].

Effects of furyl-dihydropyridine (FDP) on action potential of rabbit ventricular myocardium in vivo were observed with floating microelectrode technique. FDP 0.5 mg.kg-1 i.v. increased APD30 from 104 +/- 7 to 127 +/- 7 ms, APD90 from 146 +/- 10 to 177 +/- 9 ms (P < 0.01, n = 7), decreased the heart rate from 230 +/- 18 to 203 +/- 20 bpm (P < 0.05). Nifedipine (Nif) 0.5 mg.kg-1 i.v. reduced APD and increased the HR in rabbit. In guinea pig left atrium, FDP and Nif decreased the APD, the effects of acetylcholine to shorten the APD was antagonized by FDP 1 mumol.L-1. In rabbit's sinoatrial nodes, FDP 0.5, 1 mumol.L-1 also suppressed the APA and increased the spontaneous sinus cycle length (SCL) and APD50. These results indicate that FDP may inhibit the Ca2+ and K+ currents of myocardium.

Characteristics of depressing effect of cycloprotobuxine-A on the maximal velocity of depolarization in myocardium.

The characteristics of the depressing effect of cycloprotobuxine-A on Vmax in isolated guinea pig myocardium were investigated with a standard microelectrode technique. Cycloprotobuxine-A 3-30 mumol/l produced a concentration-dependent decrease in Vmax, associated with a prolongation of the action potential duration. At 3 mumol/l, a small resting block of Vmax, but a pronounced use-dependent block was found. This use-dependent block increased progressively as stimulation frequency increased from 0.5 to 4.0 Hz. The time constant and rate for onset of use-dependent block were 2.0-7.3 s and 0.11-0.25 AP-1 (reciprocal action potential number), respectively. The time constant and half-life for recovery from use-dependent block were 11.8 and 8.1 s. Thus, the kinetics of the depressing effect of cycloprotobuxine-A on Vmax were intermediate. In muscles depolarized by high [K+]0, the resting block was enhanced slightly, while use-dependent block was greatly augmented. These results suggested that cycloprotobuxine-A could have a low affinity for resting Na+ channels but a much higher affinity for activated and/or inactivated Na+ channels, and that the use-, frequency- and voltage-dependent effects of cycloprotobuxine-A on Vmax may play an important role in preventing the development of cardiac arrhythmias.

Protective effect of cycloprotobuxine-A against cardiac arrhythmias induced by ouabain.

Cycloprotobuxine-A (CPB-A) 1-4 mg.kg-1 iv increased the dose of ouabain required to induce ventricular arrhythmias in guinea pigs. At the equitoxic doses (1/50 LD50), CPB-A was more potent than cyclovirobuxine-D and amiodarone. Pretreatment with reserpine (5 mg.kg-1 ip), vagotomy or pithing spinal cord did not prevent the action of CPB-A, which indicate that the protective effect of CPB-A may be due to its direct action on myocardium without the involvement of nervous system. In isolated guinea pig ventricular muscles, CPB-A 3 mumol.L-1 consistently decreased the amplitude of oscillatory afterpotentials (OAP) and blocked triggered activity elicited by ouabain. At 30 mumol.L-1, CPB-A abolished the appearance of OAP. It seems that one of the mechanisms for the anti-arrhythmic action of CPB-A was a decrease in the amplitude of OAP.

[Comparison of antiarrhythmic effects of IHC-72 (an iodonium-72), lidocaine and verapamil].

The antiarrhythmic actions of 3,6-dimethylamino-dibenzopyridonium edetate (IHC-72), lidocaine (Lid) and verapamil (Ver) on several models Were compared at equitoxic doses (equal fraction of LD50). The action of IHC-72 against aconitine induced arrhythmia was similar to that of Lid but stronger than that of Ver in anesthetized rats. The effect of IHC-72 on ouabain induced arrhythmia was also similar to that of Lid, but weaker than that of Ver in anesthetized guinea pigs. The activity of IHC-72 to raise electrical ventricular fibrillation thresholds (VFT) was weaker than that of Lid and Ver. The effects of IHC-72 in decreasing the incidence of ventricular premature beat(VP B), ventricular tachycardia (VT), ventricular fibrillation (VF) and shortening the duration of VT yielded by reperfusion were similar to those of Lid anf Ver in vivo.

Histamine H3-receptors inhibit sympathetic neurotransmission in guinea pig myocardium.

The histamine H3 agonist, (R)-alpha-methylhistamine (alpha-MeHA, 10(-10) to 10(-5) M), caused a concentration-dependent inhibition of the sympathetic contractile response to electrical field stimulation of guinea pig isolated atria, but alpha-MeHA did not alter the basal tension or the contraction induced by exogenously applied norepinephrine. Blockade of H1 and H2 histamine receptors, and alpha- and beta-adrenoceptors failed to prevent the inhibitory effect of alpha-MeHA, whereas the specific H3 receptor antagonist, thioperamide, concentration dependently reversed the inhibitory effect of alpha-MeHA. At the concentration of 10(-7) M, which was effective for antagonizing the action of alpha-MeHA, thioperamide did not modify the sympathetic responses facilitated by the beta 2-adrenoceptor agonist, clenbuterol, or attenuated by the alpha 2-adrenoceptor agonist, clonidine. Our results suggest that H3 receptors exist on the cardiac sympathetic terminals, which may modulate adrenergic neurotransmission in guinea pig myocardium.

Prevention of global myocardial reperfusion injury on isolated rabbit hearts with furyl-dihydropyridines I.

In the isolated rabbit heart of recirculating nonpulsatile perfusion circuit, furyl-dihydropyridines I 20 mumol.L-1 greatly reduced the leakage of myocardial enzymes and the concentration of malondialdehyde (MDA) in plasma, decreased the myocardial calcium and sodium contents, maintained normal coronary vascular resistance and prevented reperfusion arrhythmias of global postischemic reperfusion hearts. Its mechanism of protecting the ischemic-reperfused myocardium might be associated with the diminution of calcium influx of myocardial cells and cellular lipid peroxidation induced by oxygen free radicals.

Positive inotropic effect of apomorphine on guinea pig myocardium is mediated by dopamine DA1 receptors.

Dopaminergic agonist apomorphine (Apo, 1-100 mumol.L-1) had a concentration-dependent positive inotropic effect on guinea pig left atria. This effect was not changed obviously when the influences of sympathetic and parasympathetic nerves were eliminated by reserpine and atropine, respectively. Apo had little inotropic action on guinea pig papillary muscles. The time course of positive inotropic effect of Apo was different from that of isoprenaline and phenylephrine. Apo influenced the isometric contraction curves in a different way from isoprenaline. Dopaminergic antagonist haloperidol antagonized the positive inotropic effect of Apo. This effect was also competitively antagonized by dopamine DA1 antagonist SCH 23390. While dopamine DA2 antagonist domperidone, beta-adrenergic antagonist propranolol and alpha-adrenergic antagonist phentolamine did not obviously influence the effect of Apo. We concluded that the positive inotropic effect of Apo was mediated by postsynaptic dopamine DA1 receptors in guinea pig left atria.

[Effects of furyl-dihydropyridines I on lipid peroxides of ischemic myocardium and ATPases activity of erythrocyte membranes in rats].

Acute myocardial ischemia and reperfusion in rats increased glutamic oxalacetic transaminase (GOT), non-esterified fatty acid (FFA), malondialdehyde (MDA) content. Furyl-dihydropyridines I 10 mg.kg-1 decreased the release of GOT, FFA, MDA of ischemic myocardium, and prevent ischemia-reperfusion arrhythmia. Furyl-dihydropyridines I increased Na, K-ATPase activity and N-acethylneuraminic acid (NANA) content of erythrocyte membranes, inhibited Ca-ATPase activity of erythrocyte membranes in rats. The results suggested that the mechanism of protecting the ischemic-reperfused myocardium might be associated with the inhibition of cellular lipid peroxidation and Ca-ATPase activity of cell membranes.

[Protective effects of furyl-dihydropyridine I on ischemic myocardium in isolated rabbit hearts].

A recirculating nonpulsatile perfusion circuit was used in isolated rabbit hearts. Furyl-dihydropyridine I (2,6-dimethyl-4-furyl-1,4-dihydropyridine-3, 5-dicarboxylate) 20 mumol/L was shown to inhibit the release of creatine phosphokinase (CPK) and alpha-hydroxybutyrate dehydrogenase (HBD) from myocardium, decrease myocardial calcium and sodium contents by 5.3 +/- 1.1 mumol/g dry weight (P less than 0.01, n = 6) and 1.50 +/- 0.17 mmol/g dry weight (P less than 0.05, n = 6) from 8.3 +/- 1.1 mumol/g dry weight and 1.96 +/- 0.32 mmol/g dry weight respectively. It was also found to reduce coronary resistance and increase coronary flow of the ischemic myocardium, and prevent ischemic arrhythmia, thereby limit myocardial injury during regional ischemia in isolated rabbit hearts.

[Protective effects of nicorandil on myocardial mitochondria function during ischemia and reperfusion].

Experiment with recirculating blood perfusion device showed that nicorandil 0.15 mmol/L significantly counteracted the harmful effect of ischemic and reperfused injury on the respiratory function of myocardial mitochondria. The oxidative phosphorylation efficiency (ADP/O) was increased 19% (p less than 0.01), the respiratory control rate(RCR) was also increased 40% (p less than 0.01); while the content of myocardial calcium and Ca/Mg were decreased; and the ischemia and reperfusion-induced increase of myocardial water content was abolished as compared with solvent control. The results indicate that nicorandil has protective effect on myocardial mitochondria function during ischemia and reperfusion, which may be the result of blocking Ca2+ from entering the cell and prevent lipid peroxidation.

[Protective effects of nicorandil on lipid peroxidation in ischemic and reperfused myocardium of rabbits].

The experiments of recirculating blood perfusion device showed that nicorandil (Nic) 0.15 mmol/L significantly decreased the content of malondialdehyde (MDA), inhibited the release of creatine kinase (CK), counteracted the increase of coronary vascular resistance (CR), and abolished the reperfusion-induced arrhythmias in isolated rabbit hearts during ischemia and reperfusion. The results indicate that Nic has protective effects on myocardial ischemic and reperfused damage, which may relate to the prevention of lipid peroxidation.

[A program for analysis of dose-response relationship with logistic model].

In order to avoid the defects in common methods for analysis of dose-response curves, we fit groups of dose-response curves simultaneously or separately on computer by using logistic model, with the EC50 and slope factor as the basic parameters. The pD2 and pA2 values were calculated from the best estimated EC50s. This method shows a good compatibility with the original experimental data. The BASIC program can be conveniently run on microcomputers.

Positive inotropic effect of cycloprotobuxine-A on isolated guinea pig myocardium.

Cycloprotobuxine-A (CPB-A) 0.1-100 mumoles/L produced positive inotropic effects in left and right atria in a concentration-dependent manner. CPB-A 30 mumoles/L enhanced post-rest contraction, augmented the response of left atrium to increase in stimulating frequency, and increased the developing tension evoked by paired pulse stimulation. By taking simultaneous recordings of action potentials and contractile force of papillary muscles, it was found that CPB-A 30 mumoles/L increased the contractile force and prolonged the action potential duration at 50% of depolarization. It is concluded that the positive inotropic effect of CPB-A on myocardium may be associated with an increase in transsarcolemmal influx of calcium as well as an augmentation of the amount of calcium released from intracellular stores.

Anti-arrhythmic action of cycloprotobuxine-A.

Cycloprotobuxine-A (CPB-A) 1-4 mg/kg (1/100-1/25 LD50) produced therapeutic and prophylactic effects which were found to be dose-dependent on experimental arrhythmias induced by BaCl2, aconitine and chloroform. Given at equitoxic doses, the anti-arrhythmic action of CPB-A was as potent as cyclovirobuxine-D (CVB-D) and amiodarone (Amio). However, its therapeutic index (LD50/ED50) was 1.8 times that of CVB-D and 1.2 times that of Amio. The most pronounced effects of CPB-A (0.3-30 mumol/L) on the electrophysiology of ventricular muscle of guinea pig were the lengthening of APD50, APD90 and ERP. This may contribute to its anti-arrhythmic action and suggests that CPB-A most likely belongs to class III anti-arrhythmic drugs (prolongation of APD). Perfused with the same concentration (3 mumol/L), CPB-A brought about more significant increases in APD50, APD90 and ERP than CVB-D and Amio did.

[Effects of bis(dimethyl amino)-diphenyl methane (BDDM) on action potentials in guinea pig papillary muscle].

The effects of BDDM on action potentials and slow response action potentials in guinea pig papillary muscle were investigated by microelectrode technique. BDDM prolonged action potentials duration at 30, 50, 90, and 100% repolarization (APD30, APD50, APD90, APD100) and prolonged the effective refractory period (ERP), so ERP/APD value became greater. BDDM (51.6 mumol/L) decreased the APA, Vmax and prolonged APD50, APD90. In barium-induced ventricular autorhythmicity, BDDM suppressed the maximal diastolic potential (MDP), APA and reduced the rate of spontaneous rhythm. The results suggest that BDDM may unspecifically inhibit the currents of Ca2+, K+, and Na+.