[Inotropic reactions of myocardium of patients with ischemic heart disease and rats during use of amiodarone].

AIM: To study effect of amiodarone on inotropic reactions of myocardium of patients with ischemic heart disease and rats. METHODS AND RESULTS: Excitability of rat myocardium has been found to be higher than that of myocardium of patients. Sarcoplasmic reticulum of myocardium of rats has greater functional reserve, therefore rat muscle preparations respond to extrasystolic stimuli with postextrasystolic potentiation. Perfusion with a solution containing amiodarone caused diminution of amplitude of extrasystolic response of muscular strips both from rats and patients. Amiodarone augmented ability of sarcoplasmic reticulum to accumulate Ca ions as it prevented decrease of postextrasystolic contraction of human myocardium and brought about postextrasystolic potentiation of muscular strips of rat myocardium. CONCLUSION: Amiodarone affected intracellular homeostasis of calcium ions in cardiomyocytes of both rats and patients. Amiodarone lowered myocardial excitability and facilitated ability of cardiomyocyte sarcoplasmic reticulum to accumulate calcium ions.

Metabolic alterations in rat myocardium in experimental acute atrial fibrillation.

Experimental atrial fibrillation in intact rats significantly decreased the content of catecholamines in atrial adrenergic fibers and phosphorylase activity, which attests to enhanced glycogen consumption in the heart. These changes were specific of the fibrillating myocardium and atria, but were absent in the ventricles. Induced atrial fibrillation did not modify activities of SDH and monoamine oxidase in cardiac subdivisions. It was hypothesized that increased energy requirements in the atria during myocardial fibrillation led to activation of anaerobic metabolism.

Effect of amiodarone on the dynamics of mechanical restitution of rat papillary muscles.

We studied the effect of amiodarone (class III antiarrhythmic drug) on the dynamics of mechanical restitution of rat papillary muscle. Amiodarone produced a weak negative inotropic effect and stimulated potentiation of contractility of the muscle preparation after short-term (4-60 sec) cessation of its electrical stimulation. On the other hand, the time of attaining half-maximum amplitude of contractions after amiodarone treatment did not differ from the control. Analysis of curves presenting the drop of potentiation of muscle preparation contractility after resumption of regular electrical stimulation after 60-sec arrest until attaining a stable level showed that the amplitude returned to the initial level by the 9thcontraction-relaxation cycle both in the control and after amiodarone treatment. Coefficient of the drop of contraction amplitude potentiation was virtually the same in the two groups. Presumably, amiodarone does not modulate calcium-binding capacity of the sarcoplasmic reticulum, but improves Ca retention in the sarcoplasmic reticulum stores.

[The role of opiate receptors and ATP-dependent potassium channels of mitochondria in the formation of myocardial adaptive resistance to the arrhythmogenic effect of ischemia and reperfusion]. / Rol' opiatnykh retseptorov i ATF-zavisimykh kalievykh kanalov mitokhondrii v formirovanii adaptatsionnoi ustoichivosti miokarda k aritmogennomu deistviiu ishemii i reperfuzii.

Preliminary stimulation of opiate receptors (ORs) by intravenous administration of mu agonist DALDA (0.5 mg/kg), delta 1 agonist DPDPE (0.5 mg/kg), and kappa agonist (-)-U-50.488 (1 mg/kg) increases rat myocardial resistance to arrhythmogenic effect of coronary occlusion (10 min) and reperfusion (10 min). Activation of delta 2 ORs (DSLET, 0.5 mg/kg) has no effect on the incidence rate of ischemic and reperfusion arrhythmias. Preliminary administration of glibenclamide (0.3 mg/kg), an inhibitor of KATP channels, blocks the antiarrhythmic effect of DALDA and DPDPE. Repeated short-term exposures of rats to immobilization within two weeks increases the heart tolerance to the arrhythmogenic effect of coronary occlusion and reperfusion. This effect disappears after administration of CTAP (0.5 mg/kg), a mu antagonist, or injection of 5-hydroxydecanoate (5 mg/kg), an inhibitor of mitochondrial KATP channels. The selective antagonists of delta and kappa ORs have no effect on cardiac adaptation-induced resistance to the arrhythmogenic effect of ischemia and reperfusion. We believe that stimulation of mu, delta, and kappa ORs increases myocardial tolerance to the arrhythmogenic effect of ischemia and reperfusion through activation of KATP channels. The antiarrhythmic effect of the adaptation is mediated by stimulation of mu ORs and mitochondrial KATP channels.

Effect of class III antiarrhythmic preparation nibentan on extrasystolic and post-extrasystolic contraction of rat papillary muscle.

The effect of nibentan (2.5 and 25 muM) on extrasystolic and post-extrasystolic contraction of isolated and perfused papillary muscle was studied. The muscle contracted in an isometric regimen at a rate of external electrical stimulation of 0.5 Hz in a temperature-stabilized chamber (36.0+0.5 degrees C). The extrasystolic contraction was induced with an extra electrical pulse applied 0.25 sec after the regular stimulus. Nibentan decreased the amplitude of extrasystolic contraction in a dose-dependent manner. At the same time, the effect of nibentan on extrasystolic contraction practically did not depend on its concentration. It is concluded that nibentan produces a dose-dependent effect on excitability of rat ventricular myocardium, and in parallel improves calcium-accumulating capacity of the sarcoplasmic reticulum in cardiomyocytes.

Activation of cannabinoid receptors decreases the area of ischemic myocardial necrosis.

We studied the possibility of decreasing the area of ischemic necrosis during myocardial infarction with HU-210, a selective cannabinoid receptor agonist. Activation of cannabinoid receptors with HU-210 had practically no effect on collateral blood flow in the myocardium, but considerably decreased the area of necrosis. There results indicate that cannabinoid receptor agonist HU-210 possesses cardioprotective activity and delays the formation of necrotic zones during coronary occlusion and reperfusion.

[Anandamide and R-(+)-methanandamide prevent development of ischemic and reperfusion arrhythmia in rats by stimulation of CB2-receptors]. / Anandamid i R-(+)metanandamid preduprezhdaet razvitie ishemicheskikh i reperfuzionnykh aritmii u krys posredstvom stimuliatsii CB2-retseptorov.

It has been found that prior intravenous administration of the endocannabinoid anandamide (10 mg/kg) or its synthetic analogue R-(+)-methanadamide (5 mg/kg) prevents a development of ischemic and reperfusion arrhythmias in rats. The prior injection of the CB1 receptor antagonist, SR 141716A (3 mg/kg), did no affect the antiarrhythmic action of both cannabinoids. Pretreatment with the CB2 receptor antagonist, SR 144528 (1 mg/kg), completely abolished antiarrhythmic effect of anandamide and R-(+)-methanandamide. Both CB antagonist had no effect on the arrhythmias itself. Pretreatment with the NO-synthase inhibitor, L-NAME (50 mg/kg), had no effect on the antiarrhythmic action of cannabinoids. We therefore conclude that CB2 receptor stimulation increases the heart tolerance to ischemic and reperfusion arrhythmias.

[Specificity of the anti-arrhythmic effect of kappa1-opioid receptor agonists]. / K voprosu o spetsifichnosti antiaritmicheskogo éffekta agonistov kappa1-opioidnykh retseptorov.

It is demonstrated that intravenous administration of the kappa 1-opioid receptor (OR) agonists (-)-trans-(1S,S)-U-50,488 and (+)-trans-(1R,2R)-U-50,488 increases heart tolerance to the arrhythmogenic effect of epinephrine in rats. This antiarrhythmic effect was completely abolished by preliminary kappa-OR blocking with norbinaltorphimine. Preliminary administration of of a high-affinity kappa 1-OR agonist (-)-trans-(1S,S)-U-50,488 significantly reduced the incidence of ventricular arrhythmias upon coronary artery occlusion and reperfusion in vivo. The low-affinity (+)-trans-(1R,2R)-U-50,488 does not show antiarrhythmic activity under ischemia and reperfusion of myocardium. It is concluded that the antiarrhythmic action of kappa 1-OR agonists in the adrenal, ischemic, and reperfusion arrhythmia models has a receptor-specific character.

Activation of type II cannabinoid receptors improves myocardial tolerance to arrhythmogenic effects of coronary occlusion and reperfusion.

Preliminary intravenous injection of cannabinoid receptor agonist HU-210 (0.05 mg/kg) reduced the incidence of ventricular arrhythmias during 10-min coronary occlusion and 10-min reperfusion in chloralose-anesthetized rats. Preliminary injection of type I cannabinoid receptor antagonist SR 141716A (3 mg/kg) had no effect on the antiarrhythmic effect of HU-210, while type II cannabinoid receptor antagonist SR 144528 (1 mg/kg) completely abolished the effect of HU-210. Preconditioning with glibenclamide (0.3 mg/kg), an inhibitor of ATP-dependent K(+)-channels, did not affect the antiarrhythmic activity of HU-210. These findings suggest that antiarrhythmic effect of HU-210 is mediated through activation of type II cannabinoid receptors rather than activation of K(+)-channels.

Endogenous cannabinoid anandamide increases heart resistance to arrhythmogenic effects of epinephrine: role of CB(1) and CB(2) receptors.

Intravenous injection of 10 mg/kg anandamide reduces the incidence and duration of epinephrine-induced arrhythmias in rats. SR141716A and SR144528, antagonists of cannabinoid receptor I and II did not abolish the antiarrhythmic effect of anandamide. These data suggest that the antiarrhythmic effect of anandamide is nonspecific or mediated via unknown cannabinoid receptors, but not associated with activation of cannabinoid receptors I and II.

[The anti-arrhythmia and pro-arrhythmia properties of sigma-receptor ligands]. / Antiaritmicheskie i proaritmicheskie svoistva ligandov sigma-retseptorov.

It has been found that the sigma 1- and sigma 3-receptor antagonists, DuP 734 intraperitoneally and XJ 448 intravenously, had antiarrhythmic effects against epinephrine-induced arrhythmias in rats. The ED50 for antiarrhythmic effect of DuP 734 was 0.157 mg/kg after intraperitoneal administration. Other sigma-receptor antagonists (rimcazole, BMY 14802, haloperidol) did not affect the incidence of epinephrine-induced arrhythmias. sigma 1-Receptor agonists (DTG, N-allyl-normetazocine, (+)-3-PPP, (-)-3-PPP) had proarrhythmic effect after systemic administration. The sigma-agonist N-allyl-normetazocine and sigma-antagonist XJ 488 had no effect on the incidence of epinephrine-induced arrhythmias after intracerebroventricular administration. Therefore, it appears that the central nervous system does not play a significant role in the antiarrhythmic or proarrhythmic effects of sigma ligands. We hypothesize that these effects of sigma ligands might be dependent on their action on cardiac sigma receptors.

Involvement of central and peripheral cannabinoid receptors in the regulation of heart resistance to arrhythmogenic effects of epinephrine.

Intravenous injection of the selective cannabinoid receptor agonist HU-210 in doses of 0.05 and 0.25 mg/kg increased heart resistance to arrhythmogenic effects of epinephrine, while intracerebroventricular infusion of this substance had no effect on the incidence of epinephrine-induced arrhythmia. The selective antagonist of type I cannabinoid receptors SR141716A in a dose of 3 mg/kg and ganglion blocker hexamethonium in a dose of 10 mg/kg did not modify the antiarrhythmic effect of HU-210. This effect of HU-210 is probably related to activation of type II peripheral cannabinoid receptors.

Participation of central and peripheral kappa 1 and kappa 2 opioid receptors in arrhythmogenesis.

1. The kappa 1 and kappa 2 opioid receptor agonists U-62066 (8 mg/kg, i.p.) and (-)-bremazocine (0.7 mg/kg, i.v.), respectively, both exhibit anti-arrhythmic properties against adrenaline-induced dysrhythmias in rats. 2. In contrast, (+)-bremazocine has no effect on adrenaline-induced dysrhythmias. 3. The kappa 1 opioid receptor agonists U-50488 (110 nmol) and [D-Ala2]-dynorphin A (20 nmol) and the kappa 2 opioid receptor agonist (-)-bremazocine (30 nmol) exhibit pro-arrhythmic properties following intracerebroventricular administration. 4. Prior administration of the kappa opioid receptor antagonist nor-binaltorphimine doses i.c.v. (14 nmol), i.p. (10 mg/kg), completely abolishes the pro-arrhythmic (BNI, i.c.v., 14 nmol) as well as anti-arrhythmic (BNI, 10 mg/kg, i.p.) effects of the kappa opioid receptor agonists. 5. Neither hexamethonium (10 mg/kg, i.v.) nor atropine (1 mg/kg, i.v.) have any effect on the anti-arrhythmic actions of the kappa 1 opioid receptor agonist U-62066 following systemic administration. 6. It is suggested that the anti-arrhythmic effects of U-62066 and (-)-bremazocine are associated with the activation of peripheral kappa opioid receptors and do not depend on the activation of kappa opioid receptors in the autonomic nervous system.

[Modulation of the antiarrhythmic effect by endogenous opioids during adaptation to hypoxia in rats]. / O moduliruiushchem vliianii éndogennykh opioidov na antiaritmicheskii éffect pri adaptatsii krys k gipoksii.

Adaptation of rats to hypoxia increased the heart resistance against arrhythmogenic effects. The Met-enkephaline-Arg6-Phe7 contant increased in the hypothalamus of the adapted animals. The blockers of mu- and delta-opioid receptors reduced the antiarrhythmic effect of the adaptation, whereas chi-receptor inhibitor, nor-binaltorphimine, completely abolished it. The findings suggest the antiarrhythmic effect depends on an increase of the endogenous opioids level and modulated effect of these peptides upon autonomous nervous system.

[Delta-opiate receptors and heart resistance to arrhythmogenic factors]. / Delta-opiatnye retseptory i ustoichivost' serdtsa k aritmogennym vliianiiam.

Stimulation of peripheral delta-opioid receptors exerted no effect on arrhythmias, whereas that central delta 1- and delta 2-receptor activation decrease the heart susceptibility to arrhythmogenic action of epinephrine. Pre-treatment with the delta-opioid receptor antagonist ICI 174 prevented the antiarrhythmic effect of the central delta-receptors stimulation. The findings suggest that the heart decreased vulnerability to epinephrine-induced arrhythmias following the central delta-receptors stimulation is mediated by an enhanced vagal activity.