Opioid Receptors and Heart Resistance to Arrhythmogenic Factors

We present detailed data on the role of central and peripheral opioid receptors in the regulation of heart resistance to arrhythmogenic factors. Stimulation of peripheral delta2- and kappa1-receptors increases heart resistance to the arrhythmogenic effect of acute ischemia and reperfusion. Activation of peripheral mu- and delta1-opioid receptors improves electrical stability of the heart in animals with postinfarction cardiosclerosis. Possible mechanisms for opioidergic regulation of heart resistance to arrhythmogenic factors are discussed.     

Effect of in vivo and in vitro stimulation of delta1-opioid receptors on myocardial resistance to arrhythmogenic action of ischemia and reperfusion

Preliminary intravenous injection of peptide agonist of delta1-opioid receptors DPDPE (0.5 mg/kg) decreased the incidence of occlusion (10 min) and reperfusion (10 min) arrhythmias in rats. By contrast, ₂-opioid receptor agonist DSLET produced no effect on the incidence of arrhythmias provoked by coronary occlusion and reperfusion. Preliminary injection of selective -receptor antagonist ICI 174,864 (2.5 mg/kg) or TIPP[] (0.5 mg/kg) completely abolished the antiarrhythmic effect of DPDPE. Stimulation of cardiac ₁-opioid receptors with DPDPE added to perfusion saline in concentrations of 0.1 and 0.5 mg/liter decreased the incidence of reperfusion arrhythmias. Addition of DPDPE to perfusion saline in a concentration of 0.1 mg/liter prevented reoxygenation destruction of cardiomyocytes. By contrast, no cardioprotective effect of this peptide was observed at a concentration of 0.5 mg/liter in perfusion saline or when it was injected intravenously. It is concluded that the cardioprotective and antiarrhythmic effects of DPDPE are caused by activation of cardiac ₁-opioid receptors.     

Role of Endogenous Opioid Receptor Agonists in Regulation of Heart Resistence to the Arrhythmogenic Action of Short-Term Ischemia and Reperfusion

Preliminary selective block of -, ₁-, ₂-, and -opioid receptors had no effect on the incidence of ventricular arrhythmias during 10-min coronary occlusion-reperfusion in ketamine-narcotized rats. Repetitive short-term immobilization of rats for 2 weeks improved heart resistance to the arrhythmogenic action of coronary occlusion and reperfusion. Selective -opioid receptor antagonist CTAP completely abolished, while selective - and -opioid receptor antagonists did not modulate the antiarrhythmic effect of adaptation. Probably, endogenous agonists of -opioid receptors play an important role in the adaptive improvement of heart resistance to arrhythmogenic factors, but are insignificant for the modulation of heart resistance to the arrhythmogenic action of short-term local ischemia-reperfusion in non-adapted animals.__________Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 139, No. 2, pp. 138–142, February, 2005     

Involvement of central and peripheral cannabionoid 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.     

Role of cannabinoid receptors in the regulation of cardiac contractility during ischemia/reperfusion

We studied the effect of selective ligands of cannabinoid (CB) receptors on contractility of isolated Langendorff-perfused rat heart under conditions of 45-min total ischemia and 30-min reperfusion. Perfusion with a solution containing selective CB receptor agonist HU-210 for 10 min before ischemia increased the severity of reperfusion contractile dysfunction. This drug decreased left ventricular developed pressure and maximum rates of contraction and relaxation, but had no effect on heart rate and end-diastolic pressure. The negative inotropic effect of the drug was transitory and disappeared after 5-min reperfusion. Pretreatment with selective CB1 receptor antagonist SR141716A and selective CB2 receptor antagonist SR144528 had no effect on heart rate and myocardial contractility during reperfusion. Our results indicate that stimulation of CB receptors can increase the degree of reperfusion-induced cardiac contractile dysfunction. However, endogenous cannabinoids are not involved in the development of myocardial contractile dysfunction during ischemia/reperfusion of the isolated heart. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 11, pp. 500–504, November, 2006     

Activation of k<Subscript>1</Subscript>-opioid receptor as a method for prevention of ischemic and reperfusion arrhythmias: Role of protein kinase C and K<Subscript>ATP</Subscript> channels

Intravenous pretreatment with κ-opioid receptor antagonist (−)-U-50,488 (1 mg/kg) improved heart resistance to the arrhythmogenic effect of coronary occlusion and reperfusion. Selective κ₁-opioid receptor antagonist norbinaltorphimine and nonselective blocker of peripheral opioid receptors methylnaloxone abolished this antiarrhythmic effect. Preliminary blockade of protein kinase C with chelerythrine or inhibition of ATP-dependent K⁺ channels (K_ATP channels) with glybenclamide abolished the antiarrhythmic effect of κ-opioid receptor activation. Selective inhibitor of sarcolemmal K_ATP channels did not modulate the κ-opioid receptor-mediated increase in cardiac electrical stability. Our results suggest that protein kinase C and mitochondrial K_ATP channels play an important role in the antiarrhythmic effect associated with activation of peripheral κ-opioid receptors. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 2, pp. 145–148, February, 2007     

Myocardial resistance to ischemic and reperfusion injuries under conditions of chronic administration of opioid receptor agonists and antagonists

Chronic treatment with opioid receptor ligands: nonselective peptide opioid receptor agonist dalargin (intraperitoneally in a dose of 1 mg/kg), selective nonpeptide κ-receptor agonist GR 89696 (subcutaneously in a dose of 0.03 mg/kg), nonselectrive nonpeptide antagonist quadazocine (subcutaneously in a dose of 3 mg/kg) or naltrexone (subcutaneously in a dose of 10 mg/kg) for 20 day had no effect of the incidence of ischemic ventricular arrhythmias and the size of necrotic zone after coronary occlusion and reperfusion in rats in vivo. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 145, No. 6, pp. 642–644, June, 2008     

自噬在缺血性心脏病发病机制中的作用

在心肌缺血再灌注过程中可以通过多种因素诱导细胞的自噬活动,心肌细胞自噬可以保护细胞,减少细胞损失,但是自噬也可导致心肌细胞死亡。     

Muscarinic acetylcholine receptors in the heart of rats before and after birth

Atropine-displaceable binding of (³H)quinuclidinyl benzilate (QNB) to homogenates was used to identify the muscarinic binding sites in rat heart atria and ventricles and to investigate developmental changes in their concentration and binding properties between the 15th day of prenatal life and 3 months after birth. On the 15th day of prenatal life, muscarinic binding sites were already present in the heart. Their concentration increased steeply between the 15th and 19th days of prenatal development; in the atria, it remained high until the 1st day after birth and thereafter it diminished throughout the postnatal life, while in the ventricles the decrease started before the first postnatal day. The concentration of the binding sites was 1.8–3.0 times higher in the atria than in the ventricles at all time points investigated. Their affinity for QNB (the antagonist) was the same in the atria and ventricles and did not change during postnatal development (K _D of 17.8 pmol/l at an infinitely low concentration of the binding sites). The binding of carbamoylcholine (the agonist) to muscarinic bindig sites was analysed in experiments with the displacement of (³H)QNB binding, assuming the presence of high- and low-affinity binding sites for agonists. The proportion between the concentrations of the two classes of agonist binding sites is close to 1:1 both in the atria and the ventricles and does not change with age. No statistical significant differences were discovered between the affinities of the high- and low-affinity binding sites for carbamoylcholine between the atria and the ventricles and between new-born and adult rats. It is suggested that the steep increase in the number of muscarinic binding sites between the 15th and 19th days of prenatal development is triggered by the arrival of nerve cells and fibres into the heart (occuring on the 14th–16th day) and that it is one of the factors responsible for the onset of effective neuro-effector transmission in the heart (21st day of prenatal development). The commencement of tonic cardioinhibitory vagal control (18th day after birth) appears unrelated to developmental changes of cardiac muscarinic binding sites.     

Opioid peptides selective for mu- and delta-opiate receptors reduce calcium-dependent action potential duration by increasing potassium conductance

We suggest that both mu- and delta-opiate receptors on dorsal root ganglion neuron somata are coupled to voltage- and/or calcium-dependent potassium channels since opioid peptide decreases of calcium-dependent action potential duration were: (1) not associated with a change of resting membrane potential or conductance; (2) accompanied by an increase in action potential after-hyperpolarization, and (3) blocked by intracellular injection of the potassium channel blocker cesium [18]. In contrast, norepinephrine [4] and cadmium [9], which have been reported to act on voltage-dependent calcium rather than potassium channels, shortened action potential duration and decreased after-hyperpolarization amplitude, an action not blocked by intracellular iontophoresis of cesium.     

Opioid activity in behavioral and heart rate responses of tethered pigs to acute stress

In a longitudinal experiment, effects of long-term tether housing on heart rate and behavioral responses to an acute stressor (a 15-min challenge with a nosesling) were investigated in pigs. The animals were challenged during loose housing and again after 10-11 weeks of tether housing. To detect possible changes in endogenous opioid systems modifying these responses, the pigs were pretreated with the opioid receptor antagonist naloxone (0.5 mg/kg body weight, iv). In response to the nosesling challenge, the animals showed pronounced resistance behavior and a sharp rise in heart rate. Following this initial phase of resistance, the heart rate dropped to prechallenge levels or below this line, and the pigs seemed to become sedated. Pretreatment with naloxone increased the heart rate response in animals that were long-term tether housed (n=12). No such effect was found in the control group (n=5) that was loose-housed during the entire experiment, indicating that the impact of endogenous opioid systems mitigating heart rate responses to acute stress had increased as a result of long-term tether housing. Changes in the effect of naloxone on the behavioral response were not found. Adaptive changes in opioid systems may prevent excessive physiological reactions to acute stress and, thus, may serve as a coping mechanism.     

Antiarrhythmic and arrhythmogenic effects of L-carnitine in ischemia and reperfusion

Isolated rat hearts were subjected to 30-min coronary artery occlusion followed by 120-min reperfusion. The hearts (n=8–12) were perfused with Krebs-Henseleit solution enriched with L-carnitine (0.5, 2.5 and 5 mM) for 10 min before and after ischemia or reperfusion and for the whole period of ischemia and reperfusion. Two-hour perfusion with L-carnitine during ischemia/reperfusion markedly (p<0.05) and dose-dependently decreased the incidence of ventricular tachycardia (VT, maximum 65%). The incidence of reperfusion ventricular fibrillation (VF) also decreased from 63% (control) to 17% in hearts perfused with 5 mM L-carnitine, as reflected by a significant (p<0.05) decline in VF duration from 218±99 sec in control to 19±19 sec. Perfusion of etomoxir (palmitoylcarnitinetransferase-1 inhibitor) along with L-carnitine reversed the antiarrhythmogenic action of L-carnitine. Interestingly, short time preischemic administration of L-carnitine produced a concentration-dependent arrhythmogenic effects on both ischemia and reperfusion-induced arrhythmias. These results show that L-carnitine produced a protective effect against reperfusion arrhythmias only when it was perfused for the whole period of the experiment. This protective action was reversed by concomitant use of etomoxir, suggesting that the efficacy of L-carnitine is due to its mitochondrial action but cannot be solely attributed to increased fatty acid oxidation. Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 146, No. 8, pp. 175–178, August, 2008     

Involvement of central and peripheral cannabionoid 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. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 130, No. 11, pp. 552–554, November, 2000     

Receptor specificity of the antiarrhythmic effect produced by opioid peptides Dalargin and DADLE during myocardial reperfusion

Nonselective agonists of mu- and delta-opioid receptors dalargin (D-Ala2,Leu5,Arg6-enkephalin) and DADLE (D-Ala2,D-Leu5-enkephalin) administered immediately before coronary reperfusion in a dose of 0.1 mg/kg prevented the development of ventricular arrhythmias. Blockade of mu-opioid receptors abolished the antiarrhythmic effect of these peptides. Hence, antiarrhythmic activity of dalargin and DADLE is primarily associated with activation of mu-opioid receptors.     

Effects of opioid peptides on the development of ischemic cardiac arrhythmias under conditions of partial sympathetic denervation and laser irradiation

The effects of intravenous administration of different opioid peptides on the development of ischemic cardiac arrhythmias under conditions of intraatrial laser irradiation (λ=632.8 nm) were studied in cats with transected cardiac branches of the right stellate ganglion and preserved sympathetic innervation of the ischemized area. Ischemia was caused by occlusion of the circumflex branch of the left coronary artery. It was found that the protective effects of dalargin were most powerful when sympathetic influences on the ischemic area were intestified by laser irradiation. Under these conditions DAGO showed more pronounced antiarrhythmic effects than DSLET. Translated fromByulleten' Eksperimental'noi Biologii i Medistiny, Vol. 127, No. 4, pp. 374–377, April, 1999     

Separation of early afterdepolarizations from arrhythmogenic substrate in the isolated perfused hypokalaemic murine heart through modifiers of calcium homeostasis

Aims: We resolved roles for early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in Langendorff‐perfused hypokalaemic murine hearts paced from the right ventricular epicardium. Methods: Left ventricular epicardial and endocardial monophasic action potentials (MAPs) and arrhythmogenic tendency were compared in the presence and absence of the L‐type Ca²⁺ channel blocker nifedipine (10 nm –1 μm ) and the calmodulin kinase type II inhibitor KN‐93 (2 μm ). Results: All the hypokalaemic hearts studied showed prolonged epicardial and endocardial MAPs, decreased epicardial‐endocardial APD₉₀ difference, EADs, triggered beats and ventricular tachycardia (VT) (n = 6). In all spontaneously beating hearts, 100 (but not 10) nm nifedipine reduced both the incidence of EADs and triggered beats from 66.9 ± 15.7% to 28.3 ± 8.7% and episodes of VT from 10.8 ± 6.3% to 1.2 ± 0.7% of MAPs (n = 6 hearts, P < 0.05); 1 μm nifedipine abolished all these phenomena (n = 6). In contrast programmed electrical stimulation (PES) still triggered VT in six of six hearts with 0, 10 and 100 nm but not 1 μm nifedipine. 1 μm nifedipine selectively reduced epicardial (from 66.1 ± 3.4 to 46.2 ± 2.5 ms) but not endocardial APD₉₀, thereby restoring ΔAPD₉₀ from ?5.9 ± 2.5 to 15.5 ± 3.2 ms, close to normokalaemic values. KN‐93 similarly reduced EADs, triggered beats and VT in spontaneously beating hearts to 29.6 ± 8.9% and 1.7 ± 1.1% respectively (n = 6) yet permitted PES‐induced VT (n = 6), in the presence of a persistently negative ΔAPD₉₀. Conclusions: These findings empirically implicate both EADs and triggered beats alongside arrhythmogenic substrate of ΔAPD₉₀ in VT pathogenesis at the whole heart level.