Opioid peptide deltorphin II simulates the cardioprotective effect of ischemic preconditioning: role of δ2-opioid receptors, protein kinase C, and K(ATP) channels.

The cardioprotective properties of a δ2-opioid receptor agonist deltorphin II were studied in rats with coronary occlusion and reperfusion. Opioid receptor ligands and inhibitors (glybenclamide, chelerythrine, and 5-hydroxydecanoate) were injected intravenously before ischemia and reperfusion. A δ2-opioid receptor agonist deltorphin II significantly decreased the infarction zone/risk zone index. This effect was abolished by naltrexone, naloxone methiodide, and δ2-opioid receptor antagonist naltriben, but not by a δ1-opioid receptor antagonist BNTX. The infarct-limiting effect of deltorphin II was not observed after inhibition of protein kinase C or blockade of mitochondrial K(ATP) channels.

[Adaptation of myocardium to ischemia. The early phase of ischemic preconditioning].

It has been systematized modem data on the early phase of ischemic preconditioning and cardiac resistance to pathogenic action of ischemia and reperfusion. It has been performed an analysis published works on the important role of alteration of myocardium energy metabolism in the development of adaptation resistance of the heart to ischemia. It has been shown that adenosine, bradykinin and opioid peptides and also signalling cascade involved phospholipase C and D, protein kinase C, tyrosine kinase and mitochondrial ATP-sensitive potassium channel play a key role in the mechanism of cardioprotective action of ischemic preconditioning.

[The interaction of mu-opioid receptors with ion channels and G-proteins].

The state-of-the-art in investigations of the mu-opioid receptors (ORs) is reviewed. Published information on the interaction between mu-ORs and various G-proteins is summarized and data on the neutral antagonists and inverse agonists of mu-opioid receptor are generalized. The notions about the spontaneous activation of mu-ORs are considered and numerous reports on the interaction between mu-ORs and GIRK, KATP, and Kv channels are analyzed. The role of L, N, and P/Q types of Ca(2+)-channels in mu-OR-mediated intracellular signaling is discussed.

[The interaction of mu-opioid receptors with intracellular signal systems].

Review is devoted a modem state of researches of micro-opioid receptor. It is discussed literature data on the integration of micro-opioid receptor with adenylyl cyclase, phospholipase A2, C and D. It is analyzed reports on the interaction of micro-opioid receptor with NO-synthase and guanylyl cyclase.

[Comparative study of the antiarrhythmic activity of mu- and delta-opioid receptor agonists during acute cardiac ischemia and reperfusion models in rats].

It has been established that pretreatment with the selective mu-opioid receptor (OR) agonist DALDA (0.1 mg/kg, i.v.) or the selective delta1-OR agonists DPDPE (0.09 mg/kg) and/or (-)-TAN-67 (0.08 mg/kg) has no effect on the incidence of ventricular arrhythmias induced by a 10-min coronary artery occlusion and a 10-min reperfusion in ketamine-anesthetized rats. In contrast, the pretreatment with the selective delta2-OR agonist deltorphin II (0.12 mg/kg) and the proposed delta2-OR agonists deltorphin D (0.3 mg/kg) and/or dermorphin H (0.23 mg/kg) increases cardiac resistance to the arrhythmogenic action of acute ischemia and reperfusion. Administration of the mixed mu- and delta-OR agonist dalargin (0.12 mg/kg) 15 min before the coronary artery ligation abolished only the reperfusive ventricular fibrillation. It is concluded that peptidergic stimulation of delta2-ORs can be used as a new means of increasing cardiac tolerance to the arrhythmogenic effects of acute ischemia and reperfusion.

[The antiarrhythmic effect of (-)-U-50,488 in rats with acute ischemia and reperfusion of heart is mediated by kappa1-opioid receptor activation].

Pretreatment with a selective kappa1 opioid receptor (OR) agonist (-)-U-50,488 (1 mg/kg, i.v.) prevented the development of arrhythmias induced by occlusion (10 min) and reperfusion (10 min) in ketamine anesthetized rats, while the treatment with a less active enantiomer (+)-U-50,488 in the same dose produced no such effects. Preliminary intravenous administration of a selective kappa1 OR antagonist norbinaltorphimine (9 mg/kg) fully abolished the antiarrhythmic effect of (-)-U-50,488, while the kappa2 OR antagonist quadazocine (3 mg/kg) did not eliminate this effect. The injections of norbinaltorphimine or quadazocine alone did not influence the incidence of model arrhythmias caused by the occlusion and reperfusion. It was concluded that kappa1 OR stimulation favors an increase in cardiac tolerance to the arrhythmogenic action of occlusion and reperfusion.

[Contribution of the endogenous opioid system to regulation of heart resistance to the arrhythmogenic effect of short-term ischemia and reperfusio].

Preliminary selective blockade of micro, delta1, delta2, kappa1, and kappa2 opioid receptors proved to have no effect on the incidence of ventricular arrhythmias during a 10-min coronary occlusion and subsequent reperfusion in ketamine-anesthetized rats. We propose that the endogenous opioid system has no considerable role in regulation of heart resistance to the arrhythmogenic effect of short-term local ischemia and subsequent reperfusion.

Activation of peripheral delta opioid receptors eliminates cardiac electrical instability in a rat model of post-infarction cardiosclerosis via mitochondrial ATP-dependent K+ channels.

The effects of the selective delta-1 (delta(1)) opioid receptor agonist, DPDPE, and the selective delta(2) opioid receptor agonist, DSLET, have been studied on the ventricular fibrillation threshold (VFT) in rats with an experimental post-infarction cardiosclerosis (CS). It has been found that CS induced a significant decrease in VFT. This CS-induced decrease in VFT was significantly reversed by intravenous administration of DPDPE (0.1 mg/kg) 10 min before VFT measurement. On the contrary, intravenous injection of DSLET (0.5 mg/kg) exacerbated the CS-induced cardiac electrical instability. Pretreatment with the selective delta opioid receptor antagonist, ICI 174,864 (0.5 mg/kg), completely abolished the changes in VFT produced by both DPDPE and DSLET. Previous administration of a nonselective peripherally acting opioid receptor antagonist, naloxone methiodide (5 mg/kg) also completely reversed the antifibrillatory action of DPDPE. Naloxone methiodide and ICI 174,864 alone had no effect on VFT. Pretreatment with the nonselective K(ATP) channel blocker, glibenclamide (0.3 mg/kg), or with the mitochondrial selective K(ATP) channel blocker, 5-hydroxydecanoic acid (5-HD, 5 mg/kg), completely abolished the DPDPE-induced increase in cardiac electrical stability. Glibenclamide and 5-HD alone had no effect on VFT. These results demonstrate that the delta opioid receptor plays an important role in the regulation of electrical stability in rats with post-infarction cardiosclerosis. We propose that peripheral delta(1) opioid receptor stimulation reverses CS-induced electrical instability via mitochondrial K(ATP) channels. On the contrary, delta(2) opioid receptor stimulation may exacerbate the CS-induced decrease in VFT. Further studies are necessary to determine the delta opioid receptor subtype which mediates the antifibrillatory effect of DPDPE and pro-fibrillatory effect of DSLET.

[Myocardial tolerance to arrhythmogenic exposure and pharmacological activation of K(ATP)-channels in rats]. / Tolerantnost' serdtsa krys k aritmogennym vozdeistviiam v usloviiakh farmakologicheskoi aktivatsii K(ATP)-kanalov.

The cardioselective KATP channel activator BMS 180448 (3 mg/kg) administered intravenously 15 min before the coronary artery occlusion (10 min) decreased the incidence of ischemic and reperfusion arrhythmias in rats. A similar antiarrhythmic effect was observed when BMS 180448 was infused 2 min before reperfusion. Pretreatment with BMS 180448 also prevented the occurrence of CsCl induced arrhythmias, but but did not affect the incidence of epinephrine induced arrhythmias. On the contrary, BMS 180448 potentiated the arrhythmogenic action of CaCl2. The mechanism of the antiarrhythmic activity of BMS 180448 is discussed.

[Stimulation of peripheral delta1-opioid receptors as a method of preventing ischemic and reperfusion arrhythmia: role of K(ATP)-channels]. / Stimuliatsiia perifericheskikh delta(1)-opioidnykh retseptorov kak sposob profilaktiki ishemicheskikh i reperfuzionnykh aritmii: rol' K(ATP)-kanalov.

Preliminary administration of the delta 1-opioid receptor (delta 1-OR) peptide agonist DPDPE (0.5 mg/kg, i.v.) decreased the incidence of occlusion (10 min) and reperfusion (10 min) arrhythmias in rats. The delta 2-OR agonist DSLET did not affect arrhythmias upon the coronary artery occlusion and reperfusion. Pretreatment with the selective delta-antagonists ICI 174,864 (2.5 mg/kg) or TIPP[psi] (0.5 mg/kg) completely eliminated the antiarrhythmic effect of DPDPE. Uncapable of crossing the blood brain barrier, the nonselective OR antagonist naloxone methiodide (5 mg/kg) also abolished this effect. At the same time, hexametonium (10 mg/kg) did not antagonize the antiarrhythmic effect of DPDPE. Pretreatment with the KATP channel blocker glibenclamide (0.3 mg/kg) completely eliminated the protective effect of the delta 1-OR stimulation. It was concluded that the delta 1-OR stimulation prevents the ischemic and reperfusion arrhythmias by means of the KATP channel activation.

[Participation of K(ATP)-channels in cardioprotective effect of mu-opioid receptor agonists in acute ischemia and reperfusion of the isolated heart]. / Rol' K(ATP)-kanalov v realizatsii kardioprotektornogo deistviia agonistov miu-opioidnykh retseptorov pri ostroi ishemii i reperfuzii izolirovannogo serdtsa.

Preliminary administration of the mu-opioid receptor (mu-OR) agonist DAMGO (0.1 mg/kg) 15 min before heart isolation led to attenuation of the postischemic systolic and diastolic contractility dysfunction in isolated perfused rat heart. In addition, the mu-OR decreased creatine kinase (CK) release from the heart during the postischemic period, which was indicative of an increase in the sarcolemma tolerance to reperfusion injury. This protective effects are mediated by KATP channel activation. These data show that the mu-OR stimulation in vivo increases, by means of the KATP channel activation, the cardiac tolerance to the ischemia and reperfusion injury in vitro. Pretreatment with mu-OR agonists DAMGO or DALDA in vitro (0.5 mg/liter, 15 min prior to ischemia) exacerbated the postischemic contractility dysfunction of myocardium and did not affect the CK release. It is concluded that the protective effect of mu-OR simulation in vivo is mediated by the activation of these receptors localized outside the heart, probably with an unknown circulating humoral factor.

[The mechanism of antiarrhythmic action of the endogenous ORL1 receptor agonist nociceptin]. / K mekhanizmu aniaritmicheskogo deistviia éndogennogo agonista ORL! retseptorov Notsitseptina.

Prophylactic intravenous (i.v.) injections of a selective agonist of ORL1 receptors nociceptin (orphanin FQ) in a dose of 0.4 mg/kg prevented the development of aconitine-induced arrhythmia in rats narcotized with diethyl ether or chloralose. Pretreatment with L-NAME (50 mg/kg) completely abolished this effect of orphanin FQ, while the pretreatment with indomethacin (10 mg/kg) only attenuated the agonist effect, rather than abolished it completely. At the same time, pretreatment with hexamethonium (10 mg/kg) or glibenclamide (3 mg/kg) had no effect on the nociceptin-dependent cardiac tolerance to the arrhythmogenic action of aconitine. Intracerebroventricular (i.c.v.) infusion of orphanin FQ (36 microg) also prevented the onset of aconitine-induced arrhythmia, but this effect was completely abolished by hexamethonium. It is concluded that the antiarrhythmic action of nociceptin with respect to aconitine-induced arrhythmia upon i.v. and i.c.v. administration is explained by different mechanisms. In the former case, the effect of orphanin FQ is related to the activation of NO synthase and cyclooxygenase, while the central action involves the vegetative nervous system.

[Stimulation of delta1-opioid receptors increases the ventricular fibrillation threshold in post-infarct cardiosclerosis: the role of K(ATP)-channels]. / Stimuliatsiia del'ta1 opioidnykh retseptorov povyshaet porog zheludochkovoi fibrilliatsii pri postinfarktnom kardioskleroze: rol' K(ATP)-kanalov.

Preliminary administration of the delta 1-opioid receptor (delta 1-OR) selective peptide agonist DPDPE (0.1 mg/kg, i.v.) increased the ventricular fibrillation threshold (VFT) in postinfarction cardiosclerosis in rats. Pretreatment with the selective delta 1-OR antagonists ICI 174,864 (not affecting VFT) in a dose of 0.5 mg/kg completely eliminated the DPDPE-induced increase in the VFT. Pretreatment with the KATP channel selective blocker glibenclamide (0.3 mg/kg, i.v.) completely eliminated the delta 1-OR mediated increase in the VFT protective effect of the delta 1-OR stimulation. The intravenous injection of the mitochondrial KATP channel blocker 5-hydroxydecanoate (5 mg/kg) simultaneously with DPDPE not only eliminated the delta 1-OR mediated increase on VFT, but additionally increased the VBFT drop caused by cardiosclerosis. Injected separately, neither glibenclamide nor hydroxydecanoate affected the VFT level. It is concluded that stimulation of the delta 1-OR increases VFT by activating mitochondrial KATP-channels.

[The effect of K(ATP)-channel activation on the electrical stability of myocardium in rats with postinfarction cardiosclerosis]. / Vliianie aktivatsii K(ATP)-kanalov na élektricheskuiu stabil'nost' miokarda pri postinfarktnom kardioskleroze.

Opening of the ATP-dependent K-channels (K(ATP) channels) upon intravenous administration of the cardioselective activator BMS 180448 (3 mg/kg) decreased the ventricular fibrillation threshold (VFT) in rats with postinfarction cardiosclerosis (PIC). Preliminary injection of the selective K(ATP) channel blocker glibenclamide (0.3 mg/kg, i.v.) completely abolished the profibrillatory effect of BMS 180448. At the same time, the mitochondrial K(ATP) channel blocker 5-hydroxydecanoic acid (5 mg/kg) did not influence the proarrhythmogen activity of BMS 180448. Simultaneous administration of the sarcoK(ATP) channel inhibitor HMR 1098 (3 mg/kg) and BMS 180448 increased the VFT up to a level in intact animals. Administration of the mitoK(ATP) channel activator diazoxide (5 mg/kg) after preliminary treatment with guanethidine (50 mg/kg) increased the VFT in rats with PIC. It is concluded that opening of the mitoK(ATP) channels increases the cardiac electrical stability in rats with PIC.

[Significance of opioid receptors in regulation of cardiac tolerance in pathogenic impact of long-term ischemia-reperfusion in vivo].

The study aimed at investigation of the role of opioid receptor (OR) in regulation of cardiac tolerance to ischemia-reperfusion. Opioid receptor ligands and inhibitors were administered in vivo prior to coronary artery occlusion (45 min) and reperfusion (2 hrs). Occurring infraction size/area at risk (IS/AAR) ratio was determined. Pretreatment with the micro-OR agonists DAMGO and dermorphin H exerted no effect on the IS/AAR ratio. Activation of delta 1-OR by DPDPE did not alter cardiac tolerance in ischemia-reperfusion either. Pretreatment with the delta 2-OR agonists deltorphin D and deltorphin E or ORL1 receptor agonist nociceptin exerted no effect on the IS/AAR ratio. Stimulation of K-OR by selective agonists did not modify cardiac tolerance to ischemia-reperfusion. The delta 2-OR agonist deltorphin II significantly reduced the IS/AAR index. This effect was prevented by treatment with naltrexone, naloxone methiodide and the delta 2-OR antagonist naltriben but not by the delta 1-OR antagonist BNTX. The infarction-limiting effect of deltorphin II was also abolished by inhibition of protein kinase C (PKC) and mitochondrial Katp channels. Thus, the agonists of micro, delta 1, kappa, and ORL1 receptors in used doses did not affect cardiac tolerance in ischemia-reperfusion injury in vivo. The peripheral delta 2-OR activation induces infarction size reduction. Its infarction-reducing effect of deltorphin II is mediated via PKC activation and mitochondrial Katp, channel opening.

Role of endogenous opioid receptor agonists in regulation of heart resistance to the arrhythmogenic action of short-term ischemia and reperfusion.

Preliminary selective block of mu-, delta1-, delta2-, and kappa-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 mu-opioid receptor antagonist CTAP completely abolished, while selective delta- and kappa-opioid receptor antagonists did not modulate the antiarrhythmic effect of adaptation. Probably, endogenous agonists of mu-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.

Possible mechanism underlying the antiarrhythmic effect of peptides nociceptin and DALDA on the heart.

During aconitine-induced arrhythmias the antiarrhythmic effect of DALDA (Tyr-D-Arg-Phe-Lys-NH2) and nociceptin (orphanin FQ) administered intravenously depended on activation of nitric oxide synthase. K(ATP) channels were not involved in the realization of this effect. Endogenous prostanoids played a minor role in the antiarrhythmic effect of nociceptin and did not contribute to the protective influence of DALDA. The antiarrhythmic effect of orphanin FQ administered intravenously did not depend on functional activity of the autonomic nervous system. However, the effect of orphanin FQ after intracerebroventricular infusion was determined by changes in the state of this system.

[Role of ORL1 receptors in the regulation of cardiac resistance to arrhythmogenic effects ]. / O znachenii ORL1-retseptorov v reguliatsii ustoichivosti serdtsa k aritmogennym vozdeistviiam.

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.

[Changes in cardiac resistance to arrhythmogenic effects during ATP-dependent K+ channel activation]. / Izmenenie ustoichivosti serdtsa k aritmogennym vozdeistviiam v usloviiakh aktivatsii ATF-zavisimykh K+ kanalov.

It has been found that pretreatment with ATP-dependent potassium channel (KATP-channel) opener, BMS 180448 (3 mg/kg, intravenously), increases cardiac resistance against arrhythmogenic action of coronary artery occlusion and reperfusion in anaesthetized rats. However, BMS 180448 induced a decrease in ventricular fibrillation threshold in rats postinfarction cardiac fibrosis. This effect was completely abolished by administration of the KATP-channel inhibitor, glibenclamide. By contrast, coadministration of BMS 180448 and selective sarcolemmal KATP-channel inhibitor, HMR 1098, promoted an increase in ventricular fibrillation threshold in rats with postinfarction cardiac fibrosis before normal value. The selective mitochondrial KATP-channel opener, diazoxide, also exacerbated a decrease in ventricular fibrillation threshold induced by postinfarction cardiac sclerosis. But after depletion of endogenous catecholamine storage by pretreatment with guanthidine, diazoxide, on the contrary, elevated the ventricular fibrillation threshold. It has been suggested that stimulation of mitochondrial ATP-sensitive potassium channels promotes an elevation in electrical stability of the heart, whereas opening of sarcolemmal KATP-channel increases a possibility of ventricular arrhythmias.