Comparative Analysis of Infarct Size Limiting Activity of κ-Opioid Receptor Agonists in In Vivo Reperfused Heart.

A 45-min coronary artery occlusion followed by a 120-min reperfusion was performed in rats anesthetized with α-chloralose. The selective κ1-opioid receptor (OR) agonist U-50,488 was administered intravenously in doses of 0.1 or 1 mg/kg. The selective κ2-OR agonist GR-89696 was injected in a dose of 0.1 mg/kg. The selective κ1-OR agonists ICI-199,441 and ICI-204,448 were employed in the doses of 0.1 and 4 mg/kg, respectively. These drugs were injected 5 min prior to reperfusion. U-50,488 exerted the cardioprotective effect in a dose of 1 mg/kg, but it produced no effect on infarct size in a dose of 0.1 mg/kg. ICI-199,441 reduced the reperfusion injury to the heart. The infarct size limiting effects of U-50,488 and ICI-199,441 were prevented by preliminary injection of naltrexone or nor-binaltorphimine. It is concluded that infarct size limiting effects of U-50,488 and ICI-199,441 were mediated via activation of κ1-OR.

Comparative Analysis of Infarct Size Limiting Activity of δ-Opioid Receptor Agonists in Reperfused Heart In Vivo.

The study examined the effects of δ-opioid receptor (OR) agonists on infarct size on cardiac ischemia (45 min) and reperfusion (120 min) in vivo model in rats narcotized with α-chloralose. The OR agonists were injected intravenously 5 min prior to reperfusion, OR antagonists were administered 10 min before reperfusion. A selective δ-OR agonist BW373U86 (1 mg/kg) reduced the infarct size/area at risk ratio. A selective δ1-OR agonist DPDPE injected in the doses of 0.1 or 0.969 mg/kg produced no effect on infarct size. The selective δ2-OR agonist deltorphin II (0.12 mg/kg) reduced infarct size/area at risk ratio by 2 times. The δ-OR agonist p-Cl-Phe-DPDPE (1 mg/kg) reduced infarct size/area at risk ratio by 40%. Naltrexone and naloxone methiodide, the peripheral OR antagonists, and selective δ2-OR antagonist naltriben prevented the infarct size limiting effect of deltorphin II. Therefore, activation of peripheral δ2-OR enhanced cardiac resistance against toxic action of reperfusion. During reperfusion, deltorphin II demonstrated the most pronounced cardioprotective activity.

Continuous Normobaric Hypoxia Improved Cardiac Bioenergetics after Ischemia/Reperfusion: Role of Opioid Receptors.

We analyzed the role of opioid receptors in the conditioning effect of continuous normobaric hypoxia on bioenergetics of the heart subjected to ischemia/reperfusion injury. Male Wistar rats were adapted to a 21-day continuous normobaric hypoxia (12% pO2). Then, the hearts were isolated and subjected to 45-min total ischemia followed by 30-min reperfusion. Damage to the myocardium was assessed by activity of creatine phosphokinase in the perfusate. Experiments on isolated mitochondria showed that ischemia/reperfusion injury decreased the respiration rate in state 3 (V3), the ratio of added ADP and oxygen consumption in respiration state 3 (ADP/O ratio), the mitochondrial potential across the inner membrane (Δψ), and Ca2+ binding capacity of mitochondria. In addition, ischemia/reperfusion injury decreased myocardial ATP. Preventive continuous normobaric hypoxia pronouncedly moderated these adverse effects of reperfusion. It was found that its protective effects were related to activation of cardiac µ- and δ2-opioid receptors.

The Role of Cardiac Opioid Receptors in the Cardioprotective Effect of Continuous Normobaric Hypoxia.

We studied the role of opioid receptor subtypes in improvement of the functional state of the heart during reperfusion after adaptation to continuous normobaric hypoxia. To this end, male Wistar rats were subjected to continuous normobaric hypoxia (12% O2). Then, the hearts were isolated and exposed to total 45-min ischemia followed by 30-min reperfusion. Opioid receptor antagonists were added to the perfusion solution prior to ischemia. It was found that continuous normobaric hypoxia reduced the release of creatine phosphokinase into the effluent, increased myocardial contractile force, and decreased the end-diastolic pressure during reperfusion; these positive effects were related to activation of cardiac δ2- and µ-opioid receptors.

Endomorphins and ß-Endorphin Do Not Affect Heart Tolerance to the Pathogenic Effect of Reperfusion.

Selective agonists of µ1- and µ2-opioid receptors endomorphin-2 and endomorphin-1 injected intravenously in a dose of 4500 nmol/kg in 5 min before coronary blood flow resumption had no effect on cardiac reperfusion damage. Consequently, µ1- and µ2-opioid receptors are not involved in the regulation of heart tolerance to reperfusion injury. Nonselective opioid receptor agonist ß-endorphin (100 nmol/kg) also did not affect heart tolerance to the pathogenic effect of reperfusion.

CB-Receptor Agonist HU-210 Mimics the Postconditioning Phenomenon of Isolated Heart.

CB receptor agonist HU-210 exhibits an infarction-limiting effect during in vitro reperfusion of the heart after focal ischemia. This effect is paralleled by a decrease in left-ventricular developed pressure and double product. In addition, HU-210 reduces end-diastolic pressure during the reperfusion period, which indirectly attests to reduced Ca2+ overload of cardiomyocytes.

[Remote preconditioning phenomenon. prospects for use in pathology of lung and gastrointestinal tract].

The literature data on the effectiveness of remote ischemic preconditioning (RIP) in the prevention of lung injury are contradictory. Authors of some works argue that RIP prevents lung damage during surgical interventions, the authors of other publications claim that the RIP does not protect lung against pathological processes. It is obvious that there is an urgent need for multicenter, randomized trials aimed at studying RIP protective effects against pathological processes in lung. Also required is clinical evaluation of the effectiveness of RIP in the thromboembolism of pulmonary arteries, the transplantation of the lungs and intestinal infarction. Remote preconditioning prevents the intestine injury associated with abdominal aortic aneurysm repair. Experimental data indicate that RIP has the hepatoprotective effect during ischemia and reperfusion injury of liver, septic or haemorrhagic shock. The question of whether the DIP has a protective effect during ischemia-reperfusion of the pancreas remains open.

[Neuroprotective and nephroprotective effects of remote postconditioning: Prospects for clinical use]. / Neiroprotektornyi i nefroprotektornyi éffekty distantnogo prekonditsionirovaniia. Perspektivy klinicheskogo primeneniia.

The results of experimental and clinical studies strongly suggest that remote ischemic preconditioning (RIP) has no neuroprotective effect during cardiac surgery performed under extracorporeal circulation. Remote preconditioning (RP) has no neuroprotective effect in hemorrhagic stroke. A randomized multicenter study is needed to evaluate the efficiency RIP in patients with ischemic stroke. RP reduces the severity of ischemia/reperfusion kidney injury during transplantation. RIP has been established to prevent contrast-induced nephropathy. There is a need for a multicenter trial to evaluate the efficiency of RIP in patients with abdominal aortic aneurysm repair. Analysis of the presented data indicates that RIP fails to prevent cardiorenal syndrome in infants and children during cardiac surgery. The data available in the literature on the capacity of RIP to provide nephroprotective effect in patients after coronary artery bypass surgery are discordant and indicative of the advisability of a multicenter study.

[Chronic exposure to cold is adaptation without stress ].

It has been established that prolonged continuous cold exposure (+4°C for 24 hours/day, four weeks) causes an increase in brown fat weight, hypertrophy of the adrenal gland, spleen and did not affect cortisol and corticosterone levels in the blood serum in rats. Gastric ulcers were not observed in the rats. Chronic intermittent exposure to cold (+4°C, 8 hours/day, 4 weeks) promoted an increase in the weight of brown fat, spleen, kidneys and heart, stomach ulcers and an alteration of cortisol and corticosterone levels were did observed. Short-term intermittent exposure to cold (+4°C, 1.5 hours/day, 4 weeks) did not affect the weight of brown fat, but promoted an increases in the weight of body, spleen, kidneys and heart, stomach ulcers were not found, cortisol and corticosterone levels was not changed.

[PHENOMENON OF REMOTE PRECONDITIONING THE HEART AND ITS MAIN MANIFESTATIONS].

Remote ischemic preconditioning prevents reperfusion cardiomyocyte apoptosis and has the infarct-limiting effect which is maintained in the experiments on the isolated perfused heart. Remote preconditioning promotes to recovery the contractility of the heart during reperfusion, but did not affect the incidence of occlusion and reperfusion of ventricular arrhythmias. Remote preconditioning has a mild anti-inflammatory effect. Presented article is a review and formulated conclusions based on the published literature data.

[PROBLEM OF END EFFECTOR OF ISCHEMIC PRECONDITIONING OF THE HEART].

An analysis of the literature data performed by the authors shows that the main contenders for the role of the end effector of ischemic preconditioning of the heart are: (1) MPT pore (2) nexuses (3) cytoskeleton. Thus, almost all of the known intracellular molecular cascades eventually converge on MPT pore, on the components of the cytoskeleton and nexuses.

[INFARCT-LIMITING EFFECT OF ADAPTATION TO CONTINUOUS COLD EXPOSURE].

The experiments were performed on Wistar male rats, which were subjected to continuous cold exposure (+4 °C, 4 weeks). It has been established that this exposure is not a chronic stress. It has been shown that prolonged cold impact causes cold adaptation to cold and has the infarct-limi-ting effect.

[STRESS AND INFARCT LIMITING EFFECTS OF EARLY HYPOXIC PRECONDITIONING].

It was established that early hypoxic preconditioning is an adaptive state different from eustress and distress. Hypoxic preconditioning has the cross effects, increasing the tolerance of the heart to ischemia-reperfusion and providing antiulcerogenic effect during immobilization stress.

[INVOLVEMENT OF NO-SYNTHASE IN THE INFARCT REDUCING EFFECT OF CONTINUOUS CHRONIC NORMOBARTC HYPOXTA].

It was investigated the role of inducible and endothelial NO-synthase (NOS) in the infaret reducing effect of chronic continuous normobaric hypoxia (CCNH) on the model of coronary artery occlusion and reperfusion in rats. Rats were subjected to hypoxic exposure (12% O2 during 21 days). It has found that CCNH causes an increase in total levels of nitrate and nitrite in deproteinized blood serum in 1.5-fold and 2-fold in myocardium compared with intact animals. This effect is manifested in intact animals and in rats with a 20 minute coronary artery occlusion and reperfusi- on. Chronic continuous normobaric hvoxia exhibited infarct soaring effect. which does not manifest after pretreatment with NO-synthase inhibitor NAME (10 mg/kg intravenously), the selective inhibitor of inducible NOS S-methylisothiourea (3 mg/kg intraperitoneally), but remained after blocking neuronal NOS with 7-nitronidazol (50 mg/kg intravenously). The findings suggest that the inducible NO-synthase and nitric oxide play an important role in the implementation of the infaret limiting effect of chronic continuous normobaric hvnoxia.

Prospects of Using of κ-Opioid Receptor Agonists U-50,488 and ICI 199,441 for Improving Heart Resistance to Ischemia/Reperfusion.

We studied the ability of the agonist of κ1-opioid receptors U-50,488 in doses of 0.1 and 1 mg/kg to simulate ischemic pre- and postconditioning of the heart and κ-opioid receptors ICI 199,441 in a dose of 0.1 mg/kg to simulate the antiarrhythmic effect of heart preconditioning. The duration of ischemia was 10 or 45 min and the duration of reperfusion was 10 min or 2 h. Administration of 1 mg/kg U-50,488 both before ischemia and 5 min before reperfusion produced a pronounced antiarrhythmic effect. U-50,488 injected 5 min before reperfusion 2-fold reduced the ratio of infarction to risk area. Administration of ICI 199,441 in a dose of 0.1 mg/kg 15 min before ischemia produced a potent antiarrhythmic effect. Antiarrhythmic effect of κ-opioid receptor agonists depended on activation of κ-opioid receptors.

Role of MEK, PI3, p38, Tyrosine, and mTOR Kinases in Regulation of Heart Resistance to the Arrhythmogenic Action of Short-Term Ischemia and Reperfusion.

MEK, PI3, p38, tyrosine, and mTOR kinases are not involved in the regulation of heart resistance to the arrhythmogenic action of short-term ischemia/reperfusion in non-adapted rats.

Functional state of myocardial mitochondria in ischemia reperfusion of the heart in rats adapted to hypoxia.

Parameters of respiration, transmembrane potential, and Ca(2+)-binding capacity of mitochondria isolated from Langendorff-perfused hearts of rats adapted to normobaric hypoxia were analyzed. Ischemia and reperfusion modeling in intact and adapted animals reduced Ca(2+)-binding capacity of mitochondria, which indicated increased sensitivity of mitochondrial permeability transition pores (MPTP) to calcium ions. These changes were accompanied by a decrease in transmembrane potential, ADP/O coefficient (ratio of added ADP to oxygen consumption in State 3), and inhibition of State 3 respiration. At the same time, adaptation attenuated the negative effect of ischemia and reperfusion on the functional state of mitochondria.