The Role of NO Synthase in the Infarct-Limiting Effect of Urgent and Chronic Adaptation to Normobaric Hypoxia.

We studied the role of NO synthase in the infarct-limiting effect of short-term (SNH) and chronic continuous normobaric hypoxia (CNH). In male Wistar rats, SNH (6 sessions of 10-min hypoxia 8% O2 and 10-min reoxygenation) or CNH (12% O2 for 21 days) was modeled. In 30 min after SNH or 24 h after CNH, the rats were subjected to coronary artery occlusion (45 min) and reperfusion (2 h). The following drugs were administered to rats: non-selective NO synthase inhibitor L-NAME (10 mg/kg), inhibitor of inducible NO synthase S-methylthiourea (3 mg/kg), and inhibitor of neuronal NO-synthase 7-nitroindazole (50 mg/kg). NO donor diethylenetriamine was administered intravenously in a dose 2 mg/kg. It was found that L-NAME and S-methylthiourea abolished the infarct-limiting effect of SNH and CNH. Diethylenetriamine increased cardiac tolerance to ischemia/reperfusion. It is believed that inducible NO synthase plays an important role in the cardioprotective effect of normobaric hypoxia.

The Role of Mitochondrial KATP Channels in the Infarct-Reducing Effect of Normobaric Hypoxia.

We studied the role of KATP channels in the infarct-limiting effect of short-term normobaric hypoxia. Male Wistar rats were subjected to a 45-min coronary artery occlusion followed by a 120-min reperfusion. Normobaric hypoxia was simulated 30 min before coronary artery occlusion: 6 sessions of hypoxia (8% O2, 10 min) and reoxygenation (21% O2, 10 min). The following drugs were administered to rats: glibenclamide, 5-hydroxydecanoate, and HMR1098. It was found that normobaric hypoxia contributes to a decrease in myocardial infarct size by 36%. Preliminary administration of glibenclamide or 5-hydroxydecanoate eliminated the infarct-reducing effect of normobaric hypoxia. Activator of mitochondrial KATP channel diazoxide limited the infarct size. These findings suggest that mitochondrial KATP channels are involved into the cardioprotective effect of normobaric hypoxia.

Myocardial Protection against Ischemic and Reperfusion Injuries (Experimental Study).

The effects of hypoxic, hyperoxic, and hypoxic-hyperoxic preconditioning were examined in the prospective study on narcotized and artificially ventilated rabbits. Under artificial circulation, acute myocardial ischemia was modeled by ligation of anterior descending coronary artery, which was followed by reperfusion. The degree of ventricular arrhythmias was assessed, and the ischemic area was evaluated in percent of the area at risk. Microscopic characterization of the myocardium was employed to assess the cardioprotective effect of hypoxic and/or hyperoxic preconditioning. According to Kruskal-Wallis test, the greatest resistance of the myocardium to ischemic and reperfusion injury was observed after hypoxic-hyperoxic preconditioning (H=42.459; p=0.009). The rabbits subjected to this type of preconditioning demonstrated the least damaged myocardium in comparison with nonconditioned controls.

[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.

[SIGNALING MECHANISM OF CARDIOPROTECTIVE EFFECT OF REACTIVE OXYGEN SPECIES].

Protein kinase Cepsilon (PKCepsilon) is a target for reactive oxygen species (ROS). It is activated with reaction products of OH* with phospholipids, which presumably include hydroperoxides of fatty acids or alkylperoxy radicals. Activation of PKCs with reactive oxygen species promotes to mito-K(ATP) channel opening and MPT pore (mitochondrial permeability transition pore) closing thereby it is increasing the resistance of cardiomyocytes to hypoxia-reoxygenation. P38 kinase and tyrosine kinases are targets of ROS. Hydroxyl radical or signaling molecules, resulting from its metabolism, may contribute to the activation of p38-kinase that increases the cardiac tolerance to the impact of ischemia-reperfusion. Src tyrosine kinase and P13-kinase apparently are not targets of ROS. The cardioprotective effect of ROS may be due to the activation of transcription factors NFkappaB and CREB.

Effect of Hypoxic Preconditioning on Stress Reaction in Rats.

In rats, immobilization stress (24 h) induced involution of the thymus and spleen, adrenal hypertrophy, and pronounced elevation (by 67%) of serum cortisol in comparison with intact animals; the mean number of stomach ulcers in rats subjected to stress was 6.9. Hypoxic preconditioning consisting of 6 sessions of 10-min hypoxia (8% O2) followed by 10-min reoxygenation with atmospheric air induced adrenal hypertrophy and spleen involution, but did not change blood cortisol level; no stomach ulcers were found in preconditioned rats. In rats subjected to both hypoxic preconditioning and immobilization, the weights of the thymus, adrenal glands, and spleen, as well as cortisol level did not differ from the corresponding parameters in rats subjected to immobilization stress alone. The number of stomach ulcers in experimental rats was 1.5-fold lower than in the stress-control ones. Thus, hypoxic preconditioning exerts a pronounced preventive anti-ulcer effect during immobilization, but it does not affect other indices of the stress reaction.

[TRIGGER, SIGNALING MECHANISM AND END EFFECTOR OF CARDIOPROTECTIVE EFFECT OF REMOTE POSTCONDITIONING OF HEART].

Trigger of remote postconditioning (RP) is high molecular weight peptide(s). Nitric oxide and adenosine act as intermediaries between the peptide and the intracellular structures. The autonomic nervous system is not involved in the RP. In RP signaling mechanism protein kinase C, PI3 kinase, Akt kinase, aldehyde dehydrogenase are involved. A hypothetical end effector of RP is BKca channel.

[Agonists of opioid receptors may aggravate ischemic and reperfusion damages of the heart].

Authors analyzed articles that opioids may aggravate ischemic and reperfusion damages of the heart but the opioid receptor antagonists may prevent these damages. Authors concluded the it is existed opioid receptor pool an activation of its decreases cardiac tolerance to an impact of ischemia-reperfusion.

Comparative analysis of early and delayed cardioprotective and antiarrhythmic efficacy of hypoxic preconditioning.

Hypoxic preconditioning produces an infarct-limiting effect both in the early and delayed periods. The increase in heart resistance to ischemia-repefusion was more pronounced after early preconditioning. Hypoxic preconditioning did not change heart resistance to the arrhythmogenic effect of coronary occlusion and reperfusion.

[Trigger mechanism of adaptive phenomenon of ischemic heart postconditioning].

Analysis of published data indicates on trigger role of protons, adenosine, opioids, bradykinin, calcitonin gene-related peptide, nitric oxide, epoxyeicosatrienoic acid, reactive oxygen species, hydrogen sulfide in ischemic heart postconditioning. It is shown that B-type natriuretic peptide, transforming growth factor-beta1, cardiotrophin-1, urocortin, acetylcholine, insulin and carbon monoxide can mimic postconditioning phenomenon.