Myocardial ischaemia–reperfusion injury can be significantly reduced by an episode(s) of ischaemia–reperfusion applied prior to or during myocardial ischaemia (MI) to peripheral tissue located at a distance from the heart; this phenomenon is called remote ischaemic conditioning (RIc). Here, we compared the efficacy of RIc in protecting the heart when the RIc stimulus is applied prior to, during and at different time points after MI. A rat model of myocardial ischaemia–reperfusion injury involved 30 min of left coronary artery occlusion followed by 120 min of reperfusion. Remote ischaemic conditioning was induced by 15 min occlusion of femoral arteries and conferred a similar degree of cardioprotection when applied 25 min prior to MI, 10 or 25 min after the onset of MI, or starting 10 min after the onset of reperfusion. These RIc stimuli reduced infarct size by 54, 56, 56 and 48% (all P < 0.001), respectively. Remote ischaemic conditioning applied 30 min into the reperfusion period was ineffective. Activation of sensory nerves by application of capsaicin was effective in establishing cardioprotection only when elicited prior to MI. Vagotomy or denervation of the peripheral ischaemic tissue both completely abolished cardioprotection induced by RIc applied prior to MI. Cardioprotection conferred by delayed remote postconditioning was not affected by either vagotomy or peripheral denervation. These results indicate that RIc confers potent cardioprotection even if applied with a significant delay after the onset of myocardial reperfusion. Cardioprotection by remote preconditioning is critically dependent on afferent innervation of the remote organ and intact parasympathetic activity, while delayed remote postconditioning appears to rely on a different signalling pathway(s).

Cardioprotection against ischaemia/reperfusion injury in mice can be achieved by delayed ischaemic postconditioning (IPost) applied as late as 30 min after the onset of reperfusion. We determined the efficacy of delayed IPost in a rat model of myocardial infarction (MI) and investigated potential underlying mechanisms of this phenomenon. Rats were subjected to 20, 30 or 45 min of coronary artery occlusion followed by 120 min of reperfusion (I/R). Immediate and early IPost included six cycles of I/R (10/10 s) applied 10 s or 10 min after reperfusion onset. In the second series of experiments, the rats were subjected to 30 min of coronary occlusion followed by IPost applied 10 s, 10, 30, 45 or 60 min after the onset of reperfusion. Immediate and early IPost (applied 10 s or 10 min of reperfusion) established cardioprotection only when applied after a period of myocardial ischaemia lasting 30 min. Delayed IPost applied after 30 or 45 min of reperfusion reduced infarct sizes by 36 and 41 %, respectively (both P < 0.01). IPost applied 60 min after reperfusion onset was ineffective. Inhibition of RISK pathway (administration of ERK1/2 inhibitor PD-98059 or PI3K inhibitor LY-294002) abolished cardioprotection established by immediate IPost but had no effect on cardioprotection conferred by early IPost. Blockade of SAFE pathway using JAK/STAT inhibitor AG490 had no effect on the immediate or early IPost cardioprotection. Blockade of mitochondrial KATP (mitoKATP) channels (with 5-Hydroxydecanoate) abolished cardioprotection achieved by immediate and early IPost, but had no effect on cardioprotection when IPost was applied 30 or 45 min into the reperfusion period. Immediate IPost increased phosphorylation of PI3K-AKT and ERK1/2. Early or delayed IPost had no effect on phosphorylation of PI3K-AKT, ERK1/2 or STAT3. These data show that in the rat model, delayed IPost confers significant cardioprotection even if applied 45 min after onset of reperfusion. Cardioprotection induced by immediate and early postconditioning involves recruitment of RISK pathway and/or mitoKATP channels, while delayed postconditioning appears to rely on a different mechanism.

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РЕЗюМЕЦель исследования: изучить вовлечение отдельныx парасимпатических и симпатических бета-адренергических механизмoв в развитие противоишемического эффекта дистантного ишемического кондиционирования.Материал и методы. Эксперименты проводились на белых нелинейных крысах-самцах. Дистантное ишемическое кондиционирование представляло собой 15-минутную окклюзию обеих бедренных артерий, осуществляемую до начала ишемии миокарда (ДИПК), на 10-й минуте ишемии (ДИПерК) или на 10-й минуте реперфузии (ДИПостК10'). Для изучения роли блуждающих нервов в развитии дистантного ишемического кондиционирования окклюзия бедренных артерий выполнялась в условиях двухсторонней ваготомии (Ваготомия+ДИПК, Ваготомия+ДИПерК, Ваготомия+ДИПостК10'). С целью блокады М-холинорецепторов животным вводился атропин (группы Атропин+ДИПК и Атропин+ДИПостК10'). Блокада бета-адренорецепторов осуществлялась введением метопролола или атенолола на 1-й минуте реперфузии животным с интактными блуждающими нервами (группы МетR+ДИПостК10' и АтенR+ДИПостК10') или в условиях двухсторонней ваготомии (группы Ваготомия+МетR+ДИПостК10' и Ваготомия+АтенR+ДИПостК10').Результаты. ДИПК, ДИПерК и ДИПостК10' ограничивали зону некроза на 56%, 58% и 49%, соответственно, (p<0,001 в сравнении с группой Контроль). Двухсторонняя ваготомия, осуществляемая до начала острой ишемии миокарда, предупреждала развитие противоишемического эффекта ДИПК и ДИПерК, но не оказывала влияния на выраженность кардиопротекторного эффекта ДИПостК10'. Введение атропина предупреждало развитие кардиопротекторного эффекта как ДИПК, так и ДИПостК10'. Внутривенное введение метопролола или атенолола крысам с интактными блуждающими нервами не оказывало влияния на выраженность противоише- SUMMERYThe aim of the study: to investigate the involvement of distinct parasympathetic and sympathetic beta-adrenergic mechanisms in infarct-limiting effect of remote ischemic conditioning.Materials and methods. Experiments have been conducted on white male rats. Remote ischemic conditioning was performed as 15-min bilateral femoral arteries occlusion before the onset of myocardial ischemia (RIPC, n=8), on the 10-th minute of ischemia (RIPerC, n=8) or on the 10-th minute of reperfusion (RIPostC10', n=8). To study the role of vagal nerves in the development of remote ischemic conditioning femoral arteries occlusion was performed in conditions of bilateral vagotomy (Vagotomy+RIPC, n=8; Vagotomy+RIPerC, n=7; Vagotomy+RIPostC10', n=8). M-cholinoreceptors were blocked by atropine (groups Atropine+RIPC, n=10; and Atropine+RIPostC10', n=6). Beta-adrenoreceptors blockade was induced by injection of metoprolol or atenolol on the 1-st minute of reperfusion to animals with intact vagal nerves (groups MetR+RIPostC10', n=10; and AtenR+RIPostC10', n=10) or after bilateral vagotomy (groups Vagotomy+MetR+RIPostC10', n=10; Vagotomy+AtenR+RIPostC10', n=10).Results. RIPC, RIPerC и RIPostC10' limited infarct size by 56%, 58% and 49% respectively (all p<0,001 vs Control). Bilateral vagotomy, performed before the onset of myocardial ischa...

Objective: The search for the ideal candidate for renal denervation (RDN) is one of the priority treatments of patients with resistant hypertention (RH). Our objective was to identify the predictors of the efficiency of renal denervation. Design and method: The study included 112 patients with RH. The average age of patients was 53 [19; 69] years. Twenty-four (21.4%) patients had atrial fibrillation (AF). Four (16.7%) patients had chronic AF, 8 (33.3%) patients had persistent AF, and 12 (50%) – paroxysmal AF. All patients underwent RDN. Procedure was performed by an experienced electrophysiologist at the renal arteries using specialized electrode Symplicity Flex (Medtronic): ablation power = 8 - 10 W at 55°C, 4 – 10 points for each renal artery (including brunches), 2 minutes per point. Office BP and 24-hour ambulatory BP, 24-hour ECG monitoring, arrhythmia chronocard diaries were measured before, at 6 and 12 months of follow-up. A logistic regression analysis included the following parameters: gender, age, body mass index, office and 24-hour ambulatory systolic blood pressure (SBP), diabetes mellitus and the AF presence. Results: baseline office SBP and DBP in patients with RH were 185.4 ± 29.19 and 109.96 ± 17.95 respectively. Office BP decreased by 29.8 /14.1 mmHg at 12 month after RDN (p < 0.001). 24-hour ambulatory SBP decreased from 161.3 ± 25.9 mm Hg to 148.1 ± 21.3 mm Hg at 12 months after the intervention, DBP from 94.3 ± 16.4 mm Hg to 87.2 ± 15.9 mmHg (p < 0,001). It was found that all patients (100%) with RH and AF were responders to renal denervation. This response is defined as a reduction of office SBP of less than 10 mmHg following RDN. Whereas 17.2% of non-AF group patients were non-responders. The number of symptomatic AF paroxysms significantly decreased from 9 [2; 11] to 2 [1; 3] one year after RDN (p = 0.001). Conclusions: Patients with RH and AF are among the best candidates for RDN. It may help to improve the selection of patients with arterial hypertension for the RDN.