The role of adrenergic and muscarinic receptors in stress-induced cardiac injury.

Takotsubo syndrome (TS) is a rare but dangerous disease that can be fatal. The pathogenesis of TS is not well understood because there is no animal model of TS that fully mimics TS. It has now been documented that stress exposure (24 h) of rats induced the state which is similar TS in human: contracture damage of myofibrils, elevation of the serum creatine kinase MB level, increased 99mTc-pyrophosphate (99mTc-PYP) accumulation in the heart, QTc interval prolongation, and contractility dysfunction of the heart. Immobilization stress resulted in an increase in coronary blood flow. Emotional stress increased the serum catecholamine level. Blockade of ß1-adrenergic receptor (AR) prevented stress-induced cardiac injury (SICI). Blockade of ß2-AR aggravated stress-induced cardiac injury. Stimulation of ß2-AR increased cardiac tolerance to stress. Inhibition of ß3-AR, α1-AR had no effect on SICI. Blockade of peripheral muscarinic receptors or α2-AR aggravated SICI. Pretreatment with the selective ß1-AR antagonist atenolol attenuates stress-induced cardiac contractility dysfunction, but recovery of cardiac contractility is not complete. There is indirect evidence that circulating catecholamines play an important role in SICI. Consequently, the activation of ß1-AR plays a significant role in SICI. However, there are other receptors which are also involved in SICI and require further investigation.

Preserved cardiac mitochondrial function and reduced ischaemia/reperfusion injury afforded by chronic continuous hypoxia: role of opioid receptors.

Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to acute ischaemia/reperfusion injury. The objective of this study was to find out whether the cardioprotective effect of CNH mediated by opioid receptors is associated with preservation of mitochondrial function. Rats were adapted to CNH (12% oxygen) for 3 weeks. Isolated perfused hearts were subjected to 45 min of global ischaemia and 30 min of reperfusion; subgroups were pretreated with non-selective opioid receptor antagonist naloxone (300 nmol/L) for 10 min. Cardiac contractile function, creatine kinase activity in coronary effluent, mitochondrial respiration rate, and calcium retention capacity were assessed. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the post-ischaemic recovery of contractile function, mitochondrial state 3 and uncoupled respiration rates, and calcium retention capacity compared to the normoxic group. These protective effects were completely abolished by naloxone. The contractile recovery positively correlated with state 3 respiration and calcium retention capacity. The results suggest that the preserved mitochondrial function contributes to the protected cardiac phenotype afforded by adaptation to CNH and point to an important role of opioid receptor activation.

Cardioprotective and Vasoprotective Effects of Corticotropin-Releasing Hormone and Urocortins: Receptors and Signaling.

Despite the recent progress in research and therapy, cardiovascular diseases are still the most common cause of death worldwide, thus new approaches are still needed. The aim of this review is to highlight the cardioprotective potential of urocortins and corticotropin-releasing hormone (CRH) and their signaling. It has been documented that urocortins and CRH reduce ischemic and reperfusion (I/R) injury, prevent reperfusion ventricular tachycardia and fibrillation, and improve cardiac contractility during reperfusion. Urocortin-induced increase in cardiac tolerance to I/R depends mainly on the activation of corticotropin-releasing hormone receptor-2 (CRHR2) and its downstream pathways including tyrosine kinase Src, protein kinase A and C (PKA, PKCε) and extracellular signal-regulated kinase (ERK1/2). It was discussed the possibility of the involvement of interleukin-6, Janus kinase-2 and signal transducer and activator of transcription 3 (STAT3) and microRNAs in the cardioprotective effect of urocortins. Additionally, phospholipase-A2 inhibition, mitochondrial permeability transition pore (MPT-pore) blockade and suppression of apoptosis are involved in urocortin-elicited cardioprotection. Chronic administration of urocortin-2 prevents the development of postinfarction cardiac remodeling. Urocortin possesses vasoprotective and vasodilator effect; the former is mediated by PKC activation and prevents an impairment of endothelium-dependent coronary vasodilation after I/R in the isolated heart, while the latter includes both cAMP and cGMP signaling and its downstream targets. As CRHR2 is expressed by both cardiomyocytes and vascular endothelial cells. Urocortins mediate both endothelium-dependent and -independent relaxation of coronary arteries.

Takotsubo Syndrome: Clinical Manifestations, Etiology and Pathogenesis.

The purpose of the review is the analysis of clinical and experimental data on the etiology and pathogenesis of takotsubo syndrome (TS). TS is characterized by contractile dysfunction, which usually affects the apical region of the heart without obstruction of coronary artery, moderate increase in myocardial necrosis markers, prolonged QTc interval (in 50% of patients), sometimes elevation of ST segment (in 19% of patients), increase N-Terminal Pro-B-Type Natriuretic Peptide level, microvascular dysfunction, sometimes spasm of the epicardial coronary arteries (in 10% of patients), myocardial edema, and life-threatening ventricular arrhythmias (in 11% of patients). Stress cardiomyopathy is a rare disease, it is observed in 0.6 - 2.5% of patients with acute coronary syndrome. The occurrence of takotsubo syndrome is 9 times higher in women, who are aged 60-70 years old, than in men. The hospital mortality among patients with TS corresponds to 3.5% - 12%. Physical or emotional stress do not precede disease in all patients with TS. Most of patients with TS have neurological or mental illnesses. The level of catecholamines is increased in patients with TS, therefore, the occurrence of TS is associated with excessive activation of the adrenergic system. The negative inotropic effect of catecholamines is associated with the activation of ß2 adrenergic receptors. An important role of the adrenergic system in the pathogenesis of TS is confirmed by studies which were performed using 125I-metaiodobenzylguanidine (125I -MIBG). TS causes edema and inflammation of the myocardium. The inflammatory response in TS is systemic. TS causes impaired coronary microcirculation and reduces coronary reserve. There is a reason to believe that an increase in blood viscosity may play an important role in the pathogenesis of microcirculatory dysfunction in patients with TS. Epicardial coronary artery spasm is not obligatory for the occurrence of TS. Cortisol, endothelin-1 and microRNAs are challengers for the role of TS triggers. A decrease in estrogen levels is a factor contributing to the onset of TS. The central nervous system appears to play an important role in the pathogenesis of TS.

Trigger, Signaling Mechanism and End Effector of Cardioprotective Effect of Remote Postconditioning of Heart.

The hypothetical trigger of remote postconditioning (RPost) of the heart is the highmolecular weight hydrophobic peptide(s). Nitric oxide and adenosine serve as intermediaries between the peptide and intracellular structures. The role of the autonomic nervous system in RPost requires further study. In signaling mechanism RPost, kinases are involved: protein kinase C, PI3, Akt, JAK. The hypothetical end effector of RPost is aldehyde dehydrogenase-2, the transcription factors STAT, Nrf2, and also the BKCa channel.

A Review of Humoral Factors in Remote Preconditioning of the Heart.

A humoral mechanism of cardioprotection by remote ischemic preconditioning (RIP) has been clearly demonstrated in various models of ischemia-reperfusion including upper and lower extremities, liver, and the mesenteric and renal arteries. A wide range of humoral factors for RIP have been proposed including hydrophobic peptides, opioid peptides, adenosine, prostanoids, endovanilloids, endocannabinoids, calcitonin gene-related peptide, leukotrienes, noradrenaline, adrenomedullin, erythropoietin, apolipoprotein, A-I glucagon-like peptide-1, interleukin 10, stromal cell-derived factor 1, and microRNAs. Virtually, all of the components of ischemic preconditioning's signaling pathway such as nitric oxide synthase, protein kinase C, redox signaling, PI3-kinase/Akt, glycogen synthase kinase ß, ERK1/2, mitoKATP channels, Connexin 43, and STAT were all found to play a role. The signaling pattern also depends on which remote vascular bed was subjected to ischemia and on the time between applying the rip and myocardial ischemia occurs. Because there is convincing evidence for many seemingly diverse humoral components in RIP, the most likely explanation is that the overall mechanism is complex like that seen in ischemic preconditioning where multiple components are both in series and in parallel and interact with each other. Inhibition of any single component in the right circumstance may block the resulting protective effect, and selectively activating that component may trigger the protection. Identifying the humoral factors responsible for RIP might be useful in developing drugs that confer RIP's protection in a more comfortable and reliable manner.