This study examined the protective effect of ischemic postconditioning (IPoC) and minocycline postconditioning (MT) on myocardial ischemia-reperfusion (I/R) injury in atherosclerosis (AS) animals and the possible mechanism. Forty male healthy rabbits were injected with bovine serum albumin following feeding on a high fat diet for 6 weeks to establish AS model. AS rabbits were randomly divided into 3 groups: (1) I/R group, the rabbits were subjected to myocardial ischemia for 35 min and then reperfusion for 12 h; (2) IPoC group, the myocardial ischemia lasted for 35 min, and then reperfusion for 20 s and ischemia for 20 s [a total of 3 cycles (R20s/I20s×3)], and then reperfusion was sustained for 12 h; (3) MT group, minocycline was intravenously injected 10 min before reperfusion. The blood lipids, malondialdehyde (MDA), superoxide dismutase (SOD), soluble cell adhesion molecule (sICAM), myeloperoxidase (MPO), and cardiac troponin T (cTnT) were biochemically determined. The myocardial infarction size (IS) and apoptosis index (AI) were measured by pathological examination. The expression of bcl-2 and caspase-3 was detected in the myocardial tissue by using reverse transcription-polymerase chain reaction (RT-PCR). The results showed that the AS models were successfully established. The myocardial IS, the plasma levels of MDA, sICAM, MPO and cTnT, and the enzymatic activity of MPO were significantly decreased, and the plasma SOD activity was significantly increased in IPoC group and MT group as compared with I/R group (P<0.05 for all). The myocardial AI and the caspase-3 mRNA expression were lower and the bcl-2 mRNA expression was higher in IPoC and MT groups than those in I/R group (all P<0.05). It is concluded that the IPoC and MT can effectively reduce the I/R injury in the AS rabbits, and the mechanisms involved anti-oxidation, anti-inflammation, up-regulation of bcl-2 expression and down-regulation of caspase-3 expression. Minocycline can be used as an effective pharmacologic postconditioning drug to protect myocardia from I/R injury.

Although, for many decades, the day–night rhythm in resting heart rate has been attributed to the parasympathetic branch of the autonomic nervous system (high vagal tone during sleep), recently we have shown that there is a circadian clock in the cardiac pacemaker, the sinus node, and the day–night rhythm in heart rate involves an intrinsic rhythmic transcriptional remodelling of pacemaker ion channels, particularly Hcn4 . We have now investigated the role of the sympathetic branch of the autonomic nervous system in this and shown it to have a non-canonical role. In mice, sustained long-term block of cardiac β-adrenergic receptors by propranolol administered in the drinking water abolished the day–night rhythm in pacemaking in the isolated sinus node. Concomitant with this, there was a loss of the normal day–night rhythm in many pacemaker ion channel transcripts. However, there was little or no change in the local circadian clock, indicating that the well-known day–night rhythm in sympathetic nerve activity is directly involved in pacemaker ion channel transcription. The day–night rhythm in pacemaking helps explain the occurrence of clinically significant bradyarrhythmias during sleep, and this study improves our understanding of this pathology. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

Previous studies have linked dysfunctional I to arising from mutations to KCND3 -encoded Kv4.3 and KCND2 -encoded Kv4.2 to atrial fibrillation. Using computational models, this study aimed to investigate the mechanisms underlying pro-arrhythmic effects of the gain-of-function Kv4.3 (T361S, A545P) and Kv4.2 (S447R) mutations. Wild-type and mutant I to formulations were developed from and validated against experimental data and incorporated into the Colman et al . model of human atrial cells. Single-cell models were incorporated into one- (1D) and two-dimensional (2D) models of atrial tissue, and a three-dimensional (3D) realistic model of the human atria. The three gain-of-function mutations had similar, albeit quantitatively different, effects: shortening of the action potential duration; lowering the plateau membrane potential, abbreviating the effective refractory period (ERP) and the wavelength (WL) of atrial excitation at the tissue level. Restitution curves for the WL, the ERP and the conduction velocity were leftward shifted, facilitating the conduction of atrial excitation waves at high excitation rates. The mutations also increased lifespan and stationarity of re-entry in both 2D and 3D simulations, which further highlighted a mutation-induced increase in spatial dispersion of repolarization. Collectively, these changes account for pro-arrhythmic effects of these Kv4.3 and Kv4.2 mutations in facilitating AF. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

Aging attenuates the levels and duration of the dIAD induced by one-arm exercise in healthy adults.

Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na+, K+ and Ca2+ that produce SAN action potentials (AP) and ‘pacemaker depolarizations’ in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca2+-regulated mechanism based on a requirement for phasic release of Ca2+ from intracellular stores and activation of an inward current-mediated by Na+/Ca2+ exchange; (ii) time- and voltage-dependent activation of Na+ or Ca2+ currents, as well as a cyclic nucleotide-activated current, If; and/or (iii) a combination of (i) and (ii). Electrophysiological studies of single spontaneously active SAN myocytes in both adult mouse and rabbit hearts consistently reveal significant expression of a rapidly activating time- and voltage-dependent K+ current, often denoted IKr, that is selectively expressed in the leading or primary pacemaker region of the adult mouse SAN. The main goal of the present study was to examine by combined experimental and simulation approaches the functional or physiological roles of this K+ current in the pacemaker activity. Our patch clamp data of mouse SAN myocytes on the effects of a pharmacological blocker, E4031, revealed that a rapidly activating K+ current is essential for action potential (AP) repolarization, and its deactivation during the pacemaker potential contributes a small but significant component to the pacemaker depolarization. Mathematical simulations using a murine SAN AP model confirm that well known biophysical properties of a delayed rectifier K+ current can contribute to its role in generating spontaneous myogenic activity.