Constitutive β2-adrenergic signalling enhances sarcoplasmic reticulum Ca2+ cycling to augment contraction in mouse heart

Transgenic overexpression of the β2-adrenergic receptor (β2AR) in mouse heart augments baseline cardiac function in a ligand-independent manner, due to the presence of spontaneously active β2AR (β2AR*). This study aims to elucidate the mechanism of β2AR*-mediated modulation of cardiac excitation-contraction (EC) coupling.Confocal imaging was used to analyse Ca2+ sparks and spatially resolve Ca2+ transients in single ventricular myocytes from transgenic (TG4) and non-transgenic (NTG) littermates. Whole-cell voltage- and current-clamp techniques were used to record L-type Ca2+ currents (ICa) and action potentials, respectively.In the absence of any β2AR ligand, TG4 myocytes had greater contraction amplitudes, larger Ca2+ transients and faster relaxation times than did NTG cells.The action potentials of TG4 and NTG myocytes were similar, except for a prolonged end-stage repolarization in TG4 cells; the ICa density and kinetics were nearly identical. The relationship between peak Ca2+ and contraction, which reflects myofilament Ca2+ sensitivity, was similar.In TG4 cells, the frequency of Ca2+ sparks (spontaneous or evoked at -40 mV) was 2-7 times greater, despite the absence of change in the resting Ca2+, sarcoplasmic reticulum (SR) Ca2+ content, and ICa. Individual sparks were brighter, broader and lasted longer, leading to a 2.3-fold greater signal mass. Thus, changes in both spark frequency and size underlie the greater Ca2+ transient in TG4 cells.The inverse agonist ICI 118,551 (ICI, 5 × 10−7 M), which blocks spontaneous β2AR activation, reversed the aforementioned β2AR* effects on cardiac EC coupling without affecting the sarcolemmal ICa. However, ICI failed to detect significant constitutive β2AR activity in NTG cells.We conclude that β2AR*-mediated signalling enhances SR release channel activity and Ca2+-induced Ca2+ release in TG4 cardiac myocytes, and that β2AR* enhances EC coupling by reinforcing SR Ca2+ cycling (release and reuptake), but bypassing the sarcolemmal ICa

Physical (in)activity and endothelium-derived constricting factors: overlooked adaptations

The inner surrounding of arterial vessels, the endothelium, is optimally located to detect changes in blood characteristics or blood flow that may result from changes in physical activity or from diseases. In response to physical stimuli, the endothelium varies its release of circulating vasoactive substances and serves as a source of local and systemic endothelium-derived dilator and vasoconstrictor factors. Endothelial dysfunction is one of the earliest markers of vascular abnormalities observed in cardiovascular disease and ageing. Exercise training is an efficient therapeutic strategy to improve endothelial function. Traditionally, studies on endothelial dysfunction and physical (in)activity-related effects on vascular adaptations are primarily focused on vasodilator substances (i.e. nitric oxide). One may suggest that augmentation of vasoconstrictor pathways (such as endothelin-1 and angiotensin II) contributes to the endothelial dysfunction observed after physical inactivity. Moreover, these pathways may also explain the exercise-induced beneficial cardiovascular adaptations. This review summarizes the current knowledge on the effects of physical (in)activity on several endothelium-derived vasoconstrictor substances