Abstract
Alterations of the β-adrenergic signalling, structural remodelling, and electrical failure of T-tubules are hallmarks of heart failure (HF). Here, we assess the effect of β-adrenoceptor activation on local Ca2+ release in electrically coupled and uncoupled T-tubules in ventricular myocytes from HF rats. We employ an ultrafast random access multi-photon (RAMP) microscope to simultaneously record action potentials and Ca2+ transients from multiple T-tubules in ventricular cardiomyocytes from a HF rat model of coronary ligation compared to sham-operated rats as a control. We confirmed that β-adrenergic stimulation increases the frequency of Ca2+ sparks, reduces Ca2+ transient variability, and hastens the decay of Ca2+ transients: all these effects are similarly exerted by β-adrenergic stimulation in control and HF cardiomyocytes. Conversely, β-adrenergic stimulation in HF cells accelerates a Ca2+ rise exclusively in the proximity of T-tubules that regularly conduct the action potential. The delayed Ca2+ rise found at T-tubules that fail to conduct the action potential is instead not affected by β-adrenergic signalling. Taken together, these findings indicate that HF cells globally respond to β-adrenergic stimulation, except at T-tubules that fail to conduct action potentials, where the blunted effect of the β-adrenergic signalling may be directly caused by the lack of electrical activity.
Highlights
In cardiomyocytes, stimulation of β-adrenergic receptors (β-AR) activates a powerful positive inotropic response via cAMP-dependent protein kinase A (PKA)
Action Potentials and Ca2+ Transients in Failing Cells Treated with Isoproterenol
Employing a novel functional imaging technique [38], we have demonstrated that about 6% of T-tubules fail to propagate AP in heart failure (HF) [19,20] and the entity of this defect can be much larger in other pathologies, e.g., 22.7% ± 5% in mice carrying a mutation associated with hypertrophic cardiomyopathy [39]
Summary
Stimulation of β-adrenergic receptors (β-AR) activates a powerful positive inotropic response via cAMP-dependent protein kinase A (PKA). PKA phosphorylates several key proteins that modulate cardiac function: L-type Ca2+ channels (LTCC) [1], ryanodine receptors (RyR2) [2], phospholamban [3], troponin I [4], and myosin-binding protein-C [5]. In heart failure (HF), one of the first causes of death worldwide [6], the β-AR system is compromised both in human and animal models [7,8,9,10], namely due to downregulation of mRNA and protein levels of β1-AR [11,12], one of the two main receptor isoforms that are present in the heart [13].
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