T-Tubular Electrical Defects Contribute to Blunted β-Adrenergic Response in Heart Failure.
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 Ca(2+) 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 Ca(2+) 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 Ca(2+) sparks, reduces Ca(2+) transient variability, and hastens the decay of Ca(2+) 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 Ca(2+) rise exclusively in the proximity of T-tubules that regularly conduct the action potential. The delayed Ca(2+) 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.
European Laboratory for Non-Linear Spectroscopy, Florence 50019, Italy. crocini@lens.unifi.it.|National Institute of Optics, National Research Council, Florence 50125, Italy. crocini@lens.unifi.it.
Claudia
C
Crocini
Division of Pharmacology, Department "NeuroFarBa", University of Florence, Florence 50139, Italy. raffaele.coppini@unifi.it.
Raffaele
R
Coppini
Division of Physiology, Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy. cecilia.ferrantini@unifi.it.
Cecilia
C
Ferrantini
R. D. Berlin Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, CT 06030, USA. pyan@uchc.edu.
Ping
P
Yan
R. D. Berlin Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, CT 06030, USA. les@uchc.edu.
Leslie M
LM
Loew
Division of Physiology, Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy. corrado.poggesi@unifi.it.
Corrado
C
Poggesi
Division of Pharmacology, Department "NeuroFarBa", University of Florence, Florence 50139, Italy. elisabetta.cerbai@unifi.it.
Elisabetta
E
Cerbai
European Laboratory for Non-Linear Spectroscopy, Florence 50019, Italy. francesco.pavone@unifi.it.|Department of Physics and Astronomy, University of Florence, Sesto Fiorentino 50019, Italy. francesco.pavone@unifi.it.
Francesco S
FS
Pavone
European Laboratory for Non-Linear Spectroscopy, Florence 50019, Italy. sacconi@lens.unifi.it.|National Institute of Optics, National Research Council, Florence 50125, Italy. sacconi@lens.unifi.it.
Leonardo
L
Sacconi
D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D006333:Heart Failure / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta
T-tubules; excitation-contraction coupling; heart failure; non-linear microscopy imaging; β-adrenergic signalling