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Interventricular differences in β-adrenergic responses in the canine heart: role of phosphodiesterases.

Journal of the American Heart Association (2014-06-07)
Cristina E Molina, Daniel M Johnson, Hind Mehel, Roel L H M G Spätjens, Delphine Mika, Vincent Algalarrondo, Zeineb Haj Slimane, Patrick Lechêne, Najah Abi-Gerges, Henk J van der Linde, Jérôme Leroy, Paul G A Volders, Rodolphe Fischmeister, Grégoire Vandecasteele
RÉSUMÉ

RV and LV have different embryologic, structural, metabolic, and electrophysiologic characteristics, but whether interventricular differences exist in β-adrenergic (β-AR) responsiveness is unknown. In this study, we examine whether β-AR response and signaling differ in right (RV) versus left (LV) ventricles. Sarcomere shortening, Ca(2+) transients, ICa,L and IKs currents were recorded in isolated dog LV and RV midmyocytes. Intracellular [cAMP] and PKA activity were measured by live cell imaging using FRET-based sensors. Isoproterenol increased sarcomere shortening ≈10-fold and Ca(2+)-transient amplitude ≈2-fold in LV midmyocytes (LVMs) versus ≈25-fold and ≈3-fold in RVMs. FRET imaging using targeted Epac2camps sensors revealed no change in subsarcolemmal [cAMP], but a 2-fold higher β-AR stimulation of cytoplasmic [cAMP] in RVMs versus LVMs. Accordingly, β-AR regulation of ICa,L and IKs were similar between LVMs and RVMs, whereas cytoplasmic PKA activity was increased in RVMs. Both PDE3 and PDE4 contributed to the β-AR regulation of cytoplasmic [cAMP], and the difference between LVMs and RVMs was abolished by PDE3 inhibition and attenuated by PDE4 inhibition. Finally LV and RV intracavitary pressures were recorded in anesthetized beagle dogs. A bolus injection of isoproterenol increased RV dP/dtmax≈5-fold versus 3-fold in LV. Canine RV and LV differ in their β-AR response due to intrinsic differences in myocyte β-AR downstream signaling. Enhanced β-AR responsiveness of the RV results from higher cAMP elevation in the cytoplasm, due to a decreased degradation by PDE3 and PDE4 in the RV compared to the LV.

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4-(3-Butoxy-4-methoxybenzyl)imidazolidin-2-one, solid
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Milieu essentiel minimum d′Eagle, With Hanks′ salts, L-glutamine and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
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Cilostamide, phosphodiesterase inhibitor