Interventricular Differences in beta-Adrenergic Responses in the Canine Heart: Role of Phosphodiesterases

Background-RV and LV have different embryologic, structural, metabolic, and electrophysiologic characteristics, but whether interventricular differences exist in beta-adrenergic (beta-AR) responsiveness is unknown. In this study, we examine whether beta-AR response and signaling differ in right (RV) versus left (LV) ventricles. Methods and Results-Sarcomere shortening, Ca2+ transients, I-Ca,I- L and I-Ks 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 approximate to 10-fold and Ca2+-transient amplitude approximate to 2-fold in LV midmyocytes (LVMs) versus approximate to 25-fold and approximate to 3-fold in RVMs. FRET imaging using targeted Epac2camps sensors revealed no change in subsarcolemmal [cAMP], but a 2-fold higher beta-AR stimulation of cytoplasmic [cAMP] in RVMs versus LVMs. Accordingly, beta-AR regulation of I-Ca,I- L and I-Ks were similar between LVMs and RVMs, whereas cytoplasmic PKA activity was increased in RVMs. Both PDE3 and PDE4 contributed to the beta-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/dt(max) approximate to 5-fold versus 3-fold in LV. Conclusion-Canine RV and LV differ in their beta-AR response due to intrinsic differences in myocyte beta-AR downstream signaling. Enhanced beta-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.