Interventricular Differences in β‐Adrenergic Responses in the Canine Heart: Role of Phosphodiesterases

Abstract

Background 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. Methods and Results Sarcomere shortening, Ca 2+ transients, I Ca,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 ≈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 I Ca,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 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 /dt max ≈5‐fold versus 3‐fold in LV. Conclusion 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.