PDE1 inhibition enhances cardiomyocyte contractility via a PKA-dependent increase in Cav1.2 conductance with less total intracellular calcium increase compared to β-ARs and PDE3i.
PDE1 inhibition provides a novel mechanism for positive inotropy by increasing Cav1.2 conductance without the potentially toxic calcium overload associated with beta-adrenergic or PDE3 stimulation.
Rationale: cAMP activation of PKA (protein kinase A) stimulates excitation-contraction (EC) coupling, increasing cardiac contractility. This is clinically achieved by β-ARs (β-adrenergic receptor) stimulation or PDE3i (inhibition of phosphodiesterase type-3), although both approaches are limited by arrhythmia and chronic myocardial toxicity. PDE1i (Phosphodiesterase type-1 inhibition) also augments cAMP and enhances contractility in intact dogs and rabbits. Unlike β-ARs or PDE3i, PDE1i-stimulated inotropy is unaltered by β-AR blockade and induces little whole-cell Ca 2+ (intracellular Ca 2+ concentration; Ca 2+ i ) increase. Positive inotropy from PDE1i was recently reported in human heart failure. However, mechanisms for this effect remain unknown. Objective: Define the mechanism(s) whereby PDE1i increases myocyte contractility. Methods and Results: We studied primary guinea pig myocytes that express the PDE1C isoform found in larger mammals and humans. In quiescent cells, the potent, selective PDE1i (ITI-214) did not alter cell shortening or Ca 2+ i , whereas β-ARs or PDE3i increased both. When combined with low-dose adenylate cyclase stimulation, PDE1i enhanced shortening in a PKA-dependent manner but unlike PDE3i, induced little Ca 2+ i rise nor augmented β-ARs. β-ARs or PDE3i reduced myofilament Ca 2+ sensitivity and increased sarcoplasmic reticulum Ca 2+ content and phosphorylation of PKA-targeted serines on TnI (troponin I), MYBP-C (myosin binding protein C), and PLN (phospholamban). PDE1i did not significantly alter any of these. However, PDE1i increased Ca v 1.2 channel conductance similarly as PDE3i (both PKA dependent), without altering Na + -Ca 2+ exchanger current density. Cell shortening and Ca 2+ i augmented by PDE1i were more sensitive to Ca v 1.2 blockade and to premature or irregular cell contractions and Ca 2+ i transients compared to PDE3i. Conclusions: PDE1i enhances contractility by a PKA-dependent increase in Ca v 1.2 conductance with less total Ca 2+ i increase, and no significant changes in sarcoplasmic reticulum Ca 2+ , myofilament Ca 2+ -sensitivity, or phosphorylation of critical EC-coupling proteins as observed with β-ARs and PDE3i. PDE1i could provide a novel positive inotropic therapy for heart failure without the toxicities of β-ARs and PDE3i.
Muller et al. (Wed,) conducted a other in Heart failure. PDE1 inhibition (ITI-214) vs. β-ARs or PDE3i was evaluated on Mechanism of increased myocyte contractility (cell shortening, [Ca2+]i, Cav1.2 channel conductance). PDE1 inhibition enhances cardiomyocyte contractility via a PKA-dependent increase in Cav1.2 conductance with less total intracellular calcium increase compared to β-ARs and PDE3i.