Rationale: Cyclic adenosine monophosphate (cAMP) activation of protein kinase A (PKA) stimulates excitation-contraction coupling, increasing cardiac contractility. This is clinically achieved by beta-adrenergic receptor stimulation (b-ARs) or inhibition of phosphodiesterase type-3 (PDE3i), though both approaches are limited by arrhythmia and chronic myocardial toxicity. Phosphodiesterase type-1 inhibition (PDE1i) also augments cAMP and enhances contractility in intact dogs and rabbits. Unlike b-ARs or PDE3i, PDE1i-stimulated inotropy is unaltered by b-AR blockade and induces little whole-cell Ca 2+ ([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 b-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 b-ARs. b-ARs or PDE3i reduced myofilament Ca 2+ sensitivity, and increased SR Ca 2+ content and phosphorylation of PKA-targeted serines on troponin-I, myosin binding protein C, and 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 NCX current density. Cell shortening and [Ca 2+ ]i augmented by PDE1i were more sensitive to Ca v 1.2 blockade and premature or irregular cell contractions and [Ca 2+ ]i transients less frequent than with 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 SR [Ca 2+ ], myofilament Ca 2+ -sensitivity, or phosphorylation of critical EC-coupling proteins as observed with b-ARs and/or PDE3i. PDE1i could provide a novel positive inotropic therapy for heart failure without the toxicities of b-ARs and PDE3i.
Rationale: Cyclic adenosine monophosphate (cAMP) activation of protein kinase A (PKA) stimulates excitation-contraction coupling, increasing cardiac contractility. This is clinically leveraged by beta-adrenergic stimulation (β-ARs) or phosphodiesterase-3 inhibition (PDE3i), though both approaches are limited by arrhythmia and chronic myocardial toxicity. Phosphodiesterase-1 inhibition (PDE1i) also augments cAMP and was recently shown in rabbit cardiomyocytes to augment contraction independent of β-AR stimulation or blockade, and with less intracellular calcium rise than β-ARs or PDE3i. Early testing of PDE1 inhibition in humans with neuro-degenerative disease and dilated heart failure has commenced. Yet, the molecular mechanisms for PDE1i inotropic effects remain largely unknown. Objective: Define the mechanism(s) whereby PDE1i increases contractility. Methods and Results: Primary guinea pig myocytes which express the cAMP-hydrolyzing PDE1C isoform found in larger mammals and humans were studied. The potent, selective PDE1i (ITI-214) did not alter cell shortening or Ca2+ transients under resting conditions whereas both increased with β-ARs or PDE3i. However, PDE1i enhanced shortening with less Ca2+ rise in a PKA-dependent manner when combined with low-dose adenylate cyclase stimulation (Forskolin). Unlike PDE3i, PDE1i did not augment β-AR responses. Whereas β-ARs reduced myofilament Ca2+ sensitivity and increased sarcoplasmic reticular Ca2+ content in conjunction with greater phosphorylation of troponin I, myosin binding protein C, and phospholamban, PDE1i did none of this. However, PDE1i increased Cav1.2 channel conductance similar to PDE3i in a PKA-dependent manner. Myocyte shortening and peak Ca2+ transients were more sensitive to Cav1.2 blockade with nitrendipine combined with PDE1i versus PDE3i. Lastly, PDE1i was found to be far less arrythmogenic than PDE3i. Conclusions: PDE1i enhances contractility by a PKA-dependent increase in Cav1.2 conductance without concomitant myofilament desensitization. The result is less rise in intracellular Ca2+ and arrhythmia compared to β-ARs and/or PDE3i. PDE1i could be a novel positive inotrope for failing hearts without the toxicities of β-ARs and PDE3i.
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