TY - JOUR
T1 - Pde1 inhibition modulates cav1.2 channel to stimulate cardiomyocyte contraction
AU - Muller, Grace K.
AU - Song, Joy
AU - Jani, Vivek
AU - Wu, Yuejin
AU - Liu, Ting
AU - Jeffreys, William P.D.
AU - O'Rourke, Brian
AU - Anderson, Mark E.
AU - Kass, David A.
N1 - Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.
PY - 2021/10/15
Y1 - 2021/10/15
N2 - 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, PDE1istimulated inotropy is unaltered by β-AR blockade and induces little whole-cell Ca2+ (intracellular Ca2+ concentration; [Ca2+]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 [Ca2+]i, whereas β-ARs or PDE3i increased both. When combined with low-dose adenylate cyclase stimulation, PDE1i enhanced shortening in a PKAdependent manner but unlike PDE3i, induced little [Ca2+]i rise nor augmented β-ARs. β-ARs or PDE3i reduced myofilament Ca2+ sensitivity and increased sarcoplasmic reticulum Ca2+ 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 Cav1.2 channel conductance similarly as PDE3i (both PKA dependent), without altering Na+-Ca2+ exchanger current density. Cell shortening and [Ca2+]i augmented by PDE1i were more sensitive to Cav1.2 blockade and to premature or irregular cell contractions and [Ca2+]i transients compared to PDE3i. CONCLUSIONS: PDE1i enhances contractility by a PKA-dependent increase in Cav1.2 conductance with less total [Ca2+]i increase, and no significant changes in sarcoplasmic reticulum [Ca2+], myofilament Ca2+-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.
AB - 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, PDE1istimulated inotropy is unaltered by β-AR blockade and induces little whole-cell Ca2+ (intracellular Ca2+ concentration; [Ca2+]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 [Ca2+]i, whereas β-ARs or PDE3i increased both. When combined with low-dose adenylate cyclase stimulation, PDE1i enhanced shortening in a PKAdependent manner but unlike PDE3i, induced little [Ca2+]i rise nor augmented β-ARs. β-ARs or PDE3i reduced myofilament Ca2+ sensitivity and increased sarcoplasmic reticulum Ca2+ 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 Cav1.2 channel conductance similarly as PDE3i (both PKA dependent), without altering Na+-Ca2+ exchanger current density. Cell shortening and [Ca2+]i augmented by PDE1i were more sensitive to Cav1.2 blockade and to premature or irregular cell contractions and [Ca2+]i transients compared to PDE3i. CONCLUSIONS: PDE1i enhances contractility by a PKA-dependent increase in Cav1.2 conductance with less total [Ca2+]i increase, and no significant changes in sarcoplasmic reticulum [Ca2+], myofilament Ca2+-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.
KW - Excitation contraction coupling
KW - Myocardial contraction
KW - Nucleotide
KW - Pharmacology
KW - Phosphorylation
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U2 - 10.1161/CIRCRESAHA.121.319828
DO - 10.1161/CIRCRESAHA.121.319828
M3 - Article
C2 - 34521216
AN - SCOPUS:85118903117
SN - 0009-7330
VL - 129
SP - 872
EP - 886
JO - Circulation research
JF - Circulation research
IS - 9
ER -