PDE1 Inhibition Modulates Cav1.2 Channel to Stimulate Cardiomyocyte Contraction. Issue 9 (15th October 2021)

• Record Type: Journal Article
• Authors: Muller, Grace K.; Song, Joy; Jani, Vivek; Wu, Yuejin; Liu, Ting; Jeffreys, William P.D.; O'Rourke, Brian; Anderson, Mark E.; Kass, David A.
• Is Part Of: Circulation research. Volume 129:Issue 9(2021)
• Publication Date: 2021-10-15
• Subjects: excitation contraction coupling -- myocardial contraction -- nucleotide -- pharmacology -- phosphorylation; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.121.319828
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : 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 Cav 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 Cav 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 Cav 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. Abstract : Supplemental Digital Content is available in the text.