{"doi":"10.1161/circresaha.121.319828","title":"PDE1 Inhibition Modulates Ca <sub>v</sub> 1.2 Channel to Stimulate Cardiomyocyte Contraction","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 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.","journal":"Circulation Research","year":2021,"id":186398,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":745289,"name":"Joy Song","orcid":null,"position":1,"is_corresponding":false},{"id":449495,"name":"Vivek Jani","orcid":"0000-0002-3811-4973","position":2,"is_corresponding":false},{"id":290009,"name":"Yuejin Wu","orcid":"0000-0003-3547-8082","position":3,"is_corresponding":false},{"id":328212,"name":"Ting Liu","orcid":"0000-0002-8304-5751","position":4,"is_corresponding":false},{"id":745290,"name":"William P.D. Jeffreys","orcid":null,"position":5,"is_corresponding":false},{"id":270498,"name":"Brian O’Rourke","orcid":"0000-0002-5548-4853","position":6,"is_corresponding":false},{"id":290019,"name":"Mark E. Anderson","orcid":"0000-0001-6145-5234","position":7,"is_corresponding":false},{"id":235996,"name":"David A. Kass","orcid":"0000-0003-1596-2299","position":8,"is_corresponding":false},{"id":744457,"name":"Grace K. Muller","orcid":"0000-0002-5433-8571","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T23:48:46.850806Z","pmid":"34521216","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}