ArticleCirculation2018
Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition.
Article in Circulation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
35 citing papers in PubMed, 66 citations in OpenAlex.
- Single doses of a highly selective inhibitor of phosphodiesterase 1 (lenrispodun) in healthy volunteers: a randomized pharmaco-fMRI clinical trial.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2022Trial
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.Physiological reviews · 2025Review
- Review
- Promoting proteostasis by cAMP/PKA and cGMP/PKG.Trends in molecular medicine · 2025Review
- Phosphodiesterase 5 and its inhibitors with ischaemic heart disease: a Mendelian randomization analysis and a real-world study.European heart journal. Cardiovascular pharmacotherapy · 2025Article
- The identification of adenylyl cyclase modulators as potential receptors for 6-nitrodopamine in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and their relevance in heart inotropism.Frontiers in pharmacology · 2025Article
- Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics.Annual review of pharmacology and toxicology · 2025Review
- Abnormal phosphorylation / dephosphorylation and CaHeart failure reviews · 2024Review
- Article
- Phosphodiesterase in heart and vessels: from physiology to diseases.Physiological reviews · 2024Review
- Current Targets and Future Directions of Positive Inotropes for Heart Failure.Current medicinal chemistry · 2024Review
- Article
- Compartmentalized cAMP signalling and control of cardiac rhythm.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- Phosphodiesterases and Compartmentation of cAMP and cGMP Signaling in Regulation of Cardiac Contractility in Normal and Failing Hearts.International journal of molecular sciences · 2022Review
- Physiological and pathological roles of protein kinase A in the heart.Cardiovascular research · 2022Review
- Alterations of Cardiac Protein Kinases in Cyclic Nucleotide-Dependent Signaling Pathways in Human Ischemic Heart Failure.Frontiers in cardiovascular medicine · 2022Article
- Cyclic GMP and PKG Signaling in Heart Failure.Frontiers in pharmacology · 2022Review
- PDE1 Inhibition Modulates CaCirculation research · 2021Article
- Role of phosphodiesterase 1 in the pathophysiology of diseases and potential therapeutic opportunities.Pharmacology & therapeutics · 2021Review
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundPhosphodiesterase type-1 (PDE1) hydrolyzes cAMP and cGMP and is constitutively expressed in the heart, although cardiac effects from its acute inhibition in vivo are largely unknown. Existing data are limited to rodents expressing mostly the cGMP-favoring PDE1A isoform. Human heart predominantly expresses PDE1C with balanced selectivity for cAMP and cGMP. Here, we determined the acute effects of PDE1 inhibition in PDE1C-expressing mammals, dogs, and rabbits, in normal and failing hearts, and explored its regulatory pathways.
methodsConscious dogs chronically instrumented for pressure-volume relations were studied before and after tachypacing-induced heart failure (HF). A selective PDE1 inhibitor (ITI-214) was administered orally or intravenously±dobutamine. Pressure-volume analysis in anesthetized rabbits tested the role of β-adrenergic and adenosine receptor signaling on ITI-214 effects. Sarcomere and calcium dynamics were studied in rabbit left ventricular myocytes.
resultsIn normal and HF dogs, ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance, raising cardiac output without altering systolic blood pressure. Heart rate increased, but less so in HF dogs. ITI-214 effects were additive to β-adrenergic receptor agonism (dobutamine). Dobutamine but not ITI-214 increased plasma cAMP. ITI-214 induced similar cardiovascular effects in rabbits, whereas mice displayed only mild vasodilation and no contractility effects. In rabbits, β-adrenergic receptor blockade (esmolol) prevented ITI-214-mediated chronotropy, but inotropy and vasodilation remained unchanged. By contrast, adenosine A
conclusionsPDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via β-adrenergic receptors or PDE3 modulation. ITI-214, which has completed phase I trials, may provide a novel therapy for HF.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.