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July 20, 2018CirculationOpen Access

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition

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Key result

Acute PDE1 inhibition by ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance in dogs and rabbits with and without heart failure.

Why the study?

Does PDE1 inhibition by ITI-214 improve cardiac function in normal and failing hearts of PDE1C-expressing mammals?

Population

Conscious dogs chronically instrumented for pressure-volume relations before and after tachypacing-induced…

Comparison

Selective PDE1 inhibitor administered orally or… vs Baseline, β-adrenergic receptor agonism, or PDE3…

Design

Preclinical

Follow-up

acute

Authors

THToru HashimotoKyushu UniversityRTRichard S. TuninJohns Hopkins UniversityTATolulope AdesiyunJohns Hopkins University

Discussion

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Overview

Hypothesis-generating for PDE1 inhibition in HF; human trials needed before clinical consideration.

Structured PICO

Does PDE1 inhibition by ITI-214 improve cardiac function in normal and failing hearts of PDE1C-expressing mammals?

P
Population
Conscious dogs chronically instrumented for pressure-volume relations before and after tachypacing-induced heart failure (HF), anesthetized rabbits, rabbit left ventricular myocytes, and mice.
I
Intervention
Selective PDE1 inhibitor (ITI-214) administered orally or intravenously ± dobutamine, or with specific receptor blockades (esmolol, MRS-1754).
C
Comparator
Baseline (before administration), β-adrenergic receptor agonism (isoproterenol, dobutamine), or PDE3 inhibition (cilostamide).
O
Outcome
Load-independent contractility, relaxation, systemic arterial resistance, cardiac output, heart rate, and cellular calcium dynamics.surrogate

PDE1 inhibition by ITI-214 provides acute inotropic, lusitropic, and vasodilatory effects in normal and failing hearts via a novel cAMP signaling pathway distinct from β-adrenergic or PDE3 modulation.

Cite This Study

Hashimoto et al. (2018) studied Heart failure. ITI-214 (PDE1 inhibitor) vs. Baseline and various pharmacological agents (dobutamine, esmolol, MRS-1754) was evaluated on Cardiovascular hemodynamics (contractility, relaxation, systemic arterial resistance, cardiac output). Acute PDE1 inhibition by ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance in dogs and rabbits with and without heart failure.

synapsesocial.com/papers/6a7c979bb7ca9b673b7ccd22https://doi.org/10.1161/circulationaha.117.030490

Topics

HFrEF treatmentHeart failure
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Phosphodiesterase Type 3A Regulates Basal Myocardial Contractility Through Interacting With Sarcoplasmic Reticulum Calcium ATPase Type 2a Signaling Complexes in Mouse Heart2012 · 135 citations
  2. 2Multiprotein Complex With TRPC (Transient Receptor Potential-Canonical) Channel, PDE1C (Phosphodiesterase 1C), and A2R (Adenosine A2 Receptor) Plays a Critical Role in Regulating Cardiomyocyte cAMP and Survival2018 · 53 citations
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  4. 4Long-Term Stimulation of Adenosine A2b Receptors Begun After Myocardial Infarction Prevents Cardiac Remodeling in Rats2006 · 97 citations
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