Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition

Toru Hashimoto, Grace E. Kim, Richard S. Tunin, Tolulope Adesiyun, Steven Hsu, Ryo Nakagawa, Guangshuo Zhu, Jennifer J. O'Brien, Joseph P. Hendrick, Robert E. Davis, Wei Yao, David Beard, Helen R. Hoxie, Lawrence P. Wennogle, Dong Lee, David A Kass

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Phosphodiesterase 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.

METHODS: Conscious 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.

RESULTS: In 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 A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas β-adrenergic receptor agonism (isoproterenol) or PDE3 inhibition (cilostamide) increased both. Unlike cilostamide, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only cilostamide increased calcium transients.

CONCLUSIONS: PDE1 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.

Original languageEnglish (US)
Pages (from-to)1974-1987
Number of pages14
JournalCirculation
Volume138
Issue number18
DOIs
StatePublished - Oct 30 2018

Fingerprint

Phosphoric Diester Hydrolases
Adrenergic Receptors
Heart Failure
Rabbits
Calcium
Dogs
Sarcomeres
Dobutamine
Phosphodiesterase Inhibitors
Isoproterenol
Vasodilation
Mammals
Adenosine A2B Receptors
Phosphodiesterase 3 Inhibitors
Blood Pressure
Pressure
Purinergic P1 Receptors
Colforsin
Cardiac Output
Muscle Cells

Keywords

  • adenosine
  • adrenergic beta-antagonists
  • calcium
  • cyclic AMP
  • cyclic nucleotide phosphodiesterases, type 1
  • heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition. / Hashimoto, Toru; Kim, Grace E.; Tunin, Richard S.; Adesiyun, Tolulope; Hsu, Steven; Nakagawa, Ryo; Zhu, Guangshuo; O'Brien, Jennifer J.; Hendrick, Joseph P.; Davis, Robert E.; Yao, Wei; Beard, David; Hoxie, Helen R.; Wennogle, Lawrence P.; Lee, Dong; Kass, David A.

In: Circulation, Vol. 138, No. 18, 30.10.2018, p. 1974-1987.

Research output: Contribution to journalArticle

Hashimoto, T, Kim, GE, Tunin, RS, Adesiyun, T, Hsu, S, Nakagawa, R, Zhu, G, O'Brien, JJ, Hendrick, JP, Davis, RE, Yao, W, Beard, D, Hoxie, HR, Wennogle, LP, Lee, D & Kass, DA 2018, 'Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition', Circulation, vol. 138, no. 18, pp. 1974-1987. https://doi.org/10.1161/CIRCULATIONAHA.117.030490
Hashimoto T, Kim GE, Tunin RS, Adesiyun T, Hsu S, Nakagawa R et al. Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition. Circulation. 2018 Oct 30;138(18):1974-1987. https://doi.org/10.1161/CIRCULATIONAHA.117.030490
Hashimoto, Toru ; Kim, Grace E. ; Tunin, Richard S. ; Adesiyun, Tolulope ; Hsu, Steven ; Nakagawa, Ryo ; Zhu, Guangshuo ; O'Brien, Jennifer J. ; Hendrick, Joseph P. ; Davis, Robert E. ; Yao, Wei ; Beard, David ; Hoxie, Helen R. ; Wennogle, Lawrence P. ; Lee, Dong ; Kass, David A. / Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition. In: Circulation. 2018 ; Vol. 138, No. 18. pp. 1974-1987.
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TY - JOUR

T1 - Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition

AU - Hashimoto, Toru

AU - Kim, Grace E.

AU - Tunin, Richard S.

AU - Adesiyun, Tolulope

AU - Hsu, Steven

AU - Nakagawa, Ryo

AU - Zhu, Guangshuo

AU - O'Brien, Jennifer J.

AU - Hendrick, Joseph P.

AU - Davis, Robert E.

AU - Yao, Wei

AU - Beard, David

AU - Hoxie, Helen R.

AU - Wennogle, Lawrence P.

AU - Lee, Dong

AU - Kass, David A

PY - 2018/10/30

Y1 - 2018/10/30

N2 - BACKGROUND: Phosphodiesterase 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.METHODS: Conscious 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.RESULTS: In 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 A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas β-adrenergic receptor agonism (isoproterenol) or PDE3 inhibition (cilostamide) increased both. Unlike cilostamide, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only cilostamide increased calcium transients.CONCLUSIONS: PDE1 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.

AB - BACKGROUND: Phosphodiesterase 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.METHODS: Conscious 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.RESULTS: In 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 A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas β-adrenergic receptor agonism (isoproterenol) or PDE3 inhibition (cilostamide) increased both. Unlike cilostamide, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only cilostamide increased calcium transients.CONCLUSIONS: PDE1 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.

KW - adenosine

KW - adrenergic beta-antagonists

KW - calcium

KW - cyclic AMP

KW - cyclic nucleotide phosphodiesterases, type 1

KW - heart failure

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U2 - 10.1161/CIRCULATIONAHA.117.030490

DO - 10.1161/CIRCULATIONAHA.117.030490

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VL - 138

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EP - 1987

JO - Circulation

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