A novel adenylyl cyclase type 5 inhibitor that reduces myocardial infarct size even when administered after coronary artery reperfusion

Jie Zhang, Daniel Levy, Marko Oydanich, Claudio A. Bravo, Seonghun Yoon, Dorothy Vatner, Stephen Vatner

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

We developed a novel adenylyl cyclase type 5 (AC5) inhibitor, C90, that reduces myocardial infarct size even when administered after coronary reperfusion. This is key, since it is not practical to administer a drug to a patient with myocardial infarction before revascularization, and is one reason why so many prior drugs, which reduced infarct in experimental animals, failed in clinical trials. C90 is the most potent AC5 inhibitor, as exhibited by its IC50 value for AC5 inhibition, which was 5 times lower than the next most potent AC5 inhibitor. C90 reduced cAMP in response to forskolin in wild type mice by 42%, but no longer reduced cAMP in response to forskolin in mice with disruption of AC5, indicating that the mechanism of C90 was specific for AC5 inhibition. Compared with vehicle treatment, C90 reduced infarct size by 64% at a dose of 0.6 mg/kg. Thus, C90 is a novel, selective and potent AC5 inhibitor that reduces infarct size, when delivered after coronary artery reperfusion, rendering it potentially clinically useful. It also reduces beta-adrenergic receptor signaling, which will provide additional benefit to patients with coronary artery disease or heart failure.

Original languageEnglish (US)
Pages (from-to)13-15
Number of pages3
JournalJournal of Molecular and Cellular Cardiology
Volume121
DOIs
StatePublished - Aug 1 2018

Fingerprint

Myocardial Reperfusion
Coronary Vessels
Myocardial Infarction
Colforsin
Receptors, Adrenergic, beta
adenylyl cyclase type V
Adenylyl Cyclase Inhibitors
Pharmaceutical Preparations
Inhibitory Concentration 50
Coronary Artery Disease
Heart Failure
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Keywords

  • Adenylyl cyclase
  • Coronary occlusion
  • Coronary reperfusion
  • Myocardial infarction
  • Myocardial ischemia

Cite this

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title = "A novel adenylyl cyclase type 5 inhibitor that reduces myocardial infarct size even when administered after coronary artery reperfusion",
abstract = "We developed a novel adenylyl cyclase type 5 (AC5) inhibitor, C90, that reduces myocardial infarct size even when administered after coronary reperfusion. This is key, since it is not practical to administer a drug to a patient with myocardial infarction before revascularization, and is one reason why so many prior drugs, which reduced infarct in experimental animals, failed in clinical trials. C90 is the most potent AC5 inhibitor, as exhibited by its IC50 value for AC5 inhibition, which was 5 times lower than the next most potent AC5 inhibitor. C90 reduced cAMP in response to forskolin in wild type mice by 42{\%}, but no longer reduced cAMP in response to forskolin in mice with disruption of AC5, indicating that the mechanism of C90 was specific for AC5 inhibition. Compared with vehicle treatment, C90 reduced infarct size by 64{\%} at a dose of 0.6 mg/kg. Thus, C90 is a novel, selective and potent AC5 inhibitor that reduces infarct size, when delivered after coronary artery reperfusion, rendering it potentially clinically useful. It also reduces beta-adrenergic receptor signaling, which will provide additional benefit to patients with coronary artery disease or heart failure.",
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A novel adenylyl cyclase type 5 inhibitor that reduces myocardial infarct size even when administered after coronary artery reperfusion. / Zhang, Jie; Levy, Daniel; Oydanich, Marko; Bravo, Claudio A.; Yoon, Seonghun; Vatner, Dorothy; Vatner, Stephen.

In: Journal of Molecular and Cellular Cardiology, Vol. 121, 01.08.2018, p. 13-15.

Research output: Contribution to journalArticle

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T1 - A novel adenylyl cyclase type 5 inhibitor that reduces myocardial infarct size even when administered after coronary artery reperfusion

AU - Zhang, Jie

AU - Levy, Daniel

AU - Oydanich, Marko

AU - Bravo, Claudio A.

AU - Yoon, Seonghun

AU - Vatner, Dorothy

AU - Vatner, Stephen

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KW - Adenylyl cyclase

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