title: Therapeutic synergy and complementarity for ischemia/reperfusion injury: β1-adrenergic blockade and phosphodiesterase-3 inhibition.
abstract: The β1-blocker when administered before reperfusion activates myocyte prosurvival signaling via β2-adrenergic receptor (β2-AR) and protein kinase A (PKA)-dependent mechanism during ischemia/reperfusion (I/R). The heart is endowed with powerful self-protective ability executed by endogenous β2-adrenopeptide receptor activation. I/R triggers cardiac epinephrine and neuropeptide calcitonin gene-related peptide (CGRP) release. Cardiac β1- and β2-AR stimulation mediates pro- and anti-apoptotic cell signaling, respectively. Removal of myocardial β1-AR-derived proapoptotic force with β1-AR blockade unmasks the dominance of β2-AR mediated prosurvival cell signaling through the well-defined PKA-Akt dependent mechanism. This review focuses on recent clinical and experimental findings including intrinsic cardiac β2-adrenopeptide neuroparacrine signaling mechanisms involved in I/R injury protection. While β2-adrenopeptide-mediated cardioprotection is important, age-related β2-adrenopeptide receptor decoupling can result in their ineffectiveness in response to the receptor-specific therapies. Accordingly, direct activation of receptor-coupled upstream PKA-dependent signaling may serve as a therapeutic alternative to achieve cardioprotection bypassing adrenopeptidergic receptor decoupling accompanied with aging. Phosphodiesterase-3 (PDE3) inhibitor reduces infarct-size via cAMP-dependent PKA signaling. Non-β1-AR-mediated PKA activation activates multiple prosurvival signaling pathways eventually leading to Akt activation. Combination therapy with β1-blocker esmolol and PDE3 inhibitor milrinone additively reduced infarct-size in preclinical studies. Concurrent β1-AR blockade and PDE3 inhibition provides complementary synergy with promising therapeutic potential in patients with acute myocardial infarction and beyond.
authors.affiliation: Gulf Coast Heart Clinic (MH), Houston, TX, USA; ICA Therapeutics, Houston, TX, USA; Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77036, USA. Electronic address: mhuang1458@aol.com.
authors.forename: Ming-He
authors.initials: MH
authors.lastname: Huang
authors.affiliation: Cardiac Department, National University Heart Centre, National University Health System and Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
authors.forename: Kian-Keong
authors.initials: KK
authors.lastname: Poh
authors.affiliation: Cardiac Department, National University Heart Centre, National University Health System and Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
authors.forename: Huay-Cheem
authors.initials: HC
authors.lastname: Tan
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, UT 84132, USA.
authors.forename: Frederick G P
authors.initials: FG
authors.lastname: Welt
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, UT 84132, USA.
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lui
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004357:Drug Synergism; D006801:Humans; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058987:Phosphodiesterase 3 Inhibitors; D011412:Propanolamines; C036604:esmolol
keywords: Epinephrine; ICA cells; Phosphodiesterase-3 inhibitor; Protein kinase A; Reperfusion injury; β(1)-blocker; β(2)-adrenergic receptor