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Research ArticleCardiovascular

Metoprolol Impairs β1-Adrenergic Receptor-Mediated Vasodilation in Rat Cerebral Arteries: Implications for β-Blocker Therapy

Christopher L. Moore, David S. Henry, Samantha J. McClenahan, Kelly K. Ball, Nancy J. Rusch and Sung W. Rhee
Journal of Pharmacology and Experimental Therapeutics January 2021, 376 (1) 127-135; DOI: https://doi.org/10.1124/jpet.120.000176
Christopher L. Moore
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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David S. Henry
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Samantha J. McClenahan
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Kelly K. Ball
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Nancy J. Rusch
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Sung W. Rhee
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Abstract

The practice of prescribing β-blockers to lower blood pressure and mitigate perioperative cardiovascular events has been questioned because of reports of an increased risk of stroke. The benefit of β-blocker therapy primarily relies on preventing activation of cardiac β1-adrenergic receptors (ARs). However, we reported that β1ARs also mediate vasodilator responses of rat cerebral arteries (CAs), implying that β-blockers may impair cerebral blood flow under some conditions. Here, we defined the impact of metoprolol (MET), a widely prescribed β1AR-selective antagonist, on adrenergic-elicited diameter responses of rat CAs ex vivo and in vivo. MET (1–10 µmol/l) prevented β1AR-mediated increases in diameter elicited by dobutamine in cannulated rat CAs. The β1AR-mediated dilation elicited by the endogenous adrenergic agonist norepinephrine (NE) was reversed to a sustained constriction by MET. Acute oral administration of MET (30 mg/kg) to rats in doses that attenuated resting heart rate and dobutamine-induced tachycardia also blunted β1AR-mediated dilation of CAs. In the same animals, NE-induced dilation of CAs was reversed to sustained constriction. Administration of MET for 2 weeks in drinking water (2 mg/ml) or subcutaneously (15 mg/kg per day) also resulted in NE-induced constriction of CAs in vivo. Thus, doses of MET that protect the heart from adrenergic stimulation also prevent β1AR-mediated dilation of CAs and favor anomalous adrenergic constriction. Our findings raise the possibility that the increased risk of ischemic stroke in patients on β-blockers relates in part to adrenergic dysregulation of cerebrovascular tone.

SIGNIFICANCE STATEMENT β-Blocker therapy using second-generation, cardioselective β-blockers is associated with an increased risk of stroke, but the responsible mechanisms are unclear. Here, we report that either acute or chronic systemic administration of a cardioselective β-blocker, metoprolol, mitigates adrenergic stimulation of the heart as an intended beneficial action. However, metoprolol concomitantly eliminates vasodilator responses to adrenergic stimuli of rat cerebral arteries in vivo as a potential cause of dysregulated cerebral blood flow predisposing to ischemic stroke.

Footnotes

    • Received June 19, 2020.
    • Accepted October 16, 2020.
  • ↵1 C.L.M. and D.S.H. contributed equally to this work.

  • ↵2 Current affiliation: Vanderbilt University, Nashville, Tennessee.

  • This work was supported in part by National Institutes of Health National Heart, Lung, and Blood Institute [R01-HL97107] and American Heart Association [Grant 17GRNT33670970], [Grant 19TPA34880019] (S.W.R.), and [Grant 13PRE17070035] (C.L.M.).

  • The authors declare no conflicts of interest.

  • Portions of this work were previously presented in: Moore CL (2015) The role of postsynaptic density-95 scaffolding in cerebral vasodilation: Implications for stroke in beta-blocker therapy. Doctoral dissertation. Figures 4, A and B and 5C modified from Moore CL, McClenahan SJ, Hanvey HM, Jang DS, Nelson PL, Joseph BK, and Rhee SW (2015) J Cereb Blood Flow Metab 35:1537–1546. Reprinted by Permission of SAGE Publications, Ltd.

  • https://doi.org/10.1124/jpet.120.000176.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 1
1 Jan 2021
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Research ArticleCardiovascular

Metoprolol Impairs Cerebral Vasodilator Responses

Christopher L. Moore, David S. Henry, Samantha J. McClenahan, Kelly K. Ball, Nancy J. Rusch and Sung W. Rhee
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 127-135; DOI: https://doi.org/10.1124/jpet.120.000176

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Research ArticleCardiovascular

Metoprolol Impairs Cerebral Vasodilator Responses

Christopher L. Moore, David S. Henry, Samantha J. McClenahan, Kelly K. Ball, Nancy J. Rusch and Sung W. Rhee
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 127-135; DOI: https://doi.org/10.1124/jpet.120.000176
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