Knockout of the α1A/C-adrenergic receptor subtype: The α1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure
- Cardiology Division and Research Service, Veterans Affairs Medical Center, San Francisco, CA 94121; and Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, CA 94143
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Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved May 9, 2002 (received for review October 16, 2001)
Abstract
α1-adrenergic receptors (ARs) play a major role in blood pressure regulation. The three α1-AR subtypes (A/C, B, and D) stimulate contraction of isolated arteries, but it is uncertain how different subtypes contribute to blood pressure regulation in the intact animal. We studied the role of the α1A/C subtype by using gene knockout. α1A/C knockout (KO) mice were viable and overtly normal. The LacZ reporter gene replaced α1A/C coding sequence in the KO, and β-galactosidase staining was present in resistance arteries and arterioles, but not in the thoracic aorta or its main branches. By tail cuff manometer and arterial catheter in conscious mice, α1A/C KO mice were hypotensive at rest, with an 8–12% reduction of blood pressure dependent on α1A/C gene copy number. A61603, an α1A/C-selective agonist, caused a pressor response that was lost in the KO and reduced but significant in heterozygous mice with a single copy of the α1A/C. A subtype-nonselective agonist [phenylephrine (PE)] caused a pressor response in KO mice, but the final arterial pressure was only 85% of wild type. The baroreflex was reset in the KO, and heart rate variability was decreased. After baroreflex blockade with atropine, PE increased blood pressure but did not change heart rate. Cardiac and vascular responses to the β-AR agonist isoproterenol were unchanged, and the arterial lumen area was not altered. We conclude that the α1A/C-AR subtype is a vasopressor expressed in resistance arteries and is required for normal arterial blood pressure regulation. α1A/C-selective antagonists might be desirable antihypertensive agents.
Footnotes
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↵ * Present address: Cardiology Division, Department of Medicine, University of Louisville, 570 South Preston Street, Louisville, KY 40202. E-mail: dgroko01{at}louisville.edu.
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↵ † To whom reprint requests should be addressed at: Veterans Affairs Medical Center, 111-C-8, 4150 Clement Street, San Francisco, CA 94121. E-mail: pcs{at}itsa.ucsf.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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↵ ‡ Throughout this paper we use the name α1A/C-AR to indicate that the names “A” and “C” have both been given to the same cloned subtype (24). The cloned α1D-AR was named originally the α1A (24), and accession nos. in GenBank for the α1D sequence (M60654 and M60655) still refer to this gene as the α1A.
- Abbreviations:
- AR,
- adrenergic receptor;
- F,
- filial;
- Het,
- heterozygous knockout;
- HR,
- heart rate;
- KO,
- homozygous knockout;
- MAP,
- mean arterial pressure;
- PE,
- phenylephrine;
- WT,
- wild type
- Copyright © 2002, The National Academy of Sciences
