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CLINICAL RESEARCH: CORONARY ARTERY PHYSIOLOGY

The Alpha-1D Is the Predominant Alpha-1-Adrenergic Receptor Subtype in Human Epicardial Coronary Arteries

Brian C. Jensen, MD^_*,, Philip M. Swigart, MS^_*, Marie-Eve Laden, MD^_*, Teresa DeMarco, MD, Charles Hoopes, MD and Paul C. Simpson, MD^_*,,_*

^_* Cardiology Section, San Francisco VA Medical Center, San Francisco, California
Division of Cardiology, University of California, San Francisco, San Francisco, California
Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, California

Manuscript received July 8, 2008; revised manuscript received May 13, 2009, accepted May 19, 2009.

^_* Reprint requests and correspondence: Dr. Paul C. Simpson, VA Medical Center (111-C-8), 4150 Clement Street, San Francisco, California 94121 (Email: paul.simpson{at}ucsf.edu).

Objectives: The goal was to identify alpha-1-adrenergic receptor (AR) subtypes in human coronary arteries.

Background: The 1-ARs regulate human coronary blood flow. The 1-ARs exist as 3 molecular subtypes, 1A, 1B, and 1D, and the 1D subtype mediates coronary vasoconstriction in the mouse. However, the 1A is thought to be the only subtype in human coronary arteries.

Methods: We obtained human epicardial coronary arteries and left ventricular (LV) myocardium from 19 transplant recipients and 6 unused donors (age 19 to 70 years; 68% male; 32% with coronary artery disease). We cultured coronary rings and human coronary smooth muscle cells. We assayed 1- and β-AR subtype messenger ribonucleic acid (mRNA) by quantitative real-time reverse transcription polymerase chain reaction and subtype proteins by radioligand binding and extracellular signal-regulated kinase (ERK) activation.

Results: The 1D subtype was 85% of total coronary 1-AR mRNA and 75% of total 1-AR protein, and 1D stimulation activated ERK. In contrast, the 1D was low in LV myocardium. Total coronary 1-AR levels were one-third of β-ARs, which were 99% the β2 subtype.

Conclusions: The 1D subtype is predominant and functional in human epicardial coronary arteries, whereas the 1A and 1B are present at very low levels. This distribution is similar to the mouse, where myocardial 1A- and 1B-ARs mediate beneficial functional responses and coronary 1Ds mediate vasoconstriction. Thus, 1D-selective antagonists might mediate coronary vasodilation, without the negative cardiac effects of nonselective 1-AR antagonists in current use. Furthermore, it could be possible to selectively activate beneficial myocardial 1A- and/or 1B-AR signaling without causing coronary vasoconstriction.

Key Words: adrenergic • alpha and beta • arteries • coronary disease • receptors

Abbreviations and Acronyms   AR = adrenergic receptor   CAD = coronary artery disease   CTDN = California Transplant Donors Network   CYP = cyanopindolol   EF = ejection fraction   ERK = extracellular signal-regulated kinase   LV = left ventricle/ventricular   MLC = myosin light chain   mRNA = messenger ribonucleic acid   NE = norepinephrine   qRT-PCR = quantitative real-time reverse transcription polymerase chain reaction   RNA = ribonucleic acid   SMC = smooth muscle cell   UCSF = University of California, San Francisco

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