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

https://doi.org/10.1016/j.jacc.2009.05.056Get rights and content
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Objectives

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

Background

The α1-ARs regulate human coronary blood flow. The α1-ARs exist as 3 molecular subtypes, α1A, α1B, and α1D, and the α1D subtype mediates coronary vasoconstriction in the mouse. However, the α1A 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 α1- 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 α1D subtype was 85% of total coronary α1-AR mRNA and 75% of total α1-AR protein, and α1D stimulation activated ERK. In contrast, the α1D was low in LV myocardium. Total coronary α1-AR levels were one-third of β-ARs, which were 99% the β2 subtype.

Conclusions

The α1D subtype is predominant and functional in human epicardial coronary arteries, whereas the α1A and α1B are present at very low levels. This distribution is similar to the mouse, where myocardial α1A- and α1B-ARs mediate beneficial functional responses and coronary α1Ds mediate vasoconstriction. Thus, α1D-selective antagonists might mediate coronary vasodilation, without the negative cardiac effects of nonselective α1-AR antagonists in current use. Furthermore, it could be possible to selectively activate beneficial myocardial α1A- and/or α1B-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

Cited by (0)

Dr. Simpson received funding from the Veterans Administration and the National Institutes of Health. Dr. Jensen was the recipient of a Young Investigators Award from the GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease and has received support from the University of California, San Francisco Foundation for Cardiac Research. Dr. Laden received a fellowship from the Sarnoff Cardiovascular Research Foundation, and was a medical student at Duke University, Durham, North Carolina, when this work was done. Dr. DeMarco has served as a speaker/consultant for Actelion, Gilead, Boston Scientific, Cardiokinetics, and Medtronic. Dr. Jensen is currently affiliated with the Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Dr. Laden is currently affiliated with the Department of General Surgery, Stanford University, Stanford, California.