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

Objectives The goal was to identify alpha-1-adrenergic receptor (AR) subtypes in human coronary arteries. Background The alpha 1-ARs regulate human coronary blood flow. The alpha 1-ARs exist as 3 molecular subtypes, alpha 1A, alpha 1B,and alpha 1D, and the alpha 1D subtype mediates coronary vasoconstriction in the mouse. However, the alpha 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 alpha 1-and alpha-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 alpha 1D subtype was 85% of total coronary alpha 1-AR mRNA and 75% of total alpha 1-AR protein, and alpha 1D stimulation activated ERK. In contrast, the alpha 1D was low in LV myocardium. Total coronary alpha 1-AR levels were one-third of beta-ARs, which were 99% the beta 2 subtype. Conclusions The alpha 1D subtype is predominant and functional in human epicardial coronary arteries, whereas the alpha 1A and alpha 1B are present at very low levels. This distribution is similar to the mouse, where myocardial alpha 1A-and alpha 1B-ARs mediate beneficial functional responses and coronary alpha 1Ds mediate vasoconstriction. Thus, alpha 1D-selective antagonists might mediate coronary vasodilation, without the negative cardiac effects of nonselective alpha 1-AR antagonists in current use. Furthermore, it could be possible to selectively activate beneficial myocardial alpha 1A-and/or alpha 1B-AR signaling without causing coronary vasoconstriction. (J Am Coll Cardiol 2009; 54: 1137-45) (C) 2009 by the American College of Cardiology Foundation