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Background: alpha 2-Adrenergic receptor (alpha 2AR) agonists have become important adjuncts as anesthetic agents. They act by binding to alpha 2ARs on the surface of cell membranes and cause centrally mediated sedation and analgesia. alpha 2ARs also contribute to other aspects of physiologic regulation. Three subtypes of alpha 2ARs (alpha 2-C2, alpha 2-C4, and alpha 2-C10) have been described using molecular and pharmacologic techniques. We recently demonstrated species heterogeneity in the distribution of alpha 1-adrenergic receptor subtypes, therefore making it imperative to analyze the distribution of alpha 2AR subtypes in human tissues. This information may have importance in the understanding of potential side effects of administration of alpha 2AR subtype-selective agonists for anesthesia in humans., Methods: RNA extracted from human tissues was analyzed by using quantitative ribonuclease protection assays to determine alpha 2AR subtype messenger RNA (mRNA) expression in cardiovascular, central nervous system, and peripheral tissues., Results: alpha 2AR mRNA is present in greatest concentrations in human kidney, followed by aorta > spleen > heart = lung. alpha 2-C4 mRNA predominates in heart, lung, aorta, cerebral cortex, cerebellum, spleen, kidney, and adrenal gland; alpha 2-C2 mRNA in liver; and alpha 2-C10 mRNA in pancreas and small intestine. Hence alpha 2AR subtype mRNA distribution is tissue-selective and differs from that reported for rat., Conclusions: (1) On comparison with previous research we find possible species heterogeneity in alpha 2AR subtype mRNA distribution (rat vs. human) for all three alpha 2AR subtypes. (2) We demonstrate the presence and subtype heterogeneity of alpha 2AR subtype mRNA in both brain and peripheral tissues. (3) Significant concentrations of alpha 2AR mRNA are present in adult human heart. These findings have important implications for our understanding of human adrenergic physiology, provide a possible explanation for the existence of pharmacologically similar yet distinct alpha 2AR subtypes, and may be important for the rational development of alpha 2AR subtype-selective anesthetics and other therapeutic agents for use in treating human diseases.