LOCALIZATION OF MESSENGER-RNA FOR 3 DISTINCT ALPHA(2)-ADRENERGIC RECEPTOR SUBTYPES IN HUMAN TISSUES - EVIDENCE FOR SPECIES HETEROGENEITY AND IMPLICATIONS FOR HUMAN PHARMACOLOGY

Background: alpha(2)-Adrenergic receptor (alpha(2)AR) agonists have become important adjuncts as anesthetic agents. They act by binding to alpha(2)ARs on the surface of cell membranes and cause centrally mediated sedation and analgesia. alpha(2)ARs also contribute to other aspects of physiologic regulation. Three subtypes of alpha(2)ARs (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(2)AR subtypes in human tissues. This information may have importance in the understanding of potential side effects of administration of alpha(2)AR subtype-selective agonists for anesthesia in humans. Methods: RNA extracted from human tissues was analyzed by using quantitative ribonuclease protection assays to determine alpha(2)AR subtype messenger RNA (mRNA) expression in cardiovascular, central nervous system, and peripheral tissues. Results: alpha(2),AR 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(2)AR 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(2)AR subtype mRNA distribution (rat vs. human) for all three alpha(2)AR subtypes. (2) We demonstrate the presence and subtype heterogeneity of alpha(2)AR subtype mRNA in both brain and peripheral tissues. (3) Significant concentrations of alpha(2)AR 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(2)AR subtypes, and may be important for the rational development of (alpha(2)AR subtype-selective anesthetics and other therapeutic agents for use in treating human diseases.