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 be come important adjuncts as anesthetic agents. They act by binding to a lpha(2)ARs on the surface of cell membranes and cause centrally mediat ed sedation and analgesia. alpha(2)ARs also contribute to other aspect s 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 heterog eneity in the distribution of alpha(1)-adrenergic receptor subtypes, t herefore making it imperative to analyze the distribution of alpha(2)A R subtypes in human tissues. This information may have importance in t he 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 ribon uclease protection assays to determine alpha(2)AR subtype messenger RN A (mRNA) expression in cardiovascular, central nervous system, and per ipheral tissues. Results: alpha(2),AR mRNA is present in greatest conc entrations 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 li ver; and alpha(2-C10) mRNA in pancreas and small intestine. Hence alph a(2)AR subtype mRNA distribution is tissue-selective and differs from that reported for rat. Conclusions: (1) On comparison with previous re search we find possible species heterogeneity in alpha(2)AR subtype mR NA distribution (rat vs. human) for all three alpha(2)AR subtypes. (2) We demonstrate the presence and subtype heterogeneity of alpha(2)AR s ubtype mRNA in both brain and peripheral tissues. (3) Significant conc entrations of alpha(2)AR mRNA are present in adult human heart. These findings have important implications for our understanding of human ad renergic 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-sele ctive anesthetics and other therapeutic agents for use in treating hum an diseases.