Gene substitution/knockout to delineate the role of α2-adrenoceptor subtypes in mediating central effects of catecholamines and imidazolines

Adrenergic receptors form the interface between the sympathetic nervous system and the cardiovascular system as well as many endocrine and parenchymal tissues. For the three alpha(2)-adrenergic receptors (alpha(2A), alpha(2B), and alpha(2C)), genetic mouse models have been developed that can be used to elucidate the physiologic function of each receptor subtype in vivo. Different strategies for homologous recombination in embryonic stem cells were applied to generate lines of mice with gene knockouts of the individual alpha(2)-receptor subtypes (alpha(2A)-KO, alpha(2B)-KO, and alpha(2C)-KO) or with a substitution of a mutant receptor at the wildtype locus (alpha(2)-D79N). In these transgenic mice, the cardiovascular effects of alpha(2)-agonists and imidazoline(1) receptor agonists were tested. Stimulation of alpha(2B) receptors in vascular smooth muscle produces hypertension and counteracts the clinically beneficial hypotensive effect of stimulating alpha(2A) receptors in the central nervous system.