Alpha 2 adrenergic receptors play a major role in the sympathetic nervous system control over vascular function. Alpha 2 receptors in the vasomotor center modulate sympathetic outflow. Stimulation of presynaptic alpha 2 receptors inhibits neurotransmitter release. Postsynaptic alpha 2 receptors are found on vascular smooth muscle where they mediate contraction, on endothelial cells where they stimulate release of endothelial derived relaxing factor, and on platelets where they enhance aggregation. Three genes encoding distinct subtypes of alpha 2 adrenergic receptors have been identified in mouse and man. It has not been possible to identify the physiologic role of the different alpha 2 subtypes using pharmacologic approaches or by applying the techniques of molecular biology. However, recently developed techniques of experimental mammalian embryology make it possible to selectively alter alpha 2 adrenergic receptor genes in mice. Using these techniques we propose to create strains of mice which have a targeted gene disruption for each subtype of alpha 2 adrenergic receptor. By studying alpha 2 mediated changes in vascular function in these mice it should be possible to identify specific roles for each of the receptor subtypes. These studies may provide incentive for the development of more selective agonists and antagonist for specific alpha 2 adrenergic and physiologic receptor subtypes. Furthermore, the genetically altered mice may prove useful in studying the pharmacologic and physiologic properties of newly developed drugs. Finally, the phenotypes of these recombinant mice may provide clues to the phenotypes that might be observed in humans having genetic disorders of adrenergic receptor function.
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