Phenotyping--genetic determinants of presynaptic adrenergic mechanisms

University Of California San Diego, La Jolla CA

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Abstract

In this proposal, we will systematically probe the human autonomic pharmacology of pre-synaptic catecholamine storage and release, as well as its post-synaptic consequences, using an isolated vascular bed (the human forearm, with local drug infusion, measurement of local neurotransmitter release, and local plethysmography blood flow). This phenotyping strategy therefore emphasizes regional vascular responses, so as to remove pharmacokinetic and baroreflex variables from their confounding influence, to thereby isolate and focus upon pharmacodynamic (receptor and post-receptor) determinants of drug responses. The diagnostic pre-synaptic drug responses we propose (beta2- adrenergic agonist, alpha2-adrenergic agonist, and sympathomimetic amine) will allow us to more effectively and "cleanly" probe receptor and post-receptor signaling, allowing rigorous pharmacodynamic insights to be applied later to therapeutic drug responses in humans. Diagnostic responses should allow definition of which SNP alleles contribute to variation in signaling in a particular pathway. Here we hypothesize that pre0synaptic agonist responses, obtained under carefully defined circumstances in a regional circulatory bed (forearm), will lead to the discovery of associated SNP alleles which will ultimately yield diagnostic tools to predict therapeutic drug responses (to antagonists at the same receptors).