The cardiovascular effects of adenosine are profound and widely considered clinically significant. The preeminent actions of this nucleoside are those which lead to vasodilation, hypotension and cardiac depression. The concentration of adenosine available in the extracellular space to interact with its receptors is regulated by nucleoside transporters that catalyze the movement of nucleosides across plasma membranes. The potential therapeutic value of nucleoside transport inhibitors and adenosine has been demonstrated in disease states associated with ischemia and hypertension. The nucleoside transport system may be a potential site of impaired purinergic modulation in hypertension. The contribution of adenosine-related system to the pathophysiology of hypertension, however, remains relatively unexplored. The proposed studies are a continuation of the pharmacological and biochemical characterization of cardiovascular nucleoside transporters to determine their functional significance as potential targets for developing new drug therapies. Radio-ligand binding approaches with putative probes of nucleoside transporter and adenosinergic activities will be employed to evaluate the role of nucleoside transporters in normotensive and hypertensive states especially following chronic administration of inhibitors of nucleoside transport, adenosine A1 and A2 agonists alone or in combination with a nucleoside transport inhibitor, and pretreatment with pertussis and cholera toxins. The data will enhance our understanding of the regulation of nucleoside transporter and help to define the signal transduction mechanisms and molecular characteristics. A long term objective is to isolate and purify the transporter proteins which will ultimately lead to the characterization of their peptide sequences and their three dimensional conformation thus facilitating the development of even more specific drugs.
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