The long term objectives of this proposal are to 1) pharmacologically and biochemically characterize the cardiovascular nucleoside transporters as potential targets for developing new drug therapies, 2) 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. Direct radioligand binding approaches will be employed using mainly [3H]nitrobenzylthioinosine, a putative marker of adenosine transport and metabolism and the newer radioligand probe, [3H]dipyridamole. The proposed studies will determine the functional significance of cardiovascular nucleoside transporters in relationship to the physiology of inhibitors of nucleoside transport and the subtypes of adenosine receptor ligands. The molecular characteristics of the nucleoside transporters will be defined on the basis of their effects on adenylate cyclase activity and their interactions with pertussis and cholera toxins. The latter study also will determine if nucleoside transporters can be classified into subtypes in similar ways to adenosine receptors. The nucleoside transporters will be pharmacologically characterized in normotensive and hypertensive states prior to and following chronic drug administration to determine their involvement in disease states. The potential therapeutic value of nucleoside transport inhibitors and adenosine has been demonstrated in disease state associated with ischemia and hypertension. Analyses of the data derived from these studies will aid in the evaluation of the potential nucleoside transporters as targets for new drug therapies.
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