Cellular, sub-cellular and molecular mechanisms by which adenosine produces the relaxation of coronary artery have been investigated for many years and although much progress has been made, these mechanisms are still not completely understood. Several aspects of the vascular adenosine system, including the receptor subtypes, have been addressed in this laboratory. It appears that the coronary adenosine receptor shares similar characteristics with the better characterized A2 receptor of the brain. It is still unclear what role endothelium plays in the relaxations mediated by this receptor(s). Our hypothesis is that the binding of adenosine to its receptor causes increases in cAMP and/or cGMP via a GTP-binding regulatory protein leading to a reduction in vascular tone. It is also possible that such signal transduction, via the same or different GTP-binding protein causes inhibition of PIP(2)-PLC activity resulting in a decreased intracellular Ca++ and vasorelaxation. The proposed studies which are a continuation of our earlier work are directed to investigate the cascade of events which results from activation of adenosine receptor leading to coronary relaxation. We propose to study the: (a) possible coupling of the coronary adenosine receptor to G protein using muscle bath preparation; (b) ADP-ribosylation of coronary G protein(s) by bacterial toxins to identify the toxin-sensitive G protein(s); (c) possible involvement of PlP(2)-PLC in the adenosine receptor system and whether this system is coupled to a G protein; (d) effects of adenosine receptor activation on protein kinase C enzyme system; (e) mobilizing effects of adenosine and its analogs on calcium which may explain the mechanism of their relaxation effects; (f) adenylate and guanylate cyclase activities in response to adenosine receptor stimulation to determine the extent of cyclic AMP and GMP involvement as second messengers; (g) study the adenosine receptor via establishing the order of potency for adenosine agonists in the presence and absence of endothelium to establish its involvement in the coronary relaxation; (h) characterization of coronary adenosine receptor(s) through binding studies in purified plasma membranes; (i) possible effects of adenosine analogs on vascular smooth muscle membrane potential (hyperpolarization) as a mechanism for the relaxation and finally, (j) investigation of a novel observation from this lab that adenosine at picomolar concentrations can produce a contraction response.
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