The last decade has witnessed a sharp increase in cocaine abuse and indeed a corresponding increase in young patients presenting with cardiovascular complications mediated by the drug has been observed. However, the majority of patients dying of cocaine abuse have minimal pathological changes in the heart that can not account for the patients' deaths. Preliminary data presented in the proposal suggest that opioid receptors are expressed on vascular smooth muscle and these receptors are functionally coupled to vascular contraction. Indeed, the cloned human opioid receptors have been demonstrated to inhibit cyclic nucleotide production and modulate ion channel conductivity, events that will have pronounced effects on vascular tone. The long term goals of the laboratory are to define mechanisms that modulate vascular reactivity and promote disease progression following substance abuse, to define rational approaches for pharmaceutical intervention. The objectives of this proposal are to characterize the biochemical and physiological properties of vascular smooth muscle opioid receptors in human and rodent tissue by: (1) evaluation and classification of opioid peptide binding sites in vascular tissue and cell lines; (2) evaluation of the pharmacological properties (vascular contraction) and receptor signaling (e.g., intracellular Ca2+ transients, changes in K+ channel conductivity and membrane polarization) mediated by opioid receptors in vascular tissue and cell lines, respectively, and (3) cloning and sequence analysis of the human vascular smooth muscle opioid receptors. Accomplishment of these specific aims will define the normal functioning of vascular smooth muscle opioid peptide receptors so that the role of these receptors in various disease states, including those mediated by drug abuse, can be evaluated.
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