Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Although the pulmonary vasculature is known to receive cholinergic innervation, little is known about the role of cholinergic mechanisms in regulating pulmonary vascular function. Accordingly, the principal goals of this proposal are to characterize muscarinic acetylcholine receptor (mAChR) subtypes and to evaluate the role of endothelium in mediating the actions of acetylcholine in the pulmonary vascular bed. It is known that pulmonary vascular responses to acetylcholine are both tissue and species dependent. Furthermore, studies by the applicant and others have demonstrated that endothelium can mediate both vasoconstrictor and dilator responses to acetylcholine. In addition to mAChR on endothelium and vascular smooth muscle, these receptors may also exist on prejunctional noradrenergic nerve terminals, where they act to inhibit norepinephrine release. It is not known whether the actions of acetylcholine at these prejunctional nerve terminals or at the postjunctional effector sites on endothelium and smooth muscle are mediated by different mAChR, as mAChR subtypes have not yet been identified in the pulmonary circulation. A major goal of this proposal, therefore, is to test the hypothesis that different mAChR subtypes mediate the various actions of acetylcholine in the pulmonary vascular bed (vasodilation, vasoconstriction, inhibition of transmitter release). To conduct this investigation, a functional approach will be taken. Selective mAChR subtypes antagonists will be used to characterize systematically mAChR in pulmonary arteries isolated from two species exhibiting divergent pulmonary vascular responses to acetylcholine (rabbits and rats) by determining the affinity of each agonist for specific mAChR subtypes using Schild analysis. Additional evidence from the investigator's laboratory has shown that responses to acetylcholine are diminished in hypertensive pulmonary arteries; however, nothing is known about the causes for this diminished responsiveness. Accordingly, the applicant will also attempt to characterize mAChR in hypertensive pulmonary vessels through both functional studies and radioligand binding techniques. It is hoped that these studies will provide new information on the nature and functional significance of pulmonary vascular muscarinic acetylcholine receptors.
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