Studies are proposed of synaptic events at neuroeffector junctions in pulmonary artery and in segments of the systemic vasculature from dogs. Our previous work showed that during electrical stimulation norepinephrine (NE) removal from the junctional cleft was facilitated in the saphenous vein but not in the pulmonary artery. Although we originally postulated that the facilitated NE removal was due to activation of membrane-bound catechol methyltransferase, our studies did not confirm this hypothesis. Studies are now proposed to determine whether other processes involved in clearing the synaptic cleft of NE (neuronal and extraneuronal uptakes and monoamine oxidase) can explain the enhanced removal of NE from the synaptic cleft. In addition, physiological studies will examine NE dynamics and contractile tensions in pulmonary artery having undergone changes in anatomical structure caused by chronic hypoxia. Light and electron microscopy studies will attempt to correlate synaptic cleft width with changes in NE dynamics, of particular interest will be whether the cleft width can change during pathological states such as pulmonary hypertension. Included in the proposal are also studies that will determine the effects of general anesthetic agents on neuroeffector junction function in pulmonary artery. Techniques to be used include: superfusion of isolated, helically cut strips of vessels from dogs; electrical stimulation of postganglionic nerves in these vessels; measurement of endogenous NE in tissue and in superfusate by liquid chromatography with electrochemical detection; and labeling of NE stores with [H3]NE and measurement of radiolabeled NE and its metabolites. These studies are important because changes in anatomical structure in pulmonary vasculature precede the development of pulmonary hypertension and changes in NE dynamics at structurally altered neuroeffector junctions may contribute to this hypertension. An understanding of these altered events may open new avenues of therapy directed at pulmonary hypertension.
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