The long-term objectives are a better understanding of why the pulmonary artery vasoconstricts in response to hypoxia. Hypoxic pulmonary vasoconstriction (HPV) occurs in both normal and diseased lungs and is an important component of chronic respiratory diseases and shock lung. The pulmonary hypertension consequent to this vasoconstriction often becomes an important part of the pathophysiology. While sympathetic nerves appear not to be essential for HPV to occur, the noradrenergic system appears to be capable of fine tuning the response and our studies have shown that norepinephrine (NE) dynamics at neuroeffector junctions are different in pulmonary artery than in coronary artery or in saphenous vein and are, in addition, changed during acute or chronic hypoxia in a direction which increases the availability of NE in synaptic clefts. Studies are now proposed: (1) to determine whether differences in the regulation of NE levels in synaptic clefts in pulmonary artery compared to saphenous vein are a unique feature of pulmonary artery or simply represent differences between artery and vein; (2) to determine whether the cotransmitter peptide, neuropeptide Y (NPY), which typically enhances vasoconstrictor responses, or the peptide, vasoactive intestinal polypeptide (VIP), which typically enhances vasodilator responses may influence NE dynamics or effector responses at neuroeffector units in pulmonary artery; (3) to determine whether hypoxia or the volatile anesthetic agent halothane alters the interaction bf NPY, VIP or NE at neuroeffector junctions in pulmonary or systemic arteries. Techniques to be used include: superfused, isolated, helically cut strips of blood vessel in which postganglionic nerves can be stimulated electrically, the superfusate (and the tissue) analyzed for endogenous NE using liquid chromatography with electrochemical detection and for NPY and VIP using radioimmunoassay technique; isolated organ bath studies using rings of pulmonary and systemic arteries in which the postjunctional actions of VIP and NPY will be determined during high and low oxygen tensions and during halothane. An understanding of the interactions between NE and peptides that occur at neuroeffector units during normoxia and why these change during hypoxia may open new avenues of therapy directed at pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL023217-10
Application #
3337183
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1979-08-01
Project End
1993-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
10
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Tyce, G M; Hunter, L W; Ward, L E et al. (1995) Effluxes of 3,4-dihydroxyphenylalanine, 3,4-dihydroxyphenylglycol, and norepinephrine from four blood vessels during basal conditions and during nerve stimulation. J Neurochem 64:833-41
Brown, D L; Rorie, D K (1994) Altered reactivity of isolated segmental lumbar arteries of dogs following exposure to ethanol and phenol. Pain 56:139-43
Kamath, G S; Rorie, D K; Tyce, G M (1993) Altered release and metabolism of norepinephrine in superfused canine saphenous veins in the presence of halothane and hypoxia. Anesthesiology 78:553-61
Hunter, L W; Rorie, D K; Tyce, G M (1993) Inhibition of aromatic L-amino acid decarboxylase under physiological conditions: optimization of 3-hydroxybenzylhydrazine concentration to prevent concurrent inhibition of monoamine oxidase. Biochem Pharmacol 45:1363-6
Hughes, J M; Sill, J C; Pettis, M et al. (1993) Nitrous oxide constricts epicardial coronary arteries in pigs: evidence suggesting inhibitory effects on the endothelium. Anesth Analg 77:232-40
Hunter, L W; Rorie, D K; Tyce, G M (1992) Dihydroxyphenylalanine and dopamine are released from portal vein together with noradrenaline and dihydroxyphenylglycol during nerve stimulation. J Neurochem 59:972-82
Rorie, D K; Hunter, L W; Tyce, G M (1991) Neuropeptide Y and 3,4-dihydroxyphenylglycol effluxes from artery are oxygen sensitive. Am J Physiol 261:H1371-8
Kristensen, E W; Chinnow, S L; Montreuil, R S et al. (1990) Precursors and metabolites of norepinephrine in sympathetic ganglia of the dog. J Neurochem 54:1782-90
Rorie, D K; Hunter, L W; Lunn, J J (1990) Halothane decreases the release of neuropeptide Y and 3,4-dihydroxyphenylglycol from superfused segments of dog pulmonary artery. Anesthesiology 73:722-30
Lunn, J J; Murray, M J; Rorie, D K (1990) Endotoxin does not directly alter norepinephrine release or vasoactivity in dog pulmonary artery and portal vein. Crit Care Med 18:1408-12

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