Recent studies have established the existence of a nonadrenergic noncholinergic inhibitory nervous system (NANCIS) in airways. The NANCIS appears to be the principal inhibitory nervous input to human airways. The functional significance of this nervous system and its role in pathophysiology of human airways disease are unknown. Also unknown is the identity of its neurotransmitter, although evidence suggests it is a neuropeptide. Little is known about the system's basic pharmacological characteristics and there is no information on biochemical mechanisms associated with termination of transmitter action or signal transduction mechanisms used by the system to relax airways. Studies outlined in this proposal will use physiologic, pharmacologic and biochemical approaches to: (i) assess the functional significance of the lung NANCIS; (ii) characterize the system with regard to its modulation by other neurotransmitters or hormones and determine whether it modulates release of other mediators; (iii) demonstrate release and characterize the nature of the NANCIS neurotransmitter; (iv) identify and characterize peptidases in airways that degrade neuropeptides and the NANCIS transmitter; (v) determine signal transduction mechanisms used by the NANCIS to relax airway smooth muscle; and (vi) develop cell lines of intrinsic airway neurons to aid in the investigation of the lung NANCIS. By achieving these aims, this research could provide new insight into physiologic mechanisms regulating airway caliber, pathophysiologic mechanisms underlying airways hyperreactivity and cellular events that control nerve-mediated bronchodilation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
1K04HL002356-01
Application #
3074452
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1989-09-01
Project End
1994-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Type
Schools of Pharmacy
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
Lindsay, G; Diamond, L; Thompson, D C et al. (1995) Nitric oxide. Role as a relaxant agonist and transmitter of nonadrenergic noncholinergic inhibitory nerves in guinea pig trachea. Chest 107:125S
Altiere, R J; Travis, D C; Roberts, J et al. (1994) Pharmacological characterization of muscarinic receptors mediating acetylcholine-induced contraction and relaxation in rabbit intrapulmonary arteries. J Pharmacol Exp Ther 270:269-76
Altiere, R J; Travis, D C; Thompson, D C (1994) Characterization of acetylcholinesterase in rabbit intrapulmonary arteries. Am J Physiol 267:L745-52
Altiere, R J; Thompson, D C (1992) Modulation of cholinergic responses by N omega-nitro-L-arginine in rabbit intrapulmonary arteries. Pulm Pharmacol 5:149-51
Thompson, D C; Diamond, L; Altiere, R J (1992) Atypical presynaptic alpha-adrenoceptor modulation of neurally-mediated cholinergic responses in guinea-pig tracheal smooth muscle. Pulm Pharmacol 5:251-5
Altiere, R J; Diamond, L; Thompson, D C (1992) Omega-conotoxin-sensitive calcium channels modulate autonomic neurotransmission in guinea pig airways. J Pharmacol Exp Ther 260:98-103
Thompson, D C; Szarek, J L; Altiere, R J et al. (1990) Nonadrenergic bronchodilation induced by high concentrations of sulfur dioxide. J Appl Physiol 69:1786-91
Thompson, D C; Diamond, L; Altiere, R J (1990) Presynaptic alpha adrenoceptor modulation of neurally mediated cholinergic excitatory and nonadrenergic noncholinergic inhibitory responses in guinea pig trachea. J Pharmacol Exp Ther 254:306-11
Thompson, D C; Diamond, L; Altiere, R J (1990) Enzymatic modulation of vasoactive intestinal peptide and nonadrenergic noncholinergic inhibitory responses in guinea pig tracheae. Am Rev Respir Dis 142:1119-23