Studies using a variety of experimental approaches have established the existence of an inhibitory nervous system in mammalian airways which is neither adrenergic nor cholinergic. Because the neurotransmitter has not been identified, the system commonly is referred to as the nonadrenergic noncholinergic inhibitory system (NANCIS). The functional significance of this nervous system and its role in the pathophysiology of human airways disease presently are unknown. Also unknown is the nature of the chemical transmitter utilized by the system for postganglionic neurotransmission. Further, aside from a lack of sensitivity to a variety of pharmacologic antagonists, relatively little is known about the system's basic pharmacologic characteristics. Previous studies in our laboratory have established the functional presence of the lung NANCIS in the intact cat. Experiments in vitro have since confirmed and extended these findings. The studies outlined in the current proposal will utilize both in vivo and isolated tissue techniques to: (1) assess the functional significance of the lung NANCIS by detemrining whether the system can be activated by phsiologically relevant stimuli and whether it plays a role in controlling airways responsiveness to bronchoconstrictive stimuli, (2) develop an in vivo model of the lung NANCIS in a nonhuman primate; (3) demonstrate release and characterize the nature of the NANCIS neurotransmitter in isolated cat airway smooth muscle; and (4) characterize the lung NANCIS with regard to its modulation by other neurotransmitters or hormones and identify possible mechanisms through which the system produces inhibitory effects on airways smooth muscle. By demonstrating the functional significance of the lung NANCIS, this research could provide new insight into the physiologic mechanisms regulating airway caliber and the pathogenic mechanisms underlying airways hyperreactivity. Additionally, the pharmcologic information derived from these studies could provide a rationale for the synthesis of more effective therapeutic agents for the treatment of hyperreactive airways tissue.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL027025-07
Application #
3338882
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1987-01-01
Project End
1990-07-31
Budget Start
1987-08-01
Budget End
1988-07-31
Support Year
7
Fiscal Year
1987
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
Thompson, D C; Altiere, R J (1998) Differential susceptibility of tracheal contraction to nonadrenergic noncholinergic relaxation. J Pharmacol Exp Ther 284:19-24
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
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; Altiere, R J; Diamond, L (1990) Nicotinic agonist modulation of feline bronchomotor tone. Clin Exp Pharmacol Physiol 17:83-97
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
Thompson, D C; Wells, J L; Altiere, R J et al. (1988) The effect of epithelium removal on non-adrenergic, non-cholinergic inhibitory responses in the isolated central airways of the cat and guinea pig. Eur J Pharmacol 145:231-7
Diamond, L; Altiere, R J; Thompson, D C (1988) The airway nonadrenergic noncholinergic inhibitory nervous system. Chest 93:1283-5

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