The long-term goal of this research is to understand prejunctional regulation of acetylcholine release from postganglionic parasympathetic nerves in the airways in health and in the presence of airway disease. It is hypothesized that during airway inflammtion, such as occurs in asthma and other airway diseases, there are changes in the response of nerves to prejunctional modulatory factors, and/or the milieu of mediators around parasympathetic nerves is altered so that there is either less inhibition or more facilitation of acetylcholine release. The proposed research will study factors that prejunctionally modulate acetylcholine release from horse trachealis muscle. The horse has been selected because its airways provide large amounts of muscle for concurrent studies of acetylcholine release and tension. In addition, the horse suffers from a chronic obstructive inflammatory airway disease known as heaves that has similarities to asthma and other obstructive lung diseases of humans. These diseases are characterized by airway obstruction, inflammation, and hyperresponsiveness, all of which are also feature of heaves. The mechanisms of hyperresponsiveness are not understood and may involve changes in prejunctional regulation of neurotransmitter release. Acetylcholine release in response to electrical field stimulation will be quantitated by HPLC and electrochemical detection. Concurrent measurement of the tension induced by field stimulation and exogenous acetylcholine will be made in adjacent strips of trachealis muscle. Indirect evidence of prejunctional effects derived from tension studies will be compared with measurements of acetylcholine release. The prejunctional role of muscarinic M2 receptors, sympathetic nerves, adrenoceptors, and prostanoids will be investigated in normal horses by examining the dose response to specific agonists and blocking agents. Airway obstruction will be induced in horses with heaves and the response to agonists and antagonists investigated and compared with normal horses. If differences in response are found, heavy horses will also be studied during clinical remission in order to demonstrate if the differences in prejunctional modulation are induced by airway inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL049494-01
Application #
3368616
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1993-01-01
Project End
1995-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Zhu, F X; Zhang, X Y; Robinson, N E (1997) Origin and modulation of ACh release from rat airway cholinergic nerves. Am J Physiol 272:L8-14
Zhang, X Y; Zhu, F X; Robinson, N E (1996) Excitatory prejunctional beta 2-adrenoceptor distribution within equine airway cholinergic nerves. Respir Physiol 106:81-90
Robinson, N E; Derksen, F J; Olszewski, M A et al. (1996) The pathogenesis of chronic obstructive pulmonary disease of horses. Br Vet J 152:283-306
Zhang, X Y; Robinson, N E; Zhu, F X (1996) Potentiation of acetylcholine release from tracheal parasympathetic nerves by cAMP. Am J Physiol 270:L541-6
Zhang, X Y; Olszewski, M A; Robinson, N E (1995) Beta 2-adrenoceptor activation augments acetylcholine release from tracheal parasympathetic nerves. Am J Physiol 268:L950-6
Wang, Z W; Yu, M F; Robinson, N E et al. (1995) Acetylcholine release from airway cholinergic nerves in horses with heaves, an airway obstructive disease. Am J Respir Crit Care Med 151:830-5
Zhang, X Y; Robinson, N E; Wang, Z W et al. (1995) Catecholamine affects acetylcholine release in trachea: alpha 2-mediated inhibition and beta 2-mediated augmentation. Am J Physiol 268:L368-73
Sonea, I M; Bowker, R M; Robinson, N E et al. (1994) Substance P and calcitonin gene-related peptide-like immunoreactive nerve fibers in lungs from adult equids. Am J Vet Res 55:1066-74
Zhao, W W; Robinson, N E; Yu, M F (1994) PGE2 inhibits acetylcholine release from cholinergic nerves in canine but not equine airways. Prostaglandins Leukot Essent Fatty Acids 51:347-55
Yu, M F; Wang, Z W; Robinson, N E et al. (1994) Modulation of bronchial smooth muscle function in horses with heaves. J Appl Physiol 77:2149-54

Showing the most recent 10 out of 13 publications