title: Agonist-mediated airway challenge: cardiopulmonary interactions modulate gas exchange and recovery.
abstract: Diverse agonists used for airway challenges produce a stereotypic sequence of immediate functional responses (e.g., bronchoconstriction, gas trapping, hypoxemia, etc.) at the time such reactions are triggered. The reaction incorporates both pulmonary and cardiac changes that clearly interact in an orchestrated fashion taking the subject (or animal model) through the response generally to ultimate recovery. We hypothesize that despite differences in the initiation of the response, diverse airway provocations lead to a cascade of events that converge through a common physiologic pathway. To better understand the sequence of events and the counterbalanced cardiopulmonary responses, we examined histamine, methacholine, and ovalbumin (OVA) challenges in the awake guinea pig model and assessed ventilatory and breathing mechanics in the context of associated cardiac parameters. With the histamine response as the prototype, we evaluated the role of beta-adrenoreceptors using propranolol (1.0-10 mg/kg i.p.) and found that beta-adrenoreceptors are critical in reducing challenge-induced gas trapping in the lungs. The disposition of the circulatory response to agonist challenge (the OVA model) was reflected in a significant absolute shunting of blood through poorly ventilated regions of the lung. The methacholine challenge revealed that gasping enhanced lung inflation and reversed the diminished Pa(O2). Moreover, beta-sympathetic function was critical to recovery. Collectively, the response profiles of these disparate models of airway challenge suggest a highly integrated balance to maintain gas exchange among the pulmonary airways and vasculature, modulated in recovery by beta-adrenoreceptors.
authors.affiliation: Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research Development, U.S. Environmental Protection Agency, B 143-01 Research Triangle Park, NC 27711, USA.
authors.forename: Mildred J
authors.initials: MJ
authors.lastname: Wiester
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Costa
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Tepper
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Winsett
authors.forename: Ralph
authors.initials: R
authors.lastname: Slade
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000336:Aerosols / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology*; D018721:Muscarinic Agonists / Q000494:pharmacology*; D010047:Ovalbumin / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010313:Partial Pressure; D010991:Plethysmography / Q000379:methods; D011433:Propranolol / Q000494:pharmacology; D011659:Pulmonary Gas Exchange / Q000187:drug effects*; D011897:Random Allocation; D011930:Reaction Time / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology; D012137:Respiratory System / Q000187:drug effects*; D013990:Tidal Volume / Q000187:drug effects; D013997:Time Factors; D014851:Wakefulness
chemical_list: D000319:Adrenergic beta-Antagonists; D000336:Aerosols; D018721:Muscarinic Agonists; D016210:Methacholine Chloride; D006632:Histamine; D010047:Ovalbumin; D011433:Propranolol; D010100:Oxygen