Increased cholinergic antagonism underlies impaired beta-adrenergic response in ovalbumin-sensitized guinea pigs.
The goal of this study was to determine if the hyporesponsiveness to beta-adrenoceptor stimulation observed in ovalbumin-sensitized tracheal smooth muscle is due to increased cholinergic muscarinic tone or to a defect in the beta-adrenergic cascade itself. We examined the effects of ovalbumin-sensitization on the responsiveness of guinea pig tracheae to agents that mediate relaxation at various steps in the beta-adrenergic cascade when the tracheal tissue was preconstricted with either carbachol or histamine. Ovalbumin sensitization caused significant reductions in the maximal relaxations both to the beta-adrenergic agonist isoproterenol and to prostaglandin E2 (PGE2) in guinea pig trachealis when the tracheal tissue was preconstricted with the muscarinic agonist carbachol. In contrast, sensitization had no effect on the ability of PGE2 and isoproterenol to relax histamine contractions. Preconstricting the tissues with increasing concentrations of KCl reduced the effectiveness of isoproterenol to relax equally airway tissues from both sensitized and control animals. Forskolin-induced relaxations of trachealis muscle were not altered with sensitization. When tracheal tissues were precontracted with increasing concentrations of carbachol, the effectiveness of isoproterenol and PGE2 to relax airway tissues decreased. Functional antagonism of relaxations by muscarinic agonists was enhanced in the sensitized tissues, since the concentration of carbachol necessary to reduce beta-adrenoceptor-induced relaxations to the same degree as in the control animals was a log dose lower. These results suggest that the impaired beta-adrenoceptor response in sensitized tissues is not due to an intrinsic defect in the beta-adrenergic cascade but to an enhancement of a muscarinic cholinergic pathway.
Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205.
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Wills-Karp
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Gilmour
D000818:Animals; D001249:Asthma / Q000503:physiopathology; D002217:Carbachol / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007114:Immunization; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D018727:Muscarinic Antagonists; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D010047:Ovalbumin / Q000276:immunology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology; D012132:Respiratory Muscles / Q000187:drug effects / Q000502:physiology*; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D018727:Muscarinic Antagonists; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D006632:Histamine; D002217:Carbachol; D010047:Ovalbumin; D015232:Dinoprostone; D007545:Isoproterenol