Ageing and epithelial integrity as modulators of airway smooth muscle responsiveness to endothelin-1

J.M.H. Preuss, Paul Rigby, Roy Goldie

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Abstract

This study has examined the effects of animal age on the contractile responsiveness and inositol phosphate-generating capacities of guinea-pig (0-104 weeks) and rat (4-104 weeks) isolated tracheal smooth muscle in response to endothelin-1 (ET-1). The influence of animal age on the specific binding of [I-125]ET-1 to guinea-pig and rat isolated tracheal tissue was also examined.The potency (pD(2)) of ET-1 was three to four times greater in tracheal tissue taken from 4-week-old rats than in similar tissue from 12- to 32-week-old animals, although maximum response (E-max) was not significantly altered. Neither pD(2) nor E-max were influenced by ageing in epithelium-intact guinea-pig tracheal preparations. In contrast. removal of the airway epithelium significantly increased the contractile potency of ET-1 by two- to threefold in tissue from animals of 6-20 weeks of age, but not in tissue from newborn animals.Significant falls in specific [I-125]ET-1 grain density with ageing were demonstrated during the maturation phase in both species. In the rat, the decrease between 4 and 12 weeks was reflected in the fall in ET-1 potency at 12 weeks. However, the age-associated reduction in airway smooth muscle ET receptor number in the guinea-pig was not mirrored by significant changes in sensitivity to ET-1, suggesting the presence of a functional receptor reserve.ET-1 (1 nM) caused significant increases in intracellular inositol phosphates, with levels generally higher in rat than in guinea-pig trachea. ET-1-induced inositol phosphate accumulation decreased significantly with respect to animal age in both guinea-pig and rat isolated tracheal tissue. However, this was not correlated with changes in contractile pD(2) or E-max. For example, in both rat and guinea-pig, the smallest ET-1-induced increases in intra- cellular inositol phosphates were measured in airway smooth muscle from the oldest animals tested, although tissue sensitivity to ET-1 was stable in both species after 12 weeks of age. These data suggest that relatively low levels of inositol phosphates were required to elicit E-max, consistent with the presence of more than one signal transduction process.
Original languageEnglish
Pages (from-to)391-396
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume361
DOIs
Publication statusPublished - 2000

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