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

This study has examined the effects of animal age on the contractile respon siveness 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 o f [I-125]ET-1 to guinea-pig and rat isolated tracheal tissue was also exami ned. The potency (pD(2)) of ET-1 was three to four times greater in tracheal tis sue taken from 4-week-old rats than in similar tissue from 12- to 32-week-o ld animals, although maximum response (E-max) was not significantly altered . Neither pD(2) nor E-max were influenced by ageing in epithelium-intact gu inea-pig tracheal preparations. In contrast. removal of the airway epitheli um significantly increased the contractile potency of ET-1 by two- to three fold in tissue from animals of 6-20 weeks of age, but not in tissue from ne wborn animals. Significant falls in specific [I-125]ET-1 grain density with ageing were de monstrated during the maturation phase in both species. In the rat, the dec rease between 4 and 12 weeks was reflected in the fall in ET-1 potency at 1 2 weeks. However, the age-associated reduction in airway smooth muscle ET r eceptor number in the guinea-pig was not mirrored by significant changes in sensitivity to ET-1, suggesting the presence of a functional receptor rese rve. ET-1 (1 nM) caused significant increases in intracellular inositol phosphat es, with levels generally higher in rat than in guinea-pig trachea. ET-1-in duced 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 ex ample, in both rat and guinea-pig, the smallest ET-1-induced increases in i ntra- cellular inositol phosphates were measured in airway smooth muscle fr om the oldest animals tested, although tissue sensitivity to ET-1 was stabl e in both species after 12 weeks of age. These data suggest that relatively low levels of inositol phosphates were required to elicit E-max, consisten t with the presence of more than one signal transduction process.