PHYSIOLOGICAL-MECHANISMS MEDIATING ENHANCED FORCE GENERATION DURING DEVELOPMENT AND IMMUNE SENSITIZATION

We examined the development of acetylcholinesterase (AChase) activity and tracheal smooth muscle (TSM) contraction elicited by acetyicholine (ACh) in a swine model of maturation and a dog model of allergic bronchospasm. Strips of TSM were tethered isometrically at optimal length and responses were expressed as a percentage of the maximum to KCl-substituted perfusate (% KCI). Maximal contraction (AT(max)) to ACh in 2-week-old swine (I 68 +/- 8 % KCI) was greater than in 10-week-old swine (142 +/- 2% KCl; p < 0.02). The AChase inhibitor, physostigmine, augmented ACh-elicited AT(max) in 10-week-old (27 % increase; p < 0.0 1) but not in 2-week-old swine (2% increase; p is NS) and caused a greater increase in sensitivity to muscarinic activation in 2 versus 10 week-old swine (p < 0.02), thus demonstrating increased contraction of TSM in 2 versus 10-week-old swine, which results at least in part from reduced AChase activity in immature animals. In another study, TSM from ragweed-sensitized dogs demonstrated augmented efficacy to ACh-elicited contraction (180 +/- 6% KCl) compared with TSM from sham-sensitized, littermate controls (163 + 4 % KCI; p < 0.05). In the presence of physostigmine, AT(max) was not different between ragweed-sensitized and control TSM. Direct measurement of AChase activity demonstrated reduced enzyme activity in TSM homogenates from ragweed-sensitized dogs (0.86 +/- 0.09 absorbance units . min-1 . mg-1 protein (AU . min-1 . mg-1)) versus control dogs (1.59 +/- 0.13 AU - min-1 . mg-1; p < 0.001), but similar Michaelis constants (K(M) = 0.36 +/- 0.06 for ragweed-sensitized dogs vs. 0.34 +/- 0.06 for control; p is NS). These data demonstrate that immune sensitization reduces AChase activity in TSM by a mechanism consistent with reduction in enzyme content. Together, our data suggest the functional expression of AChase activity increases with age, but may be inhibited by immune sensitization.