Increased contraction and inositol phosphate formation of tracheal smooth muscle from hyperresponsive guinea pigs

Tracheal smooth muscle from guinea pigs with documented airway hyperresponsiveness in vivo after multiple antigen challenges produced 30% to 50% greater force than tracheas from control guinea pigs, when stimulated with carbachol, histamine, or leukotriene D4. When cultured smooth muscle cells were incubated with myo[2-3H]inositol, basal uptake of [3H]inositol was similar in cells from normal and hyperresponsive guinea pigs, but when these cells were stimulated with contractile agonists, there was increased uptake of inositol in hyperresponsive cells. Analysis of inositol phosphates by column chromatography and high-performance liquid chromatography revealed the presence of inositol-1,4,5-triphosphate, inositol-1,3,4-trisphosphate, inositol-1,4-bisphosphate, and inositol-1-monophosphate. The release of inositol-1,4,5-triphosphate, inositol-1,4-biphosphate, and inositol-1-monophosphate by smooth muscle cells stimulated with carbachol, leukotriene D4, or histamine was 20% to 40% greater in cells derived from hyperresponsive animals than cells from normal animals. These data demonstrate that the increased muscle contraction of hyperresponsive guinea pig tracheas is associated with increased inositol phosphate metabolism in these cells. Delineating the mechanisms of airway smooth muscle contraction should provide new pharmacologic targets for the inhibition of bronchoconstriction in asthma.