Mechanisms of intrinsic force in small human airways

We quantified the magnitude and investigated mechanisms regulating intrinsic force (IF) in human airway smooth muscle (hASM). IF was identified by reducing extracellular calcium (Ca ²⁺) concentration to nominally zero in freshly isolated isometrically mounted 2mm human bronchi. Our results show: (1) the magnitude of IF is ~50% of the maximal total force elicited by acetylcholine (10 ^-5M) and is epithelial independent, (2) IF can also be revealed by β-adrenergic activation (isoproterenol), non-specific cationic channel blockade (La ³⁺) or L-type voltage gated Ca ²⁺ channel blockade (nifedipine), (3) atropine, indomethacin, AA-861, or pyrilamine did not affect IF, (4) IF was reduced by the intracellular Ca ²⁺ ([Ca ²⁺] _i) chelating agent BAPTA-AM, (5) ω-conotoxin had no effect on IF. In studies in cultured hASM cells nominally zero Ca ²⁺ buffer and BAPTA-AM reduced [Ca ²⁺] _i but isoproterenol and nifedipine did not. Taken together these results indicate that rapid reduction of [Ca ²⁺] _i reveals a permissive relationship between extracellular Ca ²⁺, [Ca ²⁺] _i and IF. However IF can be dissipated by mechanisms effecting Ca ²⁺ sensitivity. We speculate that an increase of IF, a fundamental property of ASM, could be related to human airway clinical hyperresponsiveness and must be accounted for in in vitro studies of hASM.