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 (Ca2+) concentration to nominally zero in freshly isolated isometrically mounted 2 mm human bronchi. Our results show: (1) the magnitude of IF is ∼50% of the maximal total force elicited by acetylcholine (10−5 M) and is epithelial independent, (2) IF can also be revealed by β-adrenergic activation (isoproterenol), non-specific cationic channel blockade (La3+) or L-type voltage gated Ca2+ channel blockade (nifedipine), (3) atropine, indomethacin, AA-861, or pyrilamine did not affect IF, (4) IF was reduced by the intracellular Ca2+ ([Ca2+]i) chelating agent BAPTA-AM, (5) ω-conotoxin had no effect on IF. In studies in cultured hASM cells nominally zero Ca2+ buffer and BAPTA-AM reduced [Ca2+]i but isoproterenol and nifedipine did not. Taken together these results indicate that rapid reduction of [Ca2+]i reveals a permissive relationship between extracellular Ca2+, [Ca2+]i and IF. However IF can be dissipated by mechanisms effecting Ca2+ 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.

► Intrinsic force generation is a fundamental property of human airway smooth muscle.
► Intrinsic force can be identified by reducing extracellular calcium concentration in isolated isometrically mounted 2 mm human bronchi.
► The magnitude of intrinsic force is ∼50% of maximal acetylcholine elicited force.
► There is a permissive relationship between extracellular Ca2+, [Ca2+]i and IF.