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Background  It has been shown that the contractile state of airway smooth muscle cells (SMCs) in response to agonists is determined by the frequency of Ca 2+  oscillations occurring within the SMCs. Therefore, we hypothesized that the relaxation of airway SMCs induced by agents that increase cAMP results from the down-regulation or slowing of the frequency of the Ca 2+  oscillations.    Methods  The effects of isoproterenol (ISO), forskolin (FSK) and 8-bromo-cAMP on the relaxation and Ca 2+  signaling of airway SMCs contracted with methacholine (MCh) was investigated in murine lung slices with phase-contrast and laser scanning microscopy.    Results  All three cAMP-elevating agents simultaneously induced a reduction in the frequency of Ca 2+  oscillations within the SMCs and the relaxation of contracted airways. The decrease in the Ca 2+  oscillation frequency correlated with the extent of airway relaxation and was concentration-dependent. The mechanism by which cAMP reduced the frequency of the Ca 2+  oscillations was investigated. Elevated cAMP did not affect the re-filling rate of the internal Ca 2+  stores after emptying by repetitive exposure to 20 mM caffeine. Neither did elevated cAMP limit the Ca 2+  available to stimulate contraction because an elevation of intracellular Ca 2+  concentration induced by exposure to a Ca 2+  ionophore (ionomycin) or by photolysis of caged-Ca 2+  did not reverse the effect of cAMP. Similar results were obtained with iberiotoxin, a blocker of Ca 2+ -activated K +  channels, which would be expected to increase Ca 2+  influx and contraction. By contrast, the photolysis of caged-IP 3  in the presence of agonist, to further elevate the intracellular IP 3  concentration, reversed the slowing of the frequency of the Ca 2+  oscillations and relaxation of the airway induced by FSK. This result implied that the sensitivity of the IP 3 R to IP 3  was reduced by FSK and this was supported by the reduced ability of IP 3  to release Ca 2+  in SMCs in the presence of FSK.    Conclusion  These results indicate that the relaxant effect of cAMP-elevating agents on airway SMCs is achieved by decreasing the Ca 2+  oscillation frequency by reducing internal Ca 2+  release through IP 3  receptors.

respiratory research

Airway smooth muscle relaxation results from a reduction in the frequency of Ca2+ oscillations induced by a cAMP-mediated inhibition of the IP3 receptor