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Rho GTPases in Lung Physiology and Disease

8-Bromo-cAMP decreases the Ca²⁺ sensitivity of airway smooth muscle contraction through a mechanism distinct from inhibition of Rho-kinase

¹Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi; and ²Gunma University Faculty of Health Sciences, Gunma 371-8511, Japan

Submitted 21 August 2003 ; accepted in final form 26 April 2004

To clarify whether cyclic AMP (cAMP)/cAMP-dependent protein kinase (PKA) activation and Rho-kinase inhibition share a common mechanism to decrease the Ca²⁺ sensitivity of airway smooth muscle contraction, we examined the effects of 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP), a stable cAMP analog, and (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide dihydrochloride, monohydrate (Y-27632), a Rho-kinase inhibitor, on carbachol (CCh)-, guanosine 5'-O-(3-thiotriphosphate) (GTPS)-, 4-phorbol 12,13-dibutyrate (PDBu)-, and leukotriene D₄ (LTD₄)-induced Ca²⁺ sensitization in -toxin-permeabilized rabbit tracheal and human bronchial smooth muscle. In rabbit trachea, CCh-induced smooth muscle contraction was inhibited by 8-BrcAMP and Y-27632 to a similar extent. However, GTPS-induced smooth muscle contraction was resistant to 8-BrcAMP. In the presence of a saturating concentration of Y-27632, PDBu-induced smooth muscle contraction was completely reversed by 8-BrcAMP. Conversely, PDBu-induced smooth muscle contraction was resistant to Y-27632. In the presence of a saturating concentration of 8-BrcAMP, GTPS-induced Ca²⁺ sensitization was also reversed by Y-27632. The 8-BrcAMP had no effect on the ATP-triggered contraction of tracheal smooth muscle that had been treated with calyculin A in rigor solutions. The 8-BrcAMP and Y-27632 additively accelerated the relaxation rate of PDBu- and GTPS-treated smooth muscle under myosin light chain kinase-inhibited conditions. In human bronchus, LTD₄-induced smooth muscle contraction was inhibited by both 8-BrcAMP and Y-27632. We conclude that cAMP/PKA-induced Ca²⁺ desensitization contains at least two mechanisms: 1) inhibition of the muscarinic receptor signaling upstream from Rho activation and 2) cAMP/PKA's preferential reversal of PKC-mediated Ca²⁺ sensitization in airway smooth muscle.

calcium sensitization; cAMP; leukotriene D₄

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