PURPOSE:Use of long-acting ×2AR agonists to treat asthma has been associated with bronchoconstrictor hyperresponsiveness, impaired ×2AR-mediated airway relaxation and worsening of the asthmatic condition, phenomena potentially reflecting the effects of prolonged homologous ×2AR desensitization (tolerance) in ASM. We recently demonstrated that upregulated PDE4 activity mediates pro-asthmatic changes in ASM function induced by prolonged ASM exposure to cAMP-elevating agents. Since the deleterious effects of long-acting ×2AR agonists are reportedly mitigated when using these agents in combination with glucocorticoids (GCs), we examined whether GCs attenuate the pro-asthmatic effects of ASM exposure to a long-acting ×2AR agonist, and whether this GC action is attributed to altered regulation of PDE4 activity.
METHODS:Isolated rabbit ASM tissues and cultured human ASM (HASM) cells were exposed to the long-acting ×2AR agonist, salmeterol (SAL; 10 αM × 24 hr) in the absence and presence of pretreatment with either the PDE4 inhibitor, rolipram (10 αM), or dexamethasone (1 αM). The tissues were then examined for altered constrictor and relaxation responsiveness to acetylcholine (ACh) and isoproterenol (ISO), respectively, and the HASM cells were examined for induced changes in PDE4 activity.
RESULTS:The data demonstrated that: 1) SAL-exposed ASM tissues exhibited markedly impaired relaxation responses to ISO and increased constrictor responses to ACh; 2) SAL-exposed HASM cells exhibited significantly increased cAMP PDE activity; and 3) both these changes in constrictor and relaxation responsiveness and increase in PDE4 activity were prevented by pretreating SAL-exposed ASM with either rolipram or dexamethasone.
CONCLUSION:Taken together, these novel data demonstrate that GCs prevent the induction of PDE4-mediated pro-asthmatic-like changes in ASM responsiveness that is associated with prolonged exposure of ASM to a long-acting ×2AR agonist.
CLINICAL IMPLICATIONS:Accordingly, these findings identify a mechanism that potentially accounts for the role of glucocorticosteroids in ameliorating the deleterious effects of prolonged exposure of the airways to long-acting ×2AR agonists.
DISCLOSURE:Gustavo Nino, No Financial Disclosure Information; No Product/Research Disclosure Information