Published online before print October 11, 2001, doi: 10.1161/hh2201.100204
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© 2001 American Heart Association, Inc.
Integrative Physiology |
ß2-Adrenergic Receptor Overexpression Increases Alveolar Fluid Clearance and Responsiveness to Endogenous Catecholamines in Rats
From Pulmonary and Critical Care Medicine (V.D., G.M.M., P.F.), Evanston Northwestern Healthcare, Evanston, Ill; Northwestern University Medical School (J.I.S., Z.S.A., G.M.M., P.F.), Chicago, Ill; and Northeastern Ohio Universities College of Medicine (J.B., M.B.M.), Rootstown, Ohio.
Correspondence to Phillip Factor, DO, Pulmonary and Critical Care Medicine, Evanston Northwestern Healthcare, 2650 Ridge Rd, Evanston, IL 60201. E-mail pfactor{at}northwestern.edu
Abstract—— ß-Adrenergic agonists accelerate the clearance of alveolar fluid by increasing the expression and activity of epithelial solute transport proteins such as amiloride-sensitive epithelial Na+ channels (ENaC) and Na,K-ATPases. Here we report that adenoviral-mediated overexpression of a human ß2-adrenergic receptor (ß2AR) cDNA increases ß2AR mRNA, membrane-bound receptor protein expression, and receptor function (procaterol-induced cAMP production) in human lung epithelial cells (A549). Receptor overexpression was associated with increased catecholamine (procaterol)-responsive active Na+ transport and increased abundance of Na,K-ATPases in the basolateral cell membrane. ß2AR gene transfer to the alveolar epithelium of normal rats improved membrane-bound ß2AR expression and function and increased levels of ENaC (
subunit) abundance and Na,K-ATPases activity in apical and basolateral cell membrane fractions isolated from the peripheral lung, respectively. Alveolar fluid clearance (AFC), an index of active Na+ transport, in ß2AR overexpressing rats was up to 100% greater than sham-infected controls and rats infected with an adenovirus that expresses no cDNA. The addition of the ß2AR-specific agonist procaterol to ß2AR overexpressing lungs did not increase AFC further. AFC in ß2AR overexpressing lungs from adrenalectomized or propranolol-treated rats revealed clearance rates that were the same or less than normal, untreated, sham-infected controls. These experiments indicate that alveolar ß2AR overexpression improves ß2AR function and maximally upregulates ß-agonist–responsive active Na+ transport by improving responsiveness to endogenous catecholamines. These studies suggest that upregulation of ß2AR function may someday prove useful for the treatment of pulmonary edema.
Key Words: ß2-adrenergic receptor • adenovirus • gene transfer • pulmonary edema • alveolar solute transport
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