ENaC-mediated effects assessed by MRI in a rat model of hypertonic saline-induced lung hydration.
OBJECTIVE
The epithelial sodium channel (ENaC) regulates airway mucosal hydration and mucus clearance. The lack of such regulation in cystic fibrosis patients leads to desiccation of the airway lumen, resulting in mucostasis that establishes the environment for infections. Osmotic agents and negative ENaC regulators can be used to restore mucosal hydration. We aimed to assess whether: (i) osmotically driven fluid flux into the rat lung could be quantified in vivo by magnetic resonance imaging (MRI); and (ii) the MRI signals could be modulated through the regulation of ENaC function.


METHODS
Lung images from spontaneously breathing rats were acquired following intra-tracheal (i.t.) administration of physiological or hypertonic saline (HS). Compounds known to modulate the ENaC function were given i.t. prior to saline. Volumes of fluid signals were quantified on the images.


RESULTS
A tonicity-dependent increase in lung fluid was demonstrated following HS administration. Pretreatment with the ENaC blockers, amiloride or 552-02, resulted in an enhancement of HS-induced lung fluid signals, which were detectable for up to 4 h, consistent with a role for ENaC in fluid clearance. Aprotinin, a serine protease inhibitor that attenuates ENaC function, likewise enhanced the HS-induced increase in lung fluid signal, while alpha(1)-anti-trypsin was without significant effect.


CONCLUSIONS
Proton MRI provides a non-invasive technique for studying modulators of lung fluid hydration in rat lung in vivo. The pharmacological sensitivity of MRI-detected fluid signals is consistent with ENaC-mediated fluid reabsorption after HS. This target-related readout may be used to characterize new ENaC modulators.
Blé
F-X
FX
Global Imaging Group, Novartis Institutes for BioMedical Research, Basel, Switzerland.
Cannet
C
C
Collingwood
S
S
Danahay
H
H
Beckmann
N
N
D000280:Administration, Inhalation; D000584:Amiloride / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D007611:Aprotinin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001834:Body Water; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels / Q000502:physiology*; D015633:Extravascular Lung Water / Q000502:physiology*; D018495:Fluid Shifts / Q000187:drug effects / Q000502:physiology; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008168:Lung / Q000737:chemistry / Q000473:pathology / Q000502:physiology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009079:Mucociliary Clearance / Q000187:drug effects / Q000502:physiology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011914:Rats, Inbred BN; D020545:Respiratory Mucosa / Q000187:drug effects / Q000502:physiology; D012462:Saline Solution, Hypertonic / Q000008:administration & dosage; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage / Q000494:pharmacology
D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D006146:Guanidines; C513153:N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N'-(4-(4-(2,3-dihydroxypropoxy)phenyl)butyl)guanidine; D011480:Protease Inhibitors; D011719:Pyrazines; D012462:Saline Solution, Hypertonic; D026941:Sodium Channel Blockers; D000515:alpha 1-Antitrypsin; D000584:Amiloride; D007611:Aprotinin