title: Blockade of ENaCs by amiloride induces c-Fos activation of the area postrema.
abstract: Epithelial sodium channels (ENaCs) are strongly expressed in the circumventricular organs (CVOs), and these structures may play an important role in sensing plasma sodium levels. Here, the potent ENaC blocker amiloride was injected intraperitoneally in rats and 2h later, the c-Fos activation pattern in the CVOs was studied. Amiloride elicited dose-related activation in the area postrema (AP) but only ~10% of the rats showed c-Fos activity in the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO). Tyrosine hydroxylase-immunoreactive (catecholamine) AP neurons were activated, but tryptophan hydroxylase-immunoreactive (serotonin) neurons were unaffected. The AP projects to FoxP2-expressing neurons in the dorsolateral pons which include the pre-locus coeruleus nucleus and external lateral part of the parabrachial nucleus; both cell groups were c-Fos activated following systemic injections of amiloride. In contrast, another AP projection target--the aldosterone-sensitive neurons of the nucleus tractus solitarius which express the enzyme 11-β-hydroxysteriod dehydrogenase type 2 (HSD2) were not activated. As shown here, plasma concentrations of amiloride used in these experiments were near or below the IC50 level for ENaCs. Amiloride did not induce changes in blood pressure, heart rate, or regional vascular resistance, so sensory feedback from the cardiovascular system was probably not a causal factor for the c-Fos activity seen in the CVOs. In summary, amiloride may have a dual effect on sodium homeostasis causing a loss of sodium via the kidney and inhibiting sodium appetite by activating the central satiety pathway arising from the AP.
authors.affiliation: Department of Anatomy and Neurobiology, Washington University School of Medicine, Box 8108, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Miller
authors.affiliation: Department of Anatomy and Neurobiology, Washington University School of Medicine, Box 8108, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: George O
authors.initials: GO
authors.lastname: Denny
authors.affiliation: Department of Pharmacological & Physiological Science, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Knuepfer
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kleyman
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.affiliation: Department of Anatomy and Neurobiology, Washington University School of Medicine, Box 8108, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Salkoff
authors.affiliation: Department of Anatomy and Neurobiology, Washington University School of Medicine, Box 8108, 660 S. Euclid Ave., St. Louis, MO 63110, USA. Electronic address: loewya@pcg.wustl.edu.
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Loewy
mesh_terms: D000584:Amiloride / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D000818:Animals; D031608:Area Postrema / Q000187:drug effects / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D062686:Epithelial Sodium Channel Blockers / Q000494:pharmacology*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D065823:Parabrachial Nucleus / Q000187:drug effects / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D051858:Forkhead Transcription Factors; C558285:Foxp2 protein, rat; D016755:Proto-Oncogene Proteins c-jun; D000584:Amiloride
keywords: Amiloride; Area postrema; Epithelial sodium channels; FoxP2; Parabrachial nucleus; Pre-locus coeruleus