title: Inhibition of colonic Na+ transport by amiloride analogues.
abstract: The potency of several amiloride analogues to inhibit electrogenic Na+ transport in colon from dexamethasone-treated rats was compared. Short-circuit current (Isc) across the colonic mucosa and 22Na+ uptake into membrane vesicles derived from colonic enterocytes was determined in dexamethasone-treated rats. Kinetic analysis of inhibition of Isc and 22Na+ uptake revealed the presence of a high- and low-affinity amiloride pathway. One pathway had a high affinity [(Ki-Isc; Ki uptake] to benzamil (15.5 nM; 5.4 nM), phenamil (19.4 nM; 7.0 nM), 3',4'-dichlorobenzamil (29.0 nM; 25.2 nM), and amiloride (115 nM; 12.4 nM) but a much lower affinity to 5-(N-ethyl-N-isopropyl)amiloride (EIPA) (greater than 100 microM; greater than 9.9 microM) and 5-(N-propyl-N-butyl)-2'-4'-dichlorobenzamil (PBDCB) (greater than microM; greater than 32.8 microM). The high-affinity pathway accounted for 75-83% of the transport of Na+. The second pathway had nearly the same low affinity for each of the analogues (e.g., amiloride Ki-Isc 1 microM; Ki uptake 4 microM) and accounted for only 15-25% of the transport of Na+. The results demonstrate that the structure-inhibitory pattern of these amiloride analogues for the high-affinity pathway is the pattern observed in other electrogenic Na+-transporting epithelia and that this pharmacological profile is preserved in membrane vesicles derived from colonic enterocytes. In addition, the potency of EIPA and benzamil to inhibit electroneutral Na+ transport across the colon from normal rats (i.e., not treated with dexamethasone) was also investigated.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Physiology and Biophysics, University of Alabama, Birmingham 35294.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bridges
authors.forename: E J
authors.initials: EJ
authors.lastname: Cragoe
authors.forename: R A
authors.initials: RA
authors.lastname: Frizzell
authors.forename: D J
authors.initials: DJ
authors.lastname: Benos
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004553:Electric Conductivity; D004594:Electrophysiology; D004848:Epithelium / Q000378:metabolism; D005260:Female; D007700:Kinetics; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism*
chemical_list: C013407:benzamil; C041470:3',4'-dichlorobenzamil; C058269:5-(N-propyl-N-butyl)-2',4'-dichlorobenzamil amiloride; C047088:phenylamil; D000584:Amiloride; D003907:Dexamethasone; D012964:Sodium; C039614:ethylisopropylamiloride