Mechanism of the inhibitory effect of imipramine on the Na+-dependent transport of L-glutamic acid in rat intestinal brush-border membrane.
The mechanism of the inhibitory effect of imipramine, a lipophilic organic cation on the Na+-dependent transport of L-glutamic acid across intestinal brush-border membrane was investigated. The uptake of L-glutamic acid by intestinal brush-border membrane vesicles was dependent on the concentration of Na+. Fitting of the uptake data in the presence of various concentrations of Na+ using Hill equation yielded a Hill coefficient of 2.18. This result suggest that the carrier system of L-glutamic acid has at least two sites for Na+-binding. By the analysis of double reciprocal plot and Dixon-type plot, it was found that imipramine inhibits the transport of L-glutamic acid by interacting competitively with the binding sites of Na+, but not inhibit L-glutamic acid binding site. Moreover, the effect of imipramine on the transport of L-alanine and D-glucose which are co-transported with only one Na+ molecule was also suggestive of interaction with the Na+-binding sites on the carrier. These results indicate that the mechanism of the inhibitory effect of imipramine on the Na+-dependent carrier systems is common for all systems regardless of the stoichiometry or substrates.
Sugawara
M
M
Department of Pharmacy, Hokkaido University Hospital, School of Medicine, Hokkaido University, Sapporo 060, Japan.
Kato
M
M
Kobayashi
M
M
Iseki
K
K
Miyazaki
K
K
D000409:Alanine / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins; D018698:Glutamic Acid / Q000378:metabolism*; D007099:Imipramine / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008871:Microvilli / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000502:physiology*; D027981:Symporters
D027322:Amino Acid Transport System X-AG; D002352:Carrier Proteins; D050491:Glutamate Plasma Membrane Transport Proteins; D027981:Symporters; D018698:Glutamic Acid; D012964:Sodium; D005947:Glucose; D000409:Alanine; D007099:Imipramine