title: Interrelationships among quinidine, amiloride, and lithium as inhibitors of the renal Na+-H+ exchanger.
abstract: We examined the effects of quinidine, amiloride and Li+ on the kinetics of Na+-H+ exchange in microvillus membrane vesicles isolated from the rabbit renal cortex. Quinidine reversibly inhibited the initial rate of Na+-H+ exchange (I50 200 microM). The plot of 1/V versus [quinidine] was curvilinear, with Hill coefficient greater than 1.0, indicating that the drug interacts at two or more inhibitory sites or at a single site on at least two different conformations of the transporter. Quinidine decreased the Vmax for Na+-H+ exchange and increased the Km for Na+, indicating a mixed-type mechanism of inhibition. In contrast, plots of 1/V versus [amiloride] and 1/V versus [Li+] were linear, indicating single inhibitory sites; amiloride and Li+ each increased the Km for Na+ with no effect on Vmax, indicating a competitive mechanism of inhibition. Addition of Li+ increased the intercept with no change in slope of the 1/V versus [amiloride] plot, indicating that Li+ and amiloride are mutually exclusive inhibitors of Na+-H+ exchange. Addition of quinidine increased the slopes of the plots of 1/V versus [amiloride] and 1/V versus [Li+], indicating that the binding of quinidine is not mutually exclusive with the binding of amiloride and Li+. Results from this and previous studies are consistent with the concept that the inhibitor amiloride and the transportable substrates Na+, H+, Li+, and NH+4 all mutually compete for binding to a single site, the external transport site of the renal Na+-H+ exchanger. However, our findings indicate that quinidine interacts with the Na+-H+ exchanger on at least one additional site that is not shared by Na+, Li+, or amiloride.
mesh_terms: D000584:Amiloride / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008094:Lithium / Q000494:pharmacology*; D008871:Microvilli / Q000378:metabolism; D011487:Protein Conformation; D011802:Quinidine / Q000494:pharmacology*; D011817:Rabbits; D017923:Sodium-Hydrogen Exchangers
chemical_list: D002352:Carrier Proteins; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D008094:Lithium; D011802:Quinidine