Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Quinidine is known to inhibit the renal clearance of digoxin without affecting glomerular filtration rate. The renal interaction between these drugs was investigated by a combination of in vivo and in vitro methods. The uptake of digoxin by brush border membrane vesicles was not affected by quinidine. Similarly, digoxin did not inhibit the uptake of the cation N-methylnicotinamide by these vesicles and did not alter the binding kinetics of digoxin to the Na+, K+-adenosine triphosphatase by the antiluminal membrane vesicles. By using the in vivo multiple indicator dilution technique transtubular transport of digoxin was documented; renal-artery infusion of quinidine did not affect the recovery of digoxin in the renal vein or urine. Clearance studies documented that the decrease in the renal clearance of digoxin is paralleled by a significant fall in renal blood flow evidenced by a decrease in p-aminohippuric acid clearance. It is concluded that quinidine inhibits the renal excretion of digoxin not by competition at the tubular cell membrane level, but rather by decreasing renal blood flow. A parallel decrease in biliary clearance of digoxin is documented and may suggest a similar mechanism.
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PMID:Effects of quinidine on the renal tubular and biliary transport of digoxin: in vivo and in vitro studies in the dog. 320 14

Addition of ouabain caused gradual increases of both the Na content of cultured myocardial cells and the rate of Ca++ uptake by the cells. Ouabain-induced irregular beating of the cells (ouabain toxicity) appeared to develop when the Na content and the rate of Ca++ uptake exceeded about 1.5 and 2.0 times, respectively, the normal levels. Quinidine and procainamide prevented ouabain-induced increases of the Na content and the rate of Ca++ uptake as well as ouabain-induced toxicity. The problem of how quinidine and procainamide counteract the effects of ouabain was then studied. Quinidine and procainamide did not affect the Na+-Ca++ exchange activity. Na+,K+-adenosine triphosphatase activity, Na+-pumping out activity or ouabain-binding activity of myocardial cells, but inhibited passive Na+ influx, which is achieved by a simple diffusion system. From these observations, it is suggested that inhibition by quinidine or procainamide of passive Na+ influx indirectly prevents ouabain-induced increase in the intracellular Na content of myocardial cells and that this presumably explains at least in part the inhibitory effect of quinidine and procainamide on ouabain-induced irregular beating.
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PMID:Inhibition of ouabain-induced increase in Na content of cultured myocardial cells by quinidine and procainamide. 629 80

Previous investigations have raised the possibility that the digoxin-quinidine interaction is associated with a reduction in the positive inotropic effect of digoxin due to displacement of digoxin from cardiac as well as skeletal muscle. To circumvent some of the complexities presented by intact animal models, this interaction was investigated in cultured chick embryo ventricular cells. Quinidine, even at relatively high concentrations (10(-4)--2 x 10(-3) M), did not significantly affect positive inotropic effects of digoxin and did not protect against cellular contracture induced by toxic digoxin concentrations, despite preincubation of cells with quinidine for 60 min. The effects of digoxin on monovalent cation transport, as judged by active uptake of the K analog 86Rb, were also not altered by 10(-4) M to 2 x 10(-3) M quinidine. These data suggest that quinidine does not displace digoxin from Na, K adenosine triphosphatase binding sites in this preparation. Although these data must be extrapolated to the intact animal with caution, our findings suggest that changes digoxin clearance are more likely of primary importance in the digoxin-quinidine interaction, and indicate that the approximately 2-fold increase in serum digoxin concentration observed after addition of quinidine would be expected to have direct effects on myocardial cells comparable with those seen with increased digoxin concentration in the absence of quinidine.
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PMID:Lack of interaction between digoxin and quinidine in cultured heart cells. 706 61

Quinidine causes a marked increase in plasma digoxin concentration in patients receiving the glycoside. Whether the sensitivity of the heart to digoxin is altered by quinidine was examined with rats and guinea pigs. In electrically stimulated rat atrial preparations, quinidine failed to affect digoxin-induced inhibition of ouabain-sensitive 42K+ uptake, an estimate of sodium pump activity. Effects of quinidine on digoxin binding to Na+, K+-adenosine triphosphatase (ATPase) in intact cells were examined by perfusion guinea-pig Langendorff preparations with digoxin and estimating the occupancy of the glycoside-binding sites on the enzyme from a reduction in the initial velocity of the ATP-dependent [3H]ouabain binding reaction. Quinidine did not alter the initial velocity of [3H]ouabain binding to ventricular homogenates obtained from digoxin-perfused preparations, indicating that digoxin binding to Na+, K+-AtPase during the perfusion was not altered. In isolated rat heart preparations, quinidine failed to affect the positive inotropic action of ouabain. Nor did quinidine modify the inotropic action of digoxin in Langendorff preparations of guinea-pig heart. Concurrent i.v. infusion of quinidine in anesthetized guinea pigs increased the digoxin concentration in plasma. Thus, quinidine does not modify digoxin-Na+, K+-ATPase interactions or the digoxin-sensitivity of the myocardium. Quinidine-induced alterations in apparent volume of digoxin distribution should quantitatively change the response of the animal to digoxin.
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PMID:Effects of quinidine on the cardiac-glycoside sensitivity of guinea-pig and rat heart. 722 93

Quinidine has been shown to alter pharmacokinetics of digoxin by displacing the glycoside from mutual binding sites which are stereospecific with respect to quinidine. Characteristics of the binding site involved in quinidine-digoxin interaction were studied further in guinea pigs and rats. In the anesthetized rat quinidine significantly increased digoxin, but not digitoxin or ouabain, concentration in plasma during an i.v. infusion of a radiolabeled glycoside. In the anesthetized guinea pig, quinidine markedly increased plasma digoxin, but not digoxigenin or dihydrodigoxin, concentrations as estimated from a competitive binding assay using [3H]ouabain and a partially purified Na+, K+-adenosine triphosphatase preparation. Plasma sodium and potassium concentrations were not altered by quinidine either in control or digoxin-treated guinea pigs. In anesthetized guinea pigs, the quinidine concentrations in plasma was 6.4 +/- 1.1 muM after a 260-min fusion of quinidine at a rate of 26 mumol/kg/hr in control animals and 7.9 +/- 1.6 muM in those which were simultaneously infused with digoxin at a rate of 0.2 mumol/kg/hr. Antiarrhythmic agents, lidocaine, DL-propranolol or verapamil, did not cause a significant change in plasma digoxin concentration in the anesthetized guinea pigs. These results indicate that the binding site involved in quinidine-digoxin interaction has a strict structural requirement with respect ot the glycoside. Additionally, of the four antiarrhythmic drugs, quinidine appears to be the only agent which interacts with digoxin.
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PMID:Tissue binding sites involved in quinidine-cardiac glycoside interactions. 725 35