Na+/K+-ATPase, inhibition

Figure 4.10 Effect of reduced glutathione (GSH) (0-1.0 mM) on Na/K ATPase inhibition associated with the addition of oxidized glutathione (GSSG) (1 me). Experiments were performed using an isolated bovine ventricular Na/K ATPase preparation. Na/K ATPase activity was quantified by the ouabain-sensitive hydrolysis of ATP to yield inorganic phosphate. The data are presented as means standard errors of the means (n = 6).

Mechanism of action Na"", K -ATPase inhibition Na /H " exchange mechanism inhibition (proximal tubule) Aldosterone antagonism Membrane effect... 

Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free calcium concentration in the vicinity of the contractile proteins during systole. The increase in calcium concentration is the result of a two-step process first, an increase of intracellular sodium concentration because of Na+,K+ ATPase inhibition and second, a relative reduction of calcium expulsion from the cell by the sodium-calcium exchanger (NCX in Figure 13-1) caused by the increase in intracellular sodium. The increased cytoplasmic calcium is sequestered by SERCA in the SR for later release. Other mechanisms have been proposed but are not well supported. 

Digoxin Na +, K+ ATPase inhibition results in reduced Ca2+ expulsion and increased Ca2+ stored in sarcoplasmic reticulum Increases cardiac contractility cardiac parasympathomimetic effect (slowed sinus heart rate, slowed atrioventricular conduction) Chronic symptomatic heart failure rapid ventricular rate in atrial fibrillation Oral, parenteral duration 36-40 h Toxicity Nausea, vomiting, diarrhea cardiac arrhythmias... 

T6. Tsakiris, S., Angelogianni, P, Schulpis, K. H., and Behrakis, P., Protective effect of L-cysteine and glutathione on rat brain Na+,K+-ATPase inhibition induced by free radicals. Z. Naturforsch. 55c, 271-277 (2000). 

Digoxin Na. K -ATPase inhibition vagomimetic Congestive heart failure Bradycardia, tachyarrhythmia, hypokalemia increases myocardial oxygen demand... 

Comparison of the relative carbonyl oxygen separations obtained from FITMOL with the Na+,K+-ATPase inhibition activities given in Table II revealed a striking correspondence. A simple linear regression model was used to test the relationship between oxygen separation and the I50 data for Na+,K+-ATPase... 

Figure 12. Correlation between the carbonyl oxygen separations relative to digitoxigenin, lb, and the log of the Na K+-ATPase inhibition activity (X) measured I so data (+) I50 data extrapolated from lower concentrations in which the analog was completely soluble...

The data presented here are consistent with the following structural correlations of digitalis genin-Na+,K+-ATPase inhibition ... 

The relationship of these structural features to Na+,K+-ATPase inhibition and receptor modeling are ... 

Cardiac glycosides found in plants, some insects and in the skin of toads (Bufonidae) are potent and well-known inhibitors of Na+/K+-ATPase. Also few alkaloids, such as harmaline, nitidine, sanguinarine, capsaicine, cassaine, and solenopsine (from ants) exhibit Na+/K+-ATPase inhibition, which interferes with the maintainance of the membrane potential and secondary active transport systems. 

Vasotab, a vasoactive 56-peptide from horse fly Hybomitra bimaculata (Diptera, Taban-idae) salivary glands. The peptide contains six cysteine residues which form three disulfide bonds similar to the disulfide pattern of the Kazal-type protease inhibitors. In comparison to the latter, vasotab has an unique 7-amino-acid insertion between the third and fourth cysteine residues within the peptide chain. Vasotab shows positive inotropism in isolated rat hearts, vasodilatation of coronary and peripheral vessels, and Na+/K+-ATPase inhibition. Furthermore, it is capable of blocking L-type calcium channels [P. Takac et al., J. Exp. Biol. 2006, 209, 343]. 

Ouabain, which is a highly specific and potent inhibitor of Na-K ATPase, inhibits ATP binding [17] by reacting at the opposite, i.e. outer membrane side. 

Agents such as cardioactive sterols inhibit Na,K-ATPase and have positive inotropic and chronotropic effects on the heart . Adenosine-3, 5 -cyclic monophosphate (cyclic AMP) has been shown to inhibit human gastro-intestinal mucosal Na,K-ATPase responsible for gastric secretions. This observation by Mozsik may also explain the positive inotropic effects of cyclic AMP since ouabain s effects on the heart appear to be related to Na,K-ATPase inhibition. 

Amiloride a drug which inhibits the influx of Na into cells. It was discovered as a natriuretic agent which increases Na excretion but does not affect K excretion (Baer et al. J. Pharmacol. Exp. Ther. 157 (1967) 472). Animal cells have 2 systems for Na transport. The Na /K ATPase (inhibited by ouabain) exports Na and imports K, each against its concentration gradient. In addition, there is a pump which imports Na and exports H, and this is inhibited by A., hence the designation amiloride-sensitive Na pump . A. has subsequently been found to be relatively unspecific, e.g. it also inhibits protein synthesis Its derivative, dimethylamiloride, is a more spedfic... 

Cantley Jr. LC, Aisen P. 1979. The fate of cytoplasmic vanadium implications of (Na,K)-ATPase inhibition. JBiol Chem 254 1781-1784. 

Corbier, A., Robineau, R, 1989. Evidence for a direct noncholinergic effect of an organophosphorous compound on guinea-pig papillary muscles are ventricular arrhythmias related to a Na /K ATPase inhibition Arch. Int. 

Coburn, R. F., 1983 Na-K ATPase inhibition stimulates prostaglandin release and phosphatidyl inositol metabolism in smooth muscle. In Ico-sanoids and Ion Transport. New York Raven Press. In Press. 

A lysophosphatidylglycerol (180), isolated from the Korean sponge Spirastrella abata, showed significant cytotoxicity and Na /K -ATPase inhibition. The structure of this compound has been determined by chemical and spectroscopic methods. ... 

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