ATPase INHIBITORS

ATPase INHIBITORS are inhibitors of ATP-driven transporter systems in the body, including Na+/K+-ATPase, H+/K+-ATPase and Ca2+-ATPase. Some are important sites of drug action and will be described from a functional, rather than a biochemical or structural viewpoint.

The Na+/K+-ATPase of the cell membrane, which constitutes the Na+/K+ pump, is the main site at which cardiac glycosides act. They bind to the K+-binding site, thus inhibiting the enzyme, and this inhibition, through a series of interrelated actions, eventually affects cardiac rhythm and the force of contraction is increased. These are the principal beneficial actions. Examples include digoxin, digitoxin and ouabain. See cardiac glycosides.

The Na+/K+/2Cl- transport system in the thick ascending loop of Henle in the kidney is a major site of action of diuretics. Here there is active reabsorption of sodium chloride, not accompanied by water, which reduces the osmolarity of the tubular fluid and makes the interstitial fluid of the medulla hypertonic. Sodium and chloride move into the cell by a cotransport system involving Na+,K+,2Cl-, a process driven by the electrochemical gradient for sodium produced by the Na+/K+-ATPase in the basolateral membrane. Chloride then passes out of the cell into the circulation, partly through a symport mechanism with potassium, and partly by diffusion through chloride channels. Loop diuretics (e.g. bumetanide. ethacrynic acid, frusemide) inhibit this process. In the distal tubule thiazide diuretics and related agents (e.g. bendrofluazide, benzthiazide, chlorthalidone, chlorothiazide, clopamide, cyclopenthiazide, hydrochloro thiazide, hydroflumethiazide, indapamide, mefruside, metolazone, polythiazide and xipamide) have a moderate action in inhibiting sodium reabsorption, entering the cell through the lumen by means of an electroneutral Na+/Cl- carrier, driven by the Na+/K+-ATPase pump of the basolateral membrane. Aldosterone antagonists (e.g. potassium canrenoate and spironolactone) work by blocking the action of the hormone aldosterone (a MINERALOCORTICOID), which is thought to work through an effect stimulating the Na”7H+ exchanger through an action on aldosterone receptors. See diuretics.

The H+/K+-ATPase — the proton pump — is the site of action of the so-called proton pump inhibitors, the first of which was omeprazole. Gastric proton pump inhibitors are used to reduce gastric acid secretion in the stomach. They act at the H+/K+-ATPase, which is the mechanism through which hydrochloric acid in an isotonic solution (150 mM), with a pH of less than 1, is secreted by the parietal cells of the stomach. The H+/K+-ATPase is unique to the parietal cells, and links to Cl’, Na+ and HCO3– exchange within the apical or basal membranes. With omeprazole and lansoprazole it is possible to attain a profound antisecretory action, markedly reducing both basal and stimulated gastric acid secretion. The inhibitors are thought to react with sulphydryl groups of the proton pump. They are valuable in the treatment of peptic ulcers resistant to histamine H2 antagonists, reflux oesophagitis, and are the drugs of choice for Zollinger-Ellison syndrome. See GASTRIC PROTON PUMP INHIBITORS.

The Ca2+-ATPase plays an essential role in the pumping of calcium out of cells, and in the control of its cytosolic concentration. In the heart, the role of the pump is minor with respect to that of the sodium-calcium exchanger, but is most probably predominant in skeletal and smooth muscle. The pump is encoded by four independent genes, showing different patterns of tissue-specific expression and alternative splicing of the primary transcripts. The intracellular Ca2+ pump proteins from skeletal muscle sarcoplasmic reticulum (SR), cardiac SR and brain microsomes are similar. Thapsigargin is a potent inhibitor, also lanthanum salts inhibit the pump at most sites.