Selective inhibition of K⁺ ‐stimulation of Na,K‐ATPase by bretylium

Abstract

The effects of bretylium were investigated on purified Na,K‐ATPase from guinea‐pig heart and on the Na/K pump in trout erythrocytes, with a view to further identifying the mechanism(s) associated with its antiarrhythmic effects. Na,K‐ATPase activity of the thiocyanate‐dispersed enzyme was determined by the measurement of inorganic phosphate produced by ATP hydrolysis. When the concentrations of each of the Na,K‐ATPase activating components were varied in turn, bretylium (1–5 mmol l−1) exhibited competitive‐type effects against K+ with a Ki of 1.4 mmol l−1 and noncompetitive‐type effects against Na+, Mg2+ and ATP. In K+ influx studies in trout erythrocytes with 86Rb+ used as the marker, the inhibition of total influx observed with bretylium (5 and 10 mmol l−1) was attributable to the bretylium cation selectively inhibiting the Na/K pump‐mediated influx with the associated tosylate anion inhibiting Na/K cotransport. The observed inhibition kinetics indicated that the bretylium cation (2–15 mmol l−1) competitively inhibited K+ stimulation of the Na/K pump at 6 and 1.25 mmol l−1 external K+ with a mean K1 of 2.3 mmol l−1. The effects demonstrated on the functioning Na/K pump in erythrocytes confirmed the Na,K‐ATPase findings, with bretylium selectively inhibiting K+ stimulation of the pump mechanism in both cases. It is suggested that Na,K‐ATPase inhibition may contribute to the antiarrhythmic and positive inotropic effects of bretylium with the cardiac accumulation of bretylium also possibly being a further important factor.

Exploring the Antimicrobial Action of Quaternary Amines against Acinetobacter baumannii

“…However, our results implicating additional processes in BZK action led us to ask if QACs with less-toxic structures could still retain antimicrobial activity. We identified three candidates ( Table 3 ); bretylium tosylate and clofilium tosylate are antiarrhythmic agents, while otilonium bromide (OB) is a muscarinic receptor inhibitor used to treat irritable bowel syndrome (IBS) ( 41 – 43 ). We tested each QAC against A. baumannii 17978 and multidrug-resistant (MDR) A. baumannii AYE.…”

The host‐defence skin peptide profiles of Peron's Tree Frog Litoria peronii in winter and summer. Sequence determination by electrospray mass spectrometry and activities of the peptides

“…the caeruleins 4 and rothein 1, 7,8 see Tables 1 and 2 29 or bretylium tosylate (inhibits release of noradrenaline from synaptic nerves). 30 So the peroniins 1.1 and 1.2 are neither acting through MAchR-or CCKR-induced release of Ach, nor through receptors which result in the release of nitric oxide or noradrenaline. The peroniins 1.1 to 1.5 are also not active at opioid receptors in the myenteric plexus-longitudinal muscle preparation of guinea pig ileum (data not shown).…”

“…This is not the case with the peroniins 1. The contractions produced by peroniins 1.1 and 1.2 in guinea pig ileum are not affected by atropine [muscarinic receptor (MAchR) antagonist],26 YM022 [CCK 2 receptor (CCK2R) antagonist],27 devazepide [CCK1 receptor (CCK1R)],28 L‐NNA [nitric oxide synthase (NOS) inhibitor]29 or bretylium tosylate (inhibits release of noradrenaline from synaptic nerves) 30. So the peroniins 1.1 and 1.2 are neither acting through MAchR‐ or CCKR‐induced release of Ach, nor through receptors which result in the release of nitric oxide or noradrenaline.…”

Release of oxygen radicals by articular chondrocytes: A study of luminol-dependent chemiluminescence and hydrogen peroxide secretion

“…'1P) Further, it was noted that chondrocystrophic cartilage had low SOD activity, implying that cellular necrosis by oxygen radicals may be a cause of chondrocytic damage. [19) It is possible that diminished bone growth in juvenile rheumatoid arthritis is a consequence of oxidative damage to growth chondrocytes resulting from unregulated oxygen radical production in inflamed joints.…”