A novel Ca2+/calmodulin-dependent protein kinase II (CaM Kinase II) inhibitor, 
KN-93 potently inhibits gastric acid secretion from parietal cells. As 
previously reported (1), treatment of parietal cells with a selective inhibitor 
of CaM kinase II, KN-62 resulted in the inhibition of cholinergic-stimulated 
rabbit parietal cell secretion, whereas it failed to inhibit the histamine and 
forskolin response. In contrast effects of carbachol, histamine and forskolin 
were significantly inhibited by KN-93 with an IC50 of 0.15, 0.3 and 1 microM, 
respectively; these effects occurred without any changes in intracellular cyclic 
AMP and Ca2+ levels. In the present study we investigated the mechanism by which 
KN-93 acts upon the acid-secreting machinery of gastric parietal cells. Neither 
redistribution of the proton pump activity nor the morphological transformation 
were affected by KN-93. The drug only weakly inhibited the H+, K(+)-ATPase 
activity but strongly dissipated the proton gradient formed in the gastric 
membrane vesicles and reduced the volume of luminal space. Thus KN-93 acts at pH 
gradient formation whereas KN-62 acts only at CaM Kinase II.