Inhibition of gastric H+,K+-ATPase and acid secretion by SCH 28080, a substituted pyridyl(1,2a)imidazole.

Wallmark, Björn; Briving, Carin; Fryklund, Jan; Munson, Keith; Jackson, Raymond J.; Mendlein, John; Rabon, E.; Sachs, George

doi:10.1016/s0021-9258(18)61620-5

Cited by 221 publications

(35 citation statements)

References 26 publications

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“…4 B). It is thus much less sensitive to this compound than the gastric H,K-ATPase (Wallmark et al, 1987), however, dearly more sensitive than the Na,K- ATPase (Fig. 5).…”

Section: Pharmacological Profilementioning

confidence: 92%

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Mechanisms of urinary K+ and H+ excretion: primary structure and functional expression of a novel H,K-ATPase.

Jaisser

Horisberger

Geering

et al. 1993

The Journal of Cell Biology

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Abstract. The kidney plays an essential role in regulating potassium and acid balance. A major site for these regulations is in the collecting tubule. In the present study, we report the primary sequence of a novel ot subunit of the P-ATPase gene family, which we isolated from the urinary bladder epithelium of the toad Bufo marinus, the amphibian equivalent of the mammalian collecting tubule. The eDNA encodes a protein of 1,042 amino acids which shares ~67% identity with the or1 subunit of the ouabain-inhibitable Na,K-ATPase and ,x,69% identity with the a subunit of the SCH28080-inhibitable gastric H,K-ATPase.When coexpressed in Xenopus oocytes with a subunit isolated from the same eDNA library, the ATPase is able to transport rubidium (a potassium surrogate) inward, and hydrogen outward, leading to alkalization of the intraeellular compartment and acidification of the external medium. The novel ATPase has a unique pharmacological profile showing intermediate sensitivity to both ouabain and SCH28080. Our findings indicate that the bladder ATPase is a member of a new ion motive P-ATPase subfamily. The bladder ATPase is expressed in the urinary tract but not in the stomach or the colon. This H,K-ATPase may be one of the molecules involved in H + and K ÷ homeostasis, mediating the transport of these ions across urinary epithelia and therefore regulating their urinary excretion.

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“…4 B). It is thus much less sensitive to this compound than the gastric H,K-ATPase (Wallmark et al, 1987), however, dearly more sensitive than the Na,K- ATPase (Fig. 5).…”

Section: Pharmacological Profilementioning

confidence: 92%

“…Na,K-and H,K-ATPase bind important drugs such as the cardiotonic glycosides in the case of Na,K-ATPase (Forbush, 1983) and the SCH28080 compound for the gastric H,K-ATPase (Wallmark et al, 1987). The bladder K-pump is inhibited by SCH28080 in a dose-dependent manner with a Ki of 230/~M (Fig.…”

Section: Pharmacological Profilementioning

confidence: 99%

Mechanisms of urinary K+ and H+ excretion: primary structure and functional expression of a novel H,K-ATPase.

Jaisser

Horisberger

Geering

et al. 1993

The Journal of Cell Biology

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“…Control experiments established that NTP/ADP exchange activity was not significantly altered by Sch-28080 (data not shown). Sch-28080 is known to prevent the turnover of the H ϩ -K ϩ -ATPase by inhibiting K ϩ -stimulated dephosphorylation of the phosphoenzyme intermediate (37), and thus it is not surprising to find that the K ϩindependent formation of phosphoenzyme intermediate from ATP and the catalyzed transfer of ␥-phosphate to ADP remains unaltered, as has been shown for another K ϩ site inhibitor of H ϩ -K ϩ -ATPase, AHR-9294 (29) Furthermore, our data summarized in Table 2 suggest that the exchange reaction is in fact a general nucleoside triphosphate/diphosphate (NTP/NDP) exchange activity, catalyzing the transfer of ␥-phosphate from a variety of nucleotides to ADP. The specificity of nucleotides for the rate of ␥-phosphate exchange was ATP Ϸ ITP Ͼ CTP Ͼ GTP.…”

Section: Nucleotide Metabolism and Interchange By Isolated Gastric Microsomesmentioning

confidence: 99%

Nucleotide metabolism by gastric glands and H⁺-K⁺-ATPase-enriched membranes

Rong

Utevskaya

Ramilo

et al. 1998

American Journal of Physiology-Gastrointestinal and Liver Physi

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α-Toxin-permeabilized gastric glands represent a functional model in which acid secretion can be elicited by either adenosine 3′,5′-cyclic monophosphate (cAMP) or ATP, with proven morphological and functional transition between resting and secretory states [X. Yao, S. M. Karam, M. Ramilo, Q. Rong, A. Thibodeau, and J. G. Forte. Am. J. Physiol. 271 ( Cell Physiol. 40): C61–C73, 1996.] In this study we use α-toxin-permeabilized rabbit gastric glands to study energy metabolism and the interplay between nucleotides to support acid secretion, as indicated by the accumulation of aminopyrine (AP). When permeabilized glands were treated with a phosphodiesterase inhibitor, the secretory response to cAMP was inhibited, whereas the secretory response to ATP was potentiated. This implied that 1) ATP provided support not only as an energy source but also as substrate for adenylate cyclase, 2) activation of acid secretion by cAMP needed ATP, and 3) ATP and cAMP exchanged rapidly inside parietal cells. To address these issues, we tested the action of adenine nucleotides in the presence and absence of oxidizable substrates. All adenine nucleotides, including AMP, ADP, ATP, and cAMP, could individually enhance the glandular AP accumulation in the presence of substrates, whereas only a high concentration of ATP (5 mM) was able to support secretory activity in substrate-free buffer. Moreover, ATP could maintain 75–80% of maximal secretory activity in phosphate-free buffer; cAMP alone could not support secretion in phosphate-free buffer. In glands and in H+-K+-adenosinetriphosphatase-rich gastric microsomes, we showed the operation of adenylate kinase, creatine kinase, and ATP/ADP exchange activities. These enzymes, together with endogenous adenylate cyclase and phosphodiesterase, provide the recycling of nucleotides essential for the viability of α-toxin-permeabilized gastric glands and imply the importance of nucleotide recycling for energy metabolism in intact parietal cells.

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“…Under conditions of K ϩ depletion, as a consequence of a low-K ϩ diet, J HCO 3 almost doubles in this nephron segment (27). Much of the enhanced proton (H ϩ ) secretion associated with the K ϩ -restricted diet was inhibited by Sch-28080, a specific blocker of the gastric H ϩ -K ϩ -ATPase (26). The contribution of bafilomycinsensitive H ϩ -ATPase to net acid secretion in tubules from K ϩ -restricted rats was not studied.…”

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confidence: 99%

Potassium depletion increases proton pump (H⁺-ATPase) activity in intercalated cells of cortical collecting duct

Silver

Breton

Brown

2000

American Journal of Physiology-Renal Physiology

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Intercalated cells (ICs) from kidney collecting ducts contain proton-transporting ATPases (H(+)-ATPases) whose plasma membrane expression is regulated under a variety of conditions. It has been shown that net proton secretion occurs in the distal nephron from chronically K(+)-depleted rats and that upregulation of tubular H(+)- ATPase is involved in this process. However, regulation of this protein at the level of individual cells has not so far been examined. In the present study, H(+)-ATPase activity was determined in individually identified ICs from control and chronically K(+)-depleted rats (9-14 days on a low-K(+) diet) by monitoring K(+)- and Na(+)-independent H(+) extrusion rates after an acute acid load. Split-open rat cortical collecting tubules were loaded with the intracellular pH (pH(i)) indicator 2', 7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, and pH(i) was determined by using ratiometric fluorescence imaging. The rate of pH(i) recovery in ICs in response to an acute acid load, a measure of plasma membrane H(+)-ATPase activity, was increased after K(+) depletion to almost three times that of controls. Furthermore, the lag time before the start of pH(i) recovery after the cells were maximally acidified fell from 93.5 +/- 13.7 s in controls to 24.5 +/- 2.1 s in K(+)-depleted rats. In all ICs tested, Na(+)- and K(+)-independent pH(i) recovery was abolished in the presence of bafilomycin (100 nM), an inhibitor of the H(+)-ATPase. Analysis of the cell-to-cell variability in the rate of pH(i) recovery reveals a change in the distribution of membrane-bound proton pumps in the IC population of cortical collecting duct from K(+)-depleted rats. Immunocytochemical analysis of collecting ducts from control and K(+)-depleted rats showed that K(+)-depletion increased the number of ICs with tight apical H(+)ATPase staining and decreased the number of cells with diffuse or basolateral H(+)-ATPase staining. Taken together, these data indicate that chronic K(+) depletion induces a marked increase in plasma membrane H(+)ATPase activity in individual ICs.

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Inhibition of gastric H+,K+-ATPase and acid secretion by SCH 28080, a substituted pyridyl(1,2a)imidazole.

Cited by 221 publications

References 26 publications

Mechanisms of urinary K+ and H+ excretion: primary structure and functional expression of a novel H,K-ATPase.

Mechanisms of urinary K+ and H+ excretion: primary structure and functional expression of a novel H,K-ATPase.

Nucleotide metabolism by gastric glands and H⁺-K⁺-ATPase-enriched membranes

Potassium depletion increases proton pump (H⁺-ATPase) activity in intercalated cells of cortical collecting duct

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Inhibition of gastric H+,K+-ATPase and acid secretion by SCH 28080, a substituted pyridyl(1,2a)imidazole.

Cited by 221 publications

References 26 publications

Mechanisms of urinary K+ and H+ excretion: primary structure and functional expression of a novel H,K-ATPase.

Mechanisms of urinary K+ and H+ excretion: primary structure and functional expression of a novel H,K-ATPase.

Nucleotide metabolism by gastric glands and H+-K+-ATPase-enriched membranes

Potassium depletion increases proton pump (H+-ATPase) activity in intercalated cells of cortical collecting duct

Contact Info

Product

Resources

About

Nucleotide metabolism by gastric glands and H⁺-K⁺-ATPase-enriched membranes

Potassium depletion increases proton pump (H⁺-ATPase) activity in intercalated cells of cortical collecting duct