Systematic expression profiling of the gastric H<sup>+</sup>/K<sup>+</sup>ATPase in human tissue

Herrmann, Michael; Selige, Jens; Raffael, Sandra; Sachs, George; Brambilla, A.; Klein, Thomas

doi:10.1080/00365520701405579

Cited by 21 publications

(20 citation statements)

References 43 publications

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“…Moreover, it has recently been reported that the only organ in humans expressing significant levels of the P-CAB target gastric H ϩ ,K ϩ -ATPase is the stomach (Herrmann et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Monofumarate (TAK-438), a Novel and Potent Potassium-Competitive Acid Blocker for the Treatment of Acid-Related Diseases

Hori

Imanishi²,

Matsukawa³

et al. 2010

J Pharmacol Exp Ther

183

169

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Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases. However, several unmet medical needs, such as suppression of night-time acid secretion and rapid symptom relief, remain. In this study, we investigated the pharmacological effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker (P-CAB), on gastric acid secretion in comparison with lansoprazole, a typical PPI, and SCH28080 [3-(cyanomethyl)-2-methyl,8-(phenylmethoxy)imidazo(1,2-a)pyridine], a prototype of P-CAB. TAK-438, SCH28080, and lansoprazole inhibited H ϩ ,K ϩ -ATPase activity in porcine gastric microsomes with IC 50 values of 0.019, 0.14, and 7.6 M, respectively, at pH 6.5. The inhibitory activity of TAK-438 was unaffected by ambient pH, whereas the inhibitory activities of SCH28080 and lansoprazole were weaker at pH 7.5. The inhibition by TAK-438 and SCH28080 was reversible and achieved in a K ϩ -competitive manner, quite different from that by lansoprazole. TAK-438, at a dose of 4 mg/kg (as the free base) orally, completely inhibited basal and 2-deoxy-D-glucose-stimulated gastric acid secretion in rats, and its effect on both was stronger than that of lansoprazole. TAK-438 increased the pH of gastric perfusate to a higher value than did lansoprazole or SCH28080, and the effect of TAK-438 was sustained longer than that of lansoprazole or SCH28080. These results indicate that TAK-438 exerts a more potent and longer-lasting inhibitory action on gastric acid secretion than either lansoprazole or SCH28080. TAK-438 is a novel antisecretory drug that may provide a new option for the patients with acid-related disease that is refractory to, or inadequately controlled by, treatment with PPIs.

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“…Moreover, it has recently been reported that the only organ in humans expressing significant levels of the P-CAB target gastric H ϩ ,K ϩ -ATPase is the stomach (Herrmann et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Monofumarate (TAK-438), a Novel and Potent Potassium-Competitive Acid Blocker for the Treatment of Acid-Related Diseases

Hori

Imanishi²,

Matsukawa³

et al. 2010

J Pharmacol Exp Ther

183

169

View full text Add to dashboard Cite

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“…The REU unit describes the expression of a target RNA relative to the 18S rRNA internal standard of the respective sample (Herrmann et al, 2007).…”

Section: Real-time Quantitative Pcr (Taqman)mentioning

confidence: 99%

The differential impact of PDE4 subtypes in human lung fibroblasts on cytokine‐induced proliferation and myofibroblast conversion

Selige¹,

Hatzelmann²,

Dunkern³

2011

Journal Cellular Physiology

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Lung fibroblast proliferation and differentiation into myofibroblasts are pathological key events during development of lung fibrosis. Cyclic nucleotide signaling is described as a negative modulator of these cellular processes, and cyclic nucleotide degrading type 4 phosphodiesterases (PDE4) are important regulators of these pathways. In this study, we elucidated expression and the role of individual subtypes of PDE4 in primary normal human lung fibroblast (NHLF) in controlling cytokines-induced proliferation and conversion to myofibroblasts by short-interfering RNAs (siRNAs) induced knockdown. We verified the expression of PDE4A, B, and D, while PDE4C was only minor or even not expressed in NHLF. An efficient liposome-mediated transfection method for mRNA silencing and a knockdown of the expressed PDE4 subtypes was achieved in these cells. This knockdown was further validated by PDE4 protein expression analysis and PDE4 activity measurements. Functionally, the knockdown of PDE4A and PDE4B inhibited proliferation induced by the cytokine combination of bFGF and IL-1β, whereas knockdown of PDE4D was ineffective. In contrast, TGF-β induced differentiation into myofibroblasts was affected by knockdown of PDE4B and PDE4D, but not by PDE4A knockdown. In summary, our data allow to assign different PDE4 subtypes to distinct functions of human lung fibroblasts and highlight the predominant role of PDE4B in controlling pathophysiological processes of human lung fibroblasts. This provides a scientific rationale for focused therapeutic targeting of PDE4B to treat respiratory diseases with fibrotic lesions in the lung.

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“…The effects induced are the same as observed by longterm PPI-use. Gastric H þ /K found in bone [Herrmann et al, 2007]. However, there are in vitro experiments suggesting that the PPI omeprazole decreases bone resorption [Tuukkanen and Vaananen, 1986] possibly through inhibition of the osteoclastic vacuolar H þ /K þ ATPase [Mizunashi et al, 1993].…”

mentioning

confidence: 95%

Decreased bone mineral density and reduced bone quality in H⁺/K⁺ATPase beta‐subunit deficient mice

Fossmark

Stunes²,

Petzold

et al. 2011

J of Cellular Biochemistry

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Proton pump inhibitors (PPIs) are widely used against gastroesophageal reflux disease. Recent epidemiological studies suggest that PPI users have an increased risk of fractures, but a causal relationship has been questioned. We have therefore investigated the skeletal phenotype in H(+) /K(+) ATPase beta-subunit knockout (KO) female mice. Skeletal parameters were determined in 6- and 20-month-old KO mice and in wild-type controls (WT). Whole body bone mineral density (BMD) and bone mineral content (BMC) were measured by dual energy X-ray absorptiometry (DXA). Femurs were examined with µCT analyses and break force were examined by a three-point bending test. Plasma levels of gastrin, RANKL, OPG, osteocalcin, leptin, and PTH were analyzed. KO mice had lower whole body BMC at 6 months (0.53 vs. 0.59 g, P = 0.035) and at 20 months (0.49 vs. 0.74 g, P < 0.01) compared to WT as well as lower BMD at 6 months (0.068 vs. 0.072 g/cm(2) , P = 0.026) and 20 months (0.067 vs. 0.077 g/cm(2) , P < 0.01). Mechanical strength was lower in KO mice at the age of 20 months (6.7 vs. 17.9 N, P < 0.01). Cortical thickness at 20 months and trabecular bone volume% at 6 months were significantly reduced in KO mice. Plasma OPG/RANKL ratio and PTH was increased in KO mice compared to controls. H(+) /K(+) ATPase beta subunit KO mice had decreased BMC and BMD, reduced cortical thickness and inferior mechanical bone strength. Whereas the mechanism is uncertain, these findings suggest a causal relationship between long-term PPI use and an increased risk of fractures.

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Systematic expression profiling of the gastric H⁺/K⁺ATPase in human tissue

Abstract: We therefore conclude that the only organ in humans expressing significant levels of the P-CAB target gastric H+/K+ ATPase is the stomach.

Cited by 21 publications

References 43 publications

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Monofumarate (TAK-438), a Novel and Potent Potassium-Competitive Acid Blocker for the Treatment of Acid-Related Diseases

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Monofumarate (TAK-438), a Novel and Potent Potassium-Competitive Acid Blocker for the Treatment of Acid-Related Diseases

The differential impact of PDE4 subtypes in human lung fibroblasts on cytokine‐induced proliferation and myofibroblast conversion

Decreased bone mineral density and reduced bone quality in H⁺/K⁺ATPase beta‐subunit deficient mice

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Systematic expression profiling of the gastric H+/K+ATPase in human tissue

Abstract: We therefore conclude that the only organ in humans expressing significant levels of the P-CAB target gastric H+/K+ ATPase is the stomach.

Cited by 21 publications

References 43 publications

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Monofumarate (TAK-438), a Novel and Potent Potassium-Competitive Acid Blocker for the Treatment of Acid-Related Diseases

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Monofumarate (TAK-438), a Novel and Potent Potassium-Competitive Acid Blocker for the Treatment of Acid-Related Diseases

The differential impact of PDE4 subtypes in human lung fibroblasts on cytokine‐induced proliferation and myofibroblast conversion

Decreased bone mineral density and reduced bone quality in H+/K+ATPase beta‐subunit deficient mice

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Systematic expression profiling of the gastric H⁺/K⁺ATPase in human tissue

Decreased bone mineral density and reduced bone quality in H⁺/K⁺ATPase beta‐subunit deficient mice