Calcium channel blockers modify jejunal uptake of d-galactose in rabbits

Hyson, Dianne A.; Thomson, A. B. R.; Kappagoda, C. T.

doi:10.1007/bf02088760

Cited by 6 publications

(5 citation statements)

References 27 publications

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“…The antiarrhythmic drug verapamil reduced the apparent Km for the (presumed) SGLT1–mediated uptake of D‐galactose by rabbit jejunum in vitro. Conversely, exposure of rabbit jejunal tissue to verapamil did not reduce D‐glucose uptake . However, verapamil was shown to improve glucose tolerance and reduce serum glucose levels in T2DM patients .…”

Section: Discussionmentioning

confidence: 88%

Novel natural and synthetic inhibitors of solute carriers SGLT1 and SGLT2

Oranje

Gouka

Burggraaff

et al. 2019

Pharmacology Res & Perspec

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Selective analogs of the natural glycoside phloridzin are marketed drugs that reduce hyperglycemia in diabetes by inhibiting the active sodium glucose cotransporter SGLT2 in the kidneys. In addition, intestinal SGLT1 is now recognized as a target for glycemic control. To expand available type 2 diabetes remedies, we aimed to find novel SGLT1 inhibitors beyond the chemical space of glycosides. We screened a bioactive compound library for SGLT1 inhibitors and tested primary hits and additional structurally similar molecules on SGLT1 and SGLT2 (SGLT1/2). Novel SGLT1/2 inhibitors were discovered in separate chemical clusters of natural and synthetic compounds. These have IC 50 ‐values in the 10‐100 μmol/L range. The most potent identified novel inhibitors from different chemical clusters are (SGLT1‐IC 50 Mean ± SD, SGLT2‐IC 50 Mean ± SD): (+)‐pteryxin (12 ± 2 μmol/L, 9 ± 4 μmol/L), (+)‐ε‐viniferin (58 ± 18 μmol/L, 110 μmol/L), quinidine (62 μmol/L, 56 μmol/L), cloperastine (9 ± 3 μmol/L, 9 ± 7 μmol/L), bepridil (10 ± 5 μmol/L, 14 ± 12 μmol/L), trihexyphenidyl (12 ± 1 μmol/L, 20 ± 13 μmol/L) and bupivacaine (23 ± 14 μmol/L, 43 ± 29 μmol/L). The discovered natural inhibitors may be further investigated as new potential (prophylactic) agents for controlling dietary glucose uptake. The new diverse structure activity data can provide a starting point for the optimization of novel SGLT1/2 inhibitors and support the development of virtual SGLT1/2 inhibitor screening models.

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Section: Discussionmentioning

confidence: 88%

Novel natural and synthetic inhibitors of solute carriers SGLT1 and SGLT2

Oranje

Gouka

Burggraaff

et al. 2019

Pharmacology Res & Perspec

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“…This is similar to the finding that D-galactose uptake in rabbit jejunum is modified when calcium channels are blocked. 48 However, TMB-8, an inhibitor of intracellular Ca 2+ release, does not modify the endotoxin effect. This could be because intracellular calcium liberated via inositolphosphates is not implicated or is not essential for LPS action.…”

Section: Discussionmentioning

confidence: 98%

“…In addition, all these intracellular second messengers are well-known regulators and/or modulators of intestinal ion transporters, 32,34,35 and sugars and amino acids. [36][37][38][39]48 Consequently, PKC and Ca 2+ /calmodulin could be involved in the intracellular mechanisms that mediate LPS induced L-leucine uptake reduction across the rabbit jejunum.…”

Section: Discussionmentioning

confidence: 99%

Cellular mechanism underlying LPS-induced inhibition of in vitro L-leucine transport across rabbit jejunum

Abad

Mesonero

Salvador

et al. 2002

Journal of Endotoxin Research

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Lipopolysaccharide (LPS) is a known causative agent of sepsis. In previous studies, we have shown that it reduces L-leucine mediated transport across the rabbit jejunum by about 30%. In this study, the mechanism(s) of LPS inhibition on amino acid transport were analysed in detail. LPS did not inhibit L-leucine transport across brush border membrane vesicles, suggesting the need for an intracellular step. The inhibitory effect of LPS was not altered by the addition of protein kinase A (PKA) inhibitor (IP(20), 10(-7) M) or an analog of cAMP (DB-cAMP, 3 x 10(-4) M), indicating that the PKA signal transduction pathway was not involved in the LPS effect. However, the inhibitory effect of LPS was suppressed by trifluoroperazine (10(-7) M), a Ca(2+)/calmodulin inhibitor and staurosporine (10(-7) M), an protein kinase C (PKC) inhibitor. Likewise, LPS inhibition disappeared in media without calcium. These results suggest that LPS could inhibit the intestinal uptake of L-leucine across the small intestine in vitro by intracellular processes related to calcium, involving PKC and calmodulin protein.

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“…It has been known that intestinal absorption of glucose is influenced by intracellular Ca 2+ concentration; however, the underlying mechanisms are poorly understood for the Ca 2+ regulation of glucose absorption. In the past study, Hyson and colleague observed that the kinetics of glucose uptake by SGLT1 were increased in the animals given two different types of calcium channel blockers, nisoldipine and verapamil [ 68 ]. Recently, a new model for Ca 2+ regulation of intestinal glucose absorption has been proposed.…”

Section: Regulation Of Glucose Absorption By Calcium Channels and mentioning

confidence: 99%

Regulation of Intestinal Glucose Absorption by Ion Channels and Transporters

2016

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The absorption of glucose is electrogenic in the small intestinal epithelium. The major route for the transport of dietary glucose from intestinal lumen into enterocytes is the Na+/glucose cotransporter (SGLT1), although glucose transporter type 2 (GLUT2) may also play a role. The membrane potential of small intestinal epithelial cells (IEC) is important to regulate the activity of SGLT1. The maintenance of membrane potential mainly depends on the activities of cation channels and transporters. While the importance of SGLT1 in glucose absorption has been systemically studied in detail, little is currently known about the regulation of SGLT1 activity by cation channels and transporters. A growing line of evidence suggests that cytosolic calcium ([Ca2+]cyt) can regulate the absorption of glucose by adjusting GLUT2 and SGLT1. Moreover, the absorption of glucose and homeostasis of Ca2+ in IEC are regulated by cation channels and transporters, such as Ca2+ channels, K+ channels, Na+/Ca2+ exchangers, and Na+/H+ exchangers. In this review, we consider the involvement of these cation channels and transporters in the regulation of glucose uptake in the small intestine. Modulation of them may be a potential strategy for the management of obesity and diabetes.

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Calcium channel blockers modify jejunal uptake of d-galactose in rabbits

Cited by 6 publications

References 27 publications

Novel natural and synthetic inhibitors of solute carriers SGLT1 and SGLT2

Novel natural and synthetic inhibitors of solute carriers SGLT1 and SGLT2

Cellular mechanism underlying LPS-induced inhibition of in vitro L-leucine transport across rabbit jejunum

Regulation of Intestinal Glucose Absorption by Ion Channels and Transporters

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