A new benzoxazine compound blocks KATP channels in pancreatic beta cells: molecular basis for tissue selectivity in vitro and hypoglycaemic action in vivo.
Br J Pharmacol
; 149(7): 870-9, 2006 Dec.
Article
en En
| MEDLINE
| ID: mdl-17057758
BACKGROUND AND PURPOSE: The 2-propyl-1,4 benzoxazine (AM10) shows a peculiar behaviour in skeletal muscle, inhibiting or opening the ATP-sensitive K(+) (KATP) channel in the absence and presence of ATP, respectively. We focused on tissue selectivity and mechanism of action of AM10 by testing its effects on pancreatic KATP channels by means of both in vitro and in vivo investigations. EXPERIMENTAL APPROACH: In vitro, patch-clamp recordings were performed in native pancreatic beta cells and in tsA201 cells expressing the Kir6.2 Delta C36 channel. In vivo, an intraperitoneal glucose tolerance test was performed in normal mice. KEY RESULTS: In contrast with what observed in the skeletal muscle, AM10, in whole cell perforated mode, did not augment KATP current (I(KATP)) of native beta cells but it inhibited it in a concentration-dependent manner (IC(50): 11.5 nM; maximal block: 60%). Accordingly, in current clamp recordings, a concentration-dependent membrane depolarization was observed. On excised patches, AM10 reduced the open-time probability of KATP channels without altering their single channel conductance; the same effect was observed in the presence of trypsin in the bath solution. Moreover, AM10 inhibited, in an ATP-independent manner, the K(+) current resulting from expressed Kir6.2 Delta C36 (maximal block: 60% at 100 microM; IC(50): 12.7 nM) corroborating an interaction with Kir. In vivo, AM10 attenuated the glycemia increase following a glucose bolus in a dose-dependent manner, without, at the dose tested, inducing fasting hypoglycaemia. CONCLUSION AND IMPLICATIONS: Altogether, these results help to gain insight into a new class of tissue specific KATP channel modulators.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Glucemia
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Adenosina Trifosfato
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Canales de Potasio de Rectificación Interna
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Bloqueadores de los Canales de Potasio
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Benzoxazinas
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Células Secretoras de Insulina
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Aminopiridinas
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Hipoglucemiantes
Límite:
Animals
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Humans
Idioma:
En
Revista:
Br J Pharmacol
Año:
2006
Tipo del documento:
Article
País de afiliación:
Italia
Pais de publicación:
Reino Unido