The activation of ATP-sensitive potassium channels (KATP), play a key role in an endogenous "self-defence" mechanism, known as ischemic preconditioning (IPC), which is fundamentally involved in the protection of the heart against the ischemia/reperfusion injury. Presently, it is widely accepted that IPC is mainly (albeit not exclusively) mediated by the activation of KATP channels expressed in the mitochondrial inner membrane (mito-KATP) rather than the sarcoplasmatic ones (sarc-K ATP). Consistently, exogenous activation of KATP channels by pharmacological tools can be viewed as one of the most promising strategies for the therapy of myocardial ischemia. As part of our research program devoted to the synthesis and the evaluation of new cardioprotective agents, we extensively studied several six-membered spiro-heterocycle-benzopyran compounds endowed of a significant anti-ischemic activity. The positive results obtained, prompted us to further explore the influence on the biopharmacological effects, of the spiro-substitution at C4 benzopyran nucleus by replacing the six-membered spirocycle of the most active compounds with 5-membered-one. The preliminary evaluation of the new compounds on cultured H9c2 cardiomyoblasts exposed to anoxia/reperfusion and on Langendorff-perfused rat hearts submitted to ischemia/reperfusion cycles, showed that some of them can exert a cardioprotective effect. This anti-ischemic activity was antagonized by 5-hydroxydecanoic acid, a selective blocker of mito-KATP channels, confirming the involvement of this channel in the cardioprotective activity

SYNTHESIS AND BIOLOGICAL EVALUATION OF 5-MEMBERED SPIRO HETEROCYCLE-BENZIPYRAN DERIVATIVES AGAINST MYOCARDIAL ISCHEMIA

RAPPOSELLI, SIMONA;BRESCHI, MARIA CRISTINA;CALDERONE, VINCENZO;DIGIACOMO, MARIA;MARTELLI, ALMA;TESTAI, LARA;
2011

Abstract

The activation of ATP-sensitive potassium channels (KATP), play a key role in an endogenous "self-defence" mechanism, known as ischemic preconditioning (IPC), which is fundamentally involved in the protection of the heart against the ischemia/reperfusion injury. Presently, it is widely accepted that IPC is mainly (albeit not exclusively) mediated by the activation of KATP channels expressed in the mitochondrial inner membrane (mito-KATP) rather than the sarcoplasmatic ones (sarc-K ATP). Consistently, exogenous activation of KATP channels by pharmacological tools can be viewed as one of the most promising strategies for the therapy of myocardial ischemia. As part of our research program devoted to the synthesis and the evaluation of new cardioprotective agents, we extensively studied several six-membered spiro-heterocycle-benzopyran compounds endowed of a significant anti-ischemic activity. The positive results obtained, prompted us to further explore the influence on the biopharmacological effects, of the spiro-substitution at C4 benzopyran nucleus by replacing the six-membered spirocycle of the most active compounds with 5-membered-one. The preliminary evaluation of the new compounds on cultured H9c2 cardiomyoblasts exposed to anoxia/reperfusion and on Langendorff-perfused rat hearts submitted to ischemia/reperfusion cycles, showed that some of them can exert a cardioprotective effect. This anti-ischemic activity was antagonized by 5-hydroxydecanoic acid, a selective blocker of mito-KATP channels, confirming the involvement of this channel in the cardioprotective activity
Rapposelli, Simona; Breschi, MARIA CRISTINA; Calderone, Vincenzo; Digiacomo, Maria; Martelli, Alma; Testai, Lara; M., Vanni; A., Balsamo
File in questo prodotto:
File Dimensione Formato  
EJMC_Rapposelli et al.2011.pdf

solo utenti autorizzati

Tipologia: Versione finale editoriale
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 590.24 kB
Formato Adobe PDF
590.24 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/199972
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 18
social impact