Title

 

Authors

L. Testai, A. Martelli, A. Arcipreti, M.C. Breschi, V. Calderone
 
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa; via Bonanno, 6, I-56126 Pisa, Italy. 

 

Abstract

Flavonoids are natural phenolic compounds widely distributed in edible plants and are known to be endowed with several biological effects, such as an overall protective activity on the cardiovascular function that has been clearly shown in experimental and epidemiological studies [1-2]. As concerns the mechanistic explanation, it is presently recognized that - together with their well-known antioxidant properties - flavonoids are endowed with further pharmacodynamic mechanisms, which involve a plethora of potential molecular targets. Among these, it has been reported that many flavonoids can induce relaxing effects on vascular smooth muscle through the opening of sarcolemmal large-conductance calcium-activated potassium channels (BK channels). These BK-activating flavonoids seem to share some common structural requirements and - in particular - they show a 5-hydroxy substituent on the bicyclic ring [3-4]. More recent studies indicate that BK channels are also expressed in the membrane of cardiac mitochondria. Since the pharmacological activation of these mitochondrial BK channels (mitoBK) protects myocardiocytes against ischemia/reperfusion (I/R) injury [5], this study was aimed to investigate the potential cardioprotective effects of some 5-hydroxy substituted flavonoids. Naringenin, Chrysin, Apigenin, 5-hydroxyflavone and 5-methoxyflavone ameliorated the post-ischemic recovery of the inotropic parameters in Langendorff-perfused rat hearts submitted to I/R. These effects were associated with an improved post-ischemic coronary flow and a reduced ventricular tissue injury. In order to investigate the potential role of mitoBK channels, Naringenin was selected for further studies on isolated rat heart mitochondria, which have been carried out by means of electropotentiometric tools. In these experimental protocols, the flavanone caused a concentration-dependent depolarization of mitochondrial membrane potential; this effect was not observed when potassium-free extramitochondrial medium was used, indicating that the depolarizing response is actually due to trans-membrane potassium flows. Moreover, the Naringenin-induced depolarizing action was antagonized by Iberiotoxin and Paxilline, selective blockers of BK channels. Finally, it is known that the accumulation of calcium ions into the mitochondrial matrix is a key step in the cell death induced by ischemia/reperfusion. In agreement with the effects shown by other activators of mitochondrial potassium channels [6], Naringenin reduced the calcium up-load in calcium-free cardiac mitochondria exposed to high calcium concentration. In conclusion, this study suggests that the overall protective activity exhibited by some flavonoids in the cardiovascular system can be also attributed to anti-ischemic cardioprotective effects due to the activation of mitoBK channels.
References
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[2]Akhlaghi M, Bandy B. J Mol Cell Cardiol. 2009, 46:309-17.
[3] Calderone V, Chericoni S, Martinelli C, Testai L, Nardi A, et al. Naunyn Schmiedebergs Arch Pharmacol. 2004, 370:290-8.
[4]Saponara S, Testai L, Iozzi D, Martinotti E, Martelli A, et al. Br J Pharmacol. 2006, 149:1013-21.
[5]Cao CM, Xia Q, Gao Q, Chen M, Wong TM. J Pharmacol Exp Ther. 2005, 312:644-50.
[6]Calderone V, Testai L, Martelli A, Rapposelli S, Digiacomo M, et al. Biochem Pharmacol. 2010, 79:39-47.