Background and purpose: The citrus flavanone hesperetin has been proposed for the treatment of several human pathologies, but its cardiovascular actions remain largely unexplored. Here, we evaluated the effect of hesperetin on cardiac electrical and contractile activities, on aortic contraction, on the wild-type voltage-gated Na V 1.5 channel, and on a channel mutant (R1623Q) associated with lethal ventricular arrhythmias in the long QT syndrome type 3 (LQT3). Experimental approach:We used cardiac surface ECG and contraction force recordings to evaluate the effects of hesperetin in rat isolated hearts and aortic rings.Whole-cell patch clamp was used to record Na V 1.5 currents (I Na ) in rat ventricular cardiomyocytes and in HEK293T cells expressing hNa V 1.5 wild-type or mutant channels.Key results: Hesperetin increased the QRS interval and heart rate and decreased the corrected QT interval and the cardiac and aortic contraction forces at concentrations equal or higher than 30 μmol·L −1 . Hesperetin blocked rat and human Na V 1.5 channels with an effective inhibitory concentration of ≈100 μmol·L −1 . This inhibition was enhanced at depolarized holding potentials and higher stimulation frequency and was reduced by the disruption of the binding site for local anaesthetics. Hesperetin increased the rate of inactivation and preferentially inhibited I Na during the slow inactivation phase, these effects being more pronounced in the R1623Q mutant. Conclusions and implications:Hesperetin preferentially inhibits the slow inactivation phase of I Na , more markedly in the mutant R1623Q. Hesperetin could be used as a template to develop drugs against lethal cardiac arrhythmias in LQT3.

1 Two sodium channel toxins, BgII and BgIII, have been isolated and puri®ed from the sea anemone Bunodosoma granulifera. Combining dierent techniques, we have investigated the electrophysiological properties of these toxins. 2 We examined the eect of BgII and BgIII on rat ventricular strips. These toxins prolong action potentials with EC 50 values of 60 and 660 nM and modify the resting potentials. 3 The eect on Na + currents in rat cardiomyocytes was studied using the patch-clamp technique. BgII and BgIII slow the rapid inactivation process and increase the current density with EC 50 values of 58 and 78 nM, respectively. 4 On the cloned hH1 cardiac Na + channel expressed in Xenopus laevis oocytes, BgII and BgIII slow the inactivation process of Na + currents (respective EC 50 values of 0.38 and 7.8 mM), shift the steady-state activation and inactivation parameters to more positive potentials and the reversal potential to more negative potentials. 5 The amino acid sequences of these toxins are almost identical except for an asparagine at position 16 in BgII which is replaced by an aspartic acid in BgIII. In all experiments, BgII was more potent than BgIII suggesting that this conservative residue is important for the toxicity of sea anemone toxins. 6 We conclude that BgII and BgIII, generally known as neurotoxins, are also cardiotoxic and combine the classical eects of sea anemone Na + channels toxins (slowing of inactivation kinetics, shift of steady-state activation and inactivation parameters) with a striking decrease on the ionic selectivity of Na + channels.

Our data suggest that I(Ca(TTX))-like current in PMI myocytes does not arise from classical Na(+) channels modified by oxidative stress or PKA phosphorylation and most probably represents a different Na(+) channel type re-expressed in some cells after remodelling.

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The alkaloid cycleanine ([12aR-(12aR,24aR)]-2,3,12a,13,14,15,24,24a-octa hydro-5,6,17,18- tetramethoxy-1,13-dimethyl-8, 11:20,23-dietheno-1H,12H [1,10]dioxacyclooctadecino[2,3,4-ij:11,12,13-i'j']diisoquinolin e) was extracted from the bulbs of Stephania glabra (Roxb) Miers and its effects on cardiac and smooth muscle preparations were studied and compared to those of nifedipine (1,4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid dimethylesther). Cycleanine inhibited the KCl-induced contraction of rabbit aortic rings with higher potency than nifedipine. IC50s for cycleanine and nifedipine were 0.8 and 7.10(-9) M respectively. Cycleanine had minor effects on the norepinephrine-induced contraction of rabbit aortic rings. Cycleanine and nifedipine also depressed the contraction of rat ventricular preparations but with lower potency (IC50 = 3 and 0.03.10(-6) M respectively). Action potential duration of rat right ventricular strips was decreased by both compounds. L-type Ca-current (ICaL) of single rat ventricular cardiomyocytes was inhibited by cycleanine in a voltage- and frequency-dependent manner. With a higher potency nifedipine inhibited ICaL in a tonic and almost frequency-independent manner. The results suggest that cycleanine can act as a potent vascular selective Ca-antagonist.