Background and purpose: Activation of the persistent sodium current in ischaemic myocardium results in calcium overload which is toxic for the cardiomyocyte. Thus, the activity of 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5 benzoxathiepine bromhydrate (F 15845), a new selective persistent sodium current blocker, in protecting against the effects of cardiac ischaemia was examined, in both in vitro and in vivo models. Experimental approach: Electrophysiological studies using patch-clamp and conventional microlelectrode techniques, isolated perfused hearts and models of angina in anaesthetized animals were used to assess the protection afforded by F 15845 against ischaemia-induced changes. Key results: F 15845 reduced the persistent sodium current activated by veratridine (IC50 1.58 ¥ 10 -6 mol·L -1). F 15845 blocked voltage-gated human cardiac sodium channels in a novel, voltage-dependent manner, selectively affecting steady-state inactivation. F 15845 did not affect action potential shape and basal function of guinea pig isolated perfused hearts but did reduce ischaemia-induced diastolic contracture in this model (IC50 0.64 ¥ 10 -6 mol·L ) in an experimental angina model of demand ischaemia, again without haemodynamic effects, confirming a direct anti-anginal activity. Conclusions and implications: F 15845 is a selective, potent blocker of the persistent sodium current, generated by the human Nav1.5 channel isoforms, and prevents cardiac angina in animal models.

Background: Retinaldehyde is a key molecule in the metabolism of vitamin A by keratinocytes. In order to evaluate its range of topical activity in acne, its comedolytic effect was compared to that of retinoic acid in the same vehicle, in the rhino mouse model. Methods: The animals were treated on the back daily for 5 consecutive days per week for 3 weeks. At the end of this period, histological slides were analyzed in order to quantify the features of comedones and epidermal thickness. Results: Topical treatment with a retinaldehyde (0.05% w/w) and a retinoic acid formulation (0.025% w/w) induced comedolysis and increased the epidermal thickness with the same intensity. Conclusion: These data indicate that retinaldehyde exerts a significant comedolytic activity.

BACKGROUND AND PURPOSEMyocardial ischaemia is associated with perturbations of electrophysiological profile of cardiac myocytes. The persistent sodium current (INap) is one of the major contributors to ischaemic arrhythmias and appears as an attractive therapeutic target. We investigated the effects of F 15845, a new anti-anginal drug on INap and in integrative models of INap-induced arrhythmias. EXPERIMENTAL APPROACHSodium current was investigated using patch clamp technique on wild-type and DKPQ-mutated hNav1.5 channels transfected in HEK293 cells. Effects of F 15845 on action potentials (APs) were studied by the glass microelectrode technique and its anti-arrhythmic activities were investigated in ischaemia-and aconitine-induced arrhythmias in the rat. KEY RESULTSWe demonstrated that F 15845 is a potent blocker of INap acting from the extracellular side of the channel. Blockade of INap was voltage dependent and characterized by an almost pure tonic block. F 15845 shortened AP from rabbit Purkinje fibres, confirming its lack of pro-arrhythmic activity, and prevented AP lengthening induced by the INap activator veratridine. F 15845 did not affect APs from rabbit atria and guinea pig papillary muscle where INap is not functional, confirming its inability to affect other cardiac ionic currents. F 15845 was effective at preventing fatal ventricular fibrillation and ventricular tachycardia during coronary ligation without modifying heart rate and blood pressure, and dose dependently increased the dose threshold of aconitine required to induce ventricular arrhythmias. CONCLUSIONS AND IMPLICATIONSF 15845, a novel anti-anginal drug targeting INap, demonstrates new anti-arrhythmic properties which may be of therapeutic benefit against ischaemia-induced arrhythmias Abbreviations AP, action potential; APD50, APD90, action potential duration at 50% and 90% repolarization; DAD, delayed afterdepolarization; EAD, early afterdepolarization; INap, persistent sodium current.

The effects of donitriptan on systemic arterial-jugular venous oxygen saturation difference were evaluated in pentobarbitoneanesthetized pigs. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (40% polyethyleneglycol in saline, n ϭ 9) or donitriptan (0.01, 0.04, 0.16, 0.63, 2.5, 10, and 40 g/kg, n ϭ 7) were cumulatively infused over 15 min/dose. The involvement of 5-hydroxytryptamine 1B (5-HT 1B ) receptors was assessed in the presence of the 5-HT 1B/1D receptor antagonist, GR 127935. Donitriptan decreased markedly and dose dependently jugular venous oxygen saturation [ED 50 0.5 (0.3-1.1) g/kg], in parallel with increases in carotid vascular resistance [ED 50 0.9 (0.7-1.1) g/kg]. Since arterial oxygen saturation and partial pressure remained unchanged, donitriptan significantly increased arteriovenous oxygen saturation difference from 0.63 g/kg (maximal variation: 57 Ϯ 18%, P Ͻ 0.05 compared with vehicle). Unexpectedly, donitriptan from 2.5 g/kg induced marked and significant increases in carbon dioxide partial pressure (pVCO 2 ) in venous blood (maximal increase 18.8 Ϯ 5.7%; P Ͻ 0.05 compared with vehicle). Pretreatment with GR 127935 (0.63 mg/kg, n ϭ 5) abolished the fall in venous oxygen saturation and the increase in carotid vascular resistance and reduced the increases in pVCO 2 induced by donitriptan. The results demonstrate that donitriptan, via 5-HT 1B receptor activation, decreases the oxygen saturation of venous blood draining the head, concomitantly with cranial vasoconstriction. Since donitriptan also increased pVCO 2 , an effect upon cerebral oxygen consumption and metabolism is suggested in addition to cranial vasoconstriction, which may be relevant to its headache-relieving effects.Donitriptan is a unique high-efficacy agonist at 5-HT 1B/1D receptors; it is currently being evaluated for efficacy in the acute relief of migraine headache in phase II clinical trials (Dukat, 2001;John et al., 1999John et al., , 2000. One of the key pharmacological actions of donitriptan is 5-HT 1B receptor-medi- Tom et al., 2002). Before the advent of the triptans, the nonselective 5-HT 1B receptor agonist ergotamine (Villalón et al., 1999) was also shown to elicit selective carotid vasoconstriction confined to cephalic AVAs (Johnston and Saxena, 1978). Moreover, increases in AVOSD due to decreases in jugular venous oxygen saturation and oxygen partial pressure (pO 2 ) without affecting systemic arterial oxygen saturation or pO 2 were also observed in this study (Johnston and Saxena, 1978). However, it is presently unknown whether the recently described triptan 5-HT 1B/1D receptor agonistinduced increases in AVOSD are due to changes in systemic arterial or jugular venous oxygen saturation, or both.The aim of the present investigation was therefore to eluArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.102...

No abstract