Introduction: Doxorubicin, an anthracycline widely used in the treatment of a broad range of tumours, causes acute QT prolongation. Dexrazoxane has been shown to prevent the QT prolongation induced by another anthracycline, epirubicin, but has not yet been reported to prevent that induced by doxorubicin. Thus, the present study was designed to test whether the acute QT effects induced by doxorubicin could be blocked by dexrazoxane and to explore the mechanism. Results were compared with those obtained with a reference human ether-a-go-go (hERG) channel blocker, moxifloxacin. Methods: The effects of moxifloxacin (100 mM) and doxorubicin (30 mM), with or without dexrazoxane (from 3 to 30 mM), have been evaluated on the QTc interval in guinea-pig isolated hearts and on IKr (rapid component of the delayed rectifier current) and IKs (slow component of the delayed rectifier current) currents stably expressed in human embryonic kidney 293 cells. Results: Moxifloxacin (100 mM), a potent hERG blocker, prolonged QTc by 22%, and this effect was not prevented by dexrazoxane. Doxorubicin (30 mM) also prolonged QTc by 13%, did not significantly block hERG channels and specifically inhibited IKs (IC50: 4.78 mM). Dexrazoxane significantly reduced the doxorubicin-induced QTc prolongation and prevented doxorubicin-induced inhibition of IKs. Conclusion and implications: Doxorubicin acutely prolonged the QT interval in guinea-pig heart by selective IKs blockade. This effect was prevented by dexrazoxane. This result is important because it illustrates the danger of neglecting IKs in favour of hERG screening alone, for early preclinical testing for possible induction of torsade de pointes.

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is caused by mutations in the Notch3 receptor expressed at the surface of vascular smooth muscle cells. The functional consequences of the disease at the peripheral microcirculation level are incompletely elucidated. In this study, we aimed to assess, in vivo, the endotheliumdependent and independent vasodilation of the skin microvasculature in CADASIL patients. Twentythree affected subjects were compared with 23 gender and age-matched controls. The brachial artery endothelium-dependent and endothelium-independent vasodilation were assessed after forearm cuff occlusion and nitroglycerin administration. Skin vasoreactivity to transcutaneous administration of acetylcholine and sodium nitroprussiate, and after postocclusive hyperemia were measured by Laser Doppler flowmetry. The maximum changes in the diameter of the brachial artery after the cuff release or after nitroglycerin administration did not differ between patients and controls. With iontopheresis, only the peak value of the dose response was found decreased in normocholesterolemic patients after nitroprussiate administration. The postocclusive test revealed a large increase of the time to peak value and whole duration of the hyperemic response in CADASIL patients. The results of this study show that the skin vasoreactivity is altered in CADASIL. Particularly, the kinetics of reactive hyperemia after cuff occlusion is dramatically changed with a lengthened and delayed response. This characteristic pattern may be related to the specific ultrastructural modifications related to Notch3 gene mutations involving smooth muscle cells in the microvasculature.

The effects of an extract of Ginkgo biloba (EGb 761) on arteriolar spasm were confirmed using a preparation of rat cremaster muscle. When vasospasm was induced by rat serum, arteriolar constriction reached 25-30% of the initial diameter after 10 min. Intravenous injection of EGb 761 (30 mg/kg) 5 min after inducing spasm inhibited about 80% of this serum-induced vasoconstriction. As previous studies have shown that EGb 761 has an antiaggregatory effect on platelets, thrombin, serotonin (platelet-derived compounds that are present in the serum) and a thromboxane analogue (U46619) were also used to induce vasospasm. Administration of EGb 761 (30 mg/kg) 5 min after exposure of the preparation to serotonin (10^-3M) or 10 min after exposure to thrombin (20 units) did not affect vasospasm induced by these agents. In contrast, treatment with this same dose of EGb 761 5 min after exposure of the preparation to U46619 (10^-4M) abolished the arteriolar constriction induced by this agent in 15 min. The thromboxane/prostaglandin H₂ receptor antagonist SQ29548 antagonized serum-induced vasospasm, indicating an involvement of thromboxane. Other experiments indicated that the effects of EGb 761 of counteracting vasospasm may be mediated in part by ginkgolide B, a triterpene constituent of the extract that is an antagonist of platelet-activating factor and in part by an ‘NO-like’ action of its proanthocyanidin constituents. Taken together, these results have revealed that EGb 761 treatment can antagonize the vasoconstrictor effect of thromboxane on arterioles. As thromboxane is implicated in many cardiovascular disorders, this property of EGb 761 may explain some of its beneficial clinical effects in such pathologies.

Purines and more specifically adenosine monophosphate (AMP) and adenosine triphosphate (ATP) have a strong relaxant effect on smooth muscle cells of the dog, rabbit and human corpus cavernosum, to approximately the same degree as nitric oxide (NO). However, purines are considered as modulators of erectile function rather than key mediators. This suggests that the use of purines combined with NO donors could be effective to treat some specific erectile disorders. The relaxation induced by the combination of l-arginine (Arg), a natural substrate for NO synthase, was assessed with a purine-nucleotide (AMP, ATP) on a rabbit corpus cavernosum model, to determine if these substances could potentiate each other's effect. When a pre-contraction was induced by phenylephrine, AMP alone induced a 43% CC relaxation rate and ATP alone a 26% rate. The relaxation rate induced by Arg was lower in comparison (8% at 5.10(-4) m vs. 25% at AMP 5.10(-4) m and 15% at ATP 5.10(-4) m). NO synthase inhibitor n-nitro-l-arginine did not modify the relaxing effect provoked by AMP suggesting that the mechanism of action of this nucleotide does not involve the NO pathway. The combination of Arg at 5.10(-4) m with either AMP or ATP at different doses ranging from 5.10(-4) to 10(-3) m significantly enhanced the relaxing response reaching rates of 62 and 80% respectively, leading to a synergistic effect. The present data indicate that a 'NO donor' combined with an 'adenosine donor' could be an effective therapeutic approach.

The effect of intravenously administered Ginkbo biloba extract (EGb 761) on the vasospastic response to platelet activation has been assessed using a cutaneous flap preparation in anaesthetized mice. Arterioles of the axillary artery were observed by intravital microscopy, and platelets were activated by topical application of ADP under two steady state conditions: normothermia (37 °C) and hypothermia (24 °C). Responses of the cutaneous arterioles to stimulation by topical application of a thromboxane agonist (U46619) were also compared in animals treated intravenously with EGb 761 or with a thromboxane synthesis inhibitor (U63557). ADP induced a 34% constriction of the arterioles in control animals. However, no arteriolar constriction occurred in response to ADP in platelet-depleted animals (collagen-induced thrombocytopenia) or in animals treated with EGb 761 (60 mg/kg, i.v.). Exposure of the arterioles to hypothermia (24°C) for 10 min induced constriction of 7-12% in all experimental groups of animals. Under these hypothermic conditions, either EGb 761 or thrombocytopenia abolished ADP-induced arteriolar constriction which was substituted by arteriolar dilation, indicating that EGb 761 can inhibit the vasospasm that is produced by platelet activation. As topically applied U46619 (10^-5M) induced arterioles constriction (about 22%) that was abolished by intravenous treatment with EGb 761, the extract appears to act directly rather than as a thromboxane synthase inhibitor. Collectively, these findings indicate that platelet factors can play a significant role in cutaneous vasospasm, and that EGb 761, via an action on the thromboxane pathway, could be useful in treating Raynaud’s phenomenon and other vascular disorders which involve increased thromboxane production.