Involvement of nitric oxide in amiodarone- and dronedarone-induced coronary vasodilation in guinea pig heart
Introduction
Amiodarone is the most effective antiarrhythmic compound currently available for clinical treatment of life threatening arrhythmias and suppression of atrial fibrillation. Initially marketed as an antianginal agent, amiodarone possesses coronary and peripheral vasodilator effects (Charlier et al., 1968) and exerts a negative chronotropic and dromotropic influence on the sinoatrial and atrioventricular nodes, respectively (Gloor et al., 1983). These pharmacological effects may be, in part, attributed to the blockade of calcium channels. Whereas calcium antagonistic properties of amiodarone have been demonstrated in myocardial cells Nattel et al., 1987, Nishimura et al., 1989, there is no evidence that relaxant effects on smooth muscles are due solely to a blockade of calcium influx. Indeed, Radino et al. (1989) showed that amiodarone does not modify smooth muscle contraction in rabbit aorta strips precontracted with noradrenaline or potassium. On the contrary, Lubic et al. (1994) observed that amiodarone could completely antagonize depolarization-induced aortic ring contraction.
In our laboratory, previous in vitro studies performed in isolated Langendorff-perfused guinea pig, rat (Cosnier et al., 1998) and rabbit hearts have shown that amiodarone possesses powerful coronary vasodilation properties. But like Radino et al. (1989), we did not observe any relaxation induced by amiodarone in rabbit aorta rings previously contracted with KCl (40 or 100 mM). Moreover, it was shown that amiodarone (Grossmann et al., 1998) and its metabolite, N-desethylamiodarone (Grossmann et al., 2000), were able to induce endothelium-dependent vasodilation in human hand vein in vivo.
In the light of these observations, we have postulated that coronary vasodilation induced by amiodarone observed in isolated hearts could be endothelium-dependent. Therefore, the aim of the present study was to investigate whether the release of vasoactive substances such as prostaglandins and/or nitric oxide (NO) could be involved in the coronary vasodilation induced by amiodarone and dronedarone. The latter substance is a recently developed non-iodinated benzofurane derivative structurally related to amiodarone with similar antiarrhythmic (Finance et al., 1995), hemodynamic (Djandjighian et al., 2000) and electrophysiological characteristics Sun et al., 1999, Aimond et al., 2000, Gautier et al., 2003.
To evaluate the pharmacological properties of amiodarone, dronedarone and verapamil on coronary resistance vessels, isolated guinea pig hearts perfused with a high concentration of potassium (40 mM) were used (Hoover, 1991).
Section snippets
Animals
Male Hartley guinea pigs weighing 450–550 g (Charles Rivers, France) were used in this study. The animals were housed in groups of two or three per cage for at least 5 days under controlled conditions of constant temperature/humidity and exposed to a 12-h light/dark cycle. They had free access to a standard diet (A04, UAR, Epinay-sur-Orge, France) and drinking water.
Our animal facilities and animal care and use programmes are in accordance with the principles laid down in the European
Coronary perfusion pressure values according to experimental settings
At the end of the stabilization period, the mean coronary perfusion pressure of all the non treated hearts (29.4±0.6 mm Hg; n=72) was not statistically different from that of the l-NAME treated group (29.1±2.2 mm Hg; n=10).
Table 1 summarizes the coronary perfusion pressure values measured during the perfusion with high K solution (KCl 40 mM) in the absence or in the presence of treatment, just before the perfusion of amiodarone, dronedarone and verapamil. In KCl 40 mM, the mean coronary
Discussion
The results of the present study show that both amiodarone and dronedarone effectively induce coronary vasodilation that involves nitric oxide but not prostaglandins or endothelium-derived hyperpolarising factor (EDHF) in isolated guinea pig hearts perfused with high K+ solution. In the presence of the cyclo-oxygenase inhibitor, indomethacin, the decrease in coronary perfusion pressure induced by both amiodarone and dronedarone was not modified. This may suggest that, under our experimental
Acknowledgements
We wish to thank Roeland Vankerckhoven for critical reading of manuscript and Michèle Boitel for excellent technical assistance.
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