Abstract 15691: Dronedarone Enhanced Endothelial Nitric Oxide Release and Reduced Nitroxidative Stress and Blood Pressure in Hypertensive Rats
Background: Dronedarone is a non-iodinatedbenzofuran antiarrhythmic agent usedfor rhythm control in patients with nonpermanent atrial fibrillation (AF). Clinical findings in paroxysmal/persistent AF studies suggest that dronedarone has cardiovascular effects beyond rhythm control, although the underlying mechanisms have not been determined. As endothelial cell (EC) dysfunction is causally associated with atherothrombotic disease, we hypothesized that dronedarone may reduce cardiovascular risk through enhanced nitric oxide (NO) bioavailability. This was tested in spontaneously hypertensive (SH) rats with EC dysfunction.
Methods: Spontaneously hypertensive (SH) rats were treated with vehicle or dronedarone at 10 and 30 mg/kg/day. At study baseline, and after treatment with vehicle or dronedarone for 4 weeks, aortic endothelial cells (ECs) were isolated, stimulated with calcium ionophore, and assayed for nitric oxide (NO) and peroxynitrite (ONOO-) release using amperometric approaches. Changes in EC function were correlated with blood pressure (BP) and inflammatory biomarker levels.
Results: Treatment with vehicle alone reduced NO release by 14% (308 ± 36 to 266 ± 33 nM, p<0.01) and increased ONOO- production by 17% (258 ± 33 to 300 ± 34 nM, p<0.01). Mean BP also increased over this treatment period (140 ± 18 to 156 ± 16 mmHg, p<0.01). Dronedarone treatment increased NO release by 11% (290 ± 39) and 23% (328 ±35 nM, p<0.001) at 10 and 30 mg/kg/day, respectively; at the same treatment levels, dronedarone reduced ONOO− production by 11% (266 ± 33, p<0.05) and 19% (242 ± 29 nM, p<0.001). The NO/ONOO− ratio, an indicator of normal EC function, increased by more than 50% (p<0.001) at the highest dose tested. Dronedarone also reduced mean BP by 13% (to 136 ± 18 mmHg, p<0.05) at this treatment level, with no observed changes in sICAM-1 or RANTES levels.
Conclusion: These results suggest that dronedarone reverses EC dysfunction in hypertensive rats as evidenced by enhanced NO bioavailability and reduced blood pressure levels. How these effects contribute to the benefits of dronedarone in non-permanent AF patients requires further evaluation.
- © 2012 by American Heart Association, Inc.