Abstract 5129: Importance of Heart Rate for the Effects of Chronic Mental Stress on Endothelial Function and Ischemic Stroke
BACKGROUND: The vascular effects of chronic mental stress are only partially understood. We therefore studied the effects of chronic mental stress on endothelial function and focal brain ischemia and characterized the role of heart rate and oxygen free radicals.
METHODS AND RESULTS: Male C57/Bl6-mice were subjected to an established chronic stress protocol (restraint, exposure to rat, tail hanging) for 6 weeks. Mice were treated with the I(f)-channel-inhibitor ivabradine, 10 mg/kg/d, p.o. or vehicle. Chronic stress increased heart rate, which was reduced by ivabradine treatment (vehicle 514±10 bpm, vehicle/stress 570±14 bpm; iva/stress 485±7 bpm). Endothelium-independent vasorelaxation induced by glyceroltrinitrate and vasoconstriction induced by phenylephrine and KCl were similar in all groups, however, endothelium-dependent relaxation of aortic rings by carbachol was significantly impaired in mice exposed to stress. Heart rate reduction by ivabradine improved endothelial function in stressed animals in contrast to vehicle treatment. Vascular NADPH oxidase activity was increased to 223±38% and lipid hydroperoxides were increased to 314±26% in mice exposed to stress. Heart rate reduction with ivabradine significantly reduced NADPH oxidase activity (169±44%) and lipid peroxidation (187±58%). To test the relevance of these findings, mice were subjected to 30 min filamentous middle cerebral artery occlusion (MCAo), followed by 72 h reperfusion. Mice exposed to chronic stress before MCAo exhibited a markedly increased lesion size in comparison to unstressed controls (vehicle/naive: 23.92±2.41 mm3 vs placebo/stress: 33.72±2.34 mm3). Heart reduction by ivabradine significantly reduced cerebral lesion size (iva/stress: 12.88±3.31 mm3). P<0.05 for all comparisons.
CONCLUSIONS: Chronic exposure to mental stress impairs endothelial function and increases lesion area following ischemic stroke. Heart rate reduction by ivabradine diminishes the negative effects of chronic stress and protects from focal brain ischemia via reduction of vascular oxidative stress and amelioration of endothelial function. Those results identify the impact of heart rate as an important mediator of vascular effects induced by chronic mental stress.