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Vol. 299, Issue 3, 1133-1139, December 2001
Laboratoire de Pharmacologie, Institut National de la
Santé et de la Recherche Médicale,
Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre,
France
We investigated the effects of the selective bradycardic agent
ivabradine, an If channel inhibitor, on
exercise-induced ischemia and resulting myocardial stunning. Seven dogs
were chronically instrumented to measure left ventricular (LV) wall
thickening (Wth), aortic pressure and coronary blood flow (CBFv)
(Doppler). Circumflex coronary artery stenosis was set up to suppress
the increase in CBFv during a 10 min treadmill exercise. During
exercise under saline, LVWth in the ischemic zone was depressed
(
70 ± 4%) and a prolonged myocardial stunning was subsequently
observed. Infusion of ivabradine started before exercise significantly
reduced heart rate (HR) at rest (22 ± 7%), during exercise
(33 ± 4%) and throughout the recovery period (21 ± 2%). By reducing HR during exercise, ivabradine simultaneously
improved LVWth compared with saline (14 ± 1% versus 7 ± 1%, respectively) and subendocardial perfusion (microspheres). This
anti-ischemic effect was subsequently responsible for a strong decrease
in the intensity and severity of myocardial stunning. All these
beneficial effects were abolished when HR reduction during exercise was
suppressed by atrial pacing. Interestingly, when ivabradine infusion
was started after exercise, LVWth was still significantly enhanced and
myocardial stunning strongly attenuated. This direct effect of
ivabradine on the stunned myocardium disappeared when HR reduction was
suppressed by atrial pacing at rest. In conclusion, this study
demonstrates that ivabradine exerts an anti-ischemic effect that is
responsible for subsequent protection against myocardial stunning.
Furthermore, administration of ivabradine after the ischemic insult
still improves LVWth of the stunned myocardium.
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