Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice

Background and purpose: High resting heart rate is a predictor for total and cardiovascular mortality independent of other risk factors in patients with coronary artery disease. We tested the hypothesis that a reduction of resting heart rate with the cardiac pacemaker I f current inhibitor ivabradine prevents the endothelial dysfunction associated with dyslipidaemia. Experimental approach: Three‐month‐old dyslipidaemic (DL) male mice expressing the human ApoB‐100 were assigned or not (DL, n =16), to treatment for 3 months with ivabradine (10 mg kg −1  d −1 , n =17). Wild‐type C57Bl/6 mice (WT, n =15) were used as controls. Heart rate was measured at 3, 4.5 and 6 months. Dilatation to acetylcholine (ACh) of isolated cerebral and renal arteries was investigated at 6 months. Key results: Heart rate remained stable in anaesthetized WT mice, increased (25%, P <0.05) with age in DL mice but was limited (11%, P <0.05) by ivabradine. At 6 months, left ventricular maximal pressure was similar in all groups. The minimal and end‐diastolic left ventricular pressures were increased ( P <0.05) in DL (10.2±1.0 and 18.7±1.4 mm Hg) compared to WT (−0.4±0.7 and 6.3±1.0 mm Hg) and reduced ( P <0.05) by ivabradine (4.2±1.3 and 11.5±1.5 mm Hg). ACh‐induced maximal dilatation was impaired ( P <0.05) in renal and cerebral arteries isolated from DL compared to WT (56±7 versus 83±3% in renal arteries; 22±2 versus 42±2% in cerebral arteries). Ivabradine completely prevented ( P <0.05) this dysfunction in renal and cerebral arteries. Conclusions and implications: Selective heart rate reduction with ivabradine limits cardiac dysfunction and prevents the renovascular and cerebrovascular endothelial dysfunction associated with dyslipidaemia. British Journal of Pharmacology (2008) 154 , 749–757; doi: fn2 ; published online 14 April 2008