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

Abstract：

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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Drouin A,Gendron ME,Thorin E,Gillis MA,Mahlberg-Gaudin F,Tardif JC

doi

10.1038/bjp.2008.116

subject

Has Abstract

pub_date

2008-06-01 00:00:00

pages

749-57

issue

4

eissn

0007-1188

issn

1476-5381

pii

bjp2008116

journal_volume

154

pub_type

杂志文章

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