Effect of Chronic Heart Rate Reduction with Ivabradine on Carotid and Aortic Structure and Function in Normotensive and Hypertensive Rats

Abstract

Background: A reduction of heart rate (HR) by surgical means or pharmacological agents affects the progression and/or regression of atherosclerotic lesions. Nevertheless, the effect of bradycardia per se on large artery structure and function has never been investigated in rat models of hypertension. Methods: Four groups of Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were treated for 28 days either by placebo or by the selective HR-reducing agent ivabradine (8.4 mg/kg/day), a novel compound devoid of inotropic or vasodilating effects and without direct action on the autonomic nervous system. At the end of the follow-up period, intra-arterial blood pressure, carotid pulsatile arterial hemodynamics (echo tracking techniques) and the medial cross-sectional area (MCSA) of the aorta and the carotid artery were determined. Results: In conscious animals, chronic administration of ivabradine significantly reduced HR by 26–30% with no change in tail systolic blood pressure. In anesthetized animals, the decrease in HR and the subsequent increase in the diastolic period were responsible for a decrease in diastolic blood pressure. At the site of the large arteries, ivabradine produced a decrease in the MCSA of the thoracic but not of the abdominal aorta, as well as an increase in pulsatile change of the carotid diameter without change in the isobaric distensibility and MCSA. The changes in pulsatile diameter were significantly larger in WKY rats than in SHRs. Conclusion: In normotensive and mainly in SHRs, selective chronic HR reduction by ivabradine is associated with alterations in large arteries involving an aortic antihypertrophic effect.