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


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          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.

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          Most cited references 7

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          Association between high heart rate and high arterial rigidity in normotensive and hypertensive subjects.

          The dynamic elastic modulus of central arteries is very frequency-dependent Although resting heart rate is a potent independent risk factor for morbidity and mortality both from cardiovascular and from noncardiovascular disease, no link between tachycardia and arterial stiffness has ever been established. To relate arterial stiffness to heart rate in a population with relatively low cardiovascular risk. Pulse-wave velocity measurements and high-resolution echo-tracking techniques were used to determine the degree of arterial distension (of carotid and femoral arteries, and terminal aorta) and the velocity of the pulse wave (aorta and upper and lower limbs) at the same time as heart rate, in members of a large population of normotensive and hypertensive subjects in a multicenter study in Paris, Fleury-Merogis and Grenoble (France). A high heart rate was strongly associated with reduced distension and elevated pulse-wave velocity, even after adjustment for age and blood pressure. A high aortic pulse-wave velocity was also negatively associated with a low baroreflex sensitivity. The most significant associations between high heart rate and high arterial rigidity were found for the carotid artery, the thoracic aorta, and the lower limbs, but there was no significant result for the terminal aorta and the arm arteries. This study demonstrates that there is a statistically significant positive link between high heart rate and high arterial stiffness measured at the site of central and lower limb arteries. Since an elevated heart rate has been shown to be associated with cardiovascular risk, such findings may be relevant for future cardiovascular studies in epidemiology.
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            The static elastic properties of 45 human thoracic and 20 abdominal aortas in vitro and the parameters of a new model

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              Mechanical influences on vascular smooth muscle cell function.

               B. Williams (1998)
              The increase in vascular wall stress imposed by hypertension has been strongly implicated in the pathogenesis of cardiovascular disease. Much of this chronic cyclical mechanical strain is experienced by the vascular smooth (VSM) cells of the vascular media. The cellular mechanisms whereby VSM cells sense and respond to changing mechanical forces are poorly understood. This review focuses on an emerging field of cardiovascular research in which the direct effects of mechanical strain on VSM cells and isolated blood vessels in organ culture have been characterized, in vitro. Cyclical mechanical strain profoundly influences cultured VSM cell orientation, growth and phenotype. Mechanical strain also increases the secretory function of VSM cells leading to increased extracellular matrix protein production. Vasoactive mediators such as angiotensin II potentiate these effects. Mechanical strain increases VSM cell release of platelet derived growth factor, transforming growth factor beta1, fibroblast growth factor and vascular endothelial growth factor, which act in autocrine or paracrine loops to influence VSM and endothelial cell growth and function. Mechanical strain may also activate local tissue renin-angiotensin systems and regulate expression of angiotensin II receptors within the cardiovascular system. The mechanism whereby VSM cells transduce mechanical stimuli into an intracellular signal and biological response, i.e. 'mechanotransduction', is strongly dependent on integrins. Moreover, specific matrix protein:integrin engagements lead to differential VSM cells responses via the selective activation of numerous intracellular signalling pathways including; mitogen-activated protein kinase, focal adhesion kinase and c-Src. The study of vascular mechanotransduction has begun to delineate the complex cellular basis of cardiovascular structural and functional modification in hypertension.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                August 2003
                26 September 2003
                : 40
                : 4
                : 320-328
                aDepartment of Anesthesiology, Hôpital Beaujon, Clichy, bINSERM, EMI 0107, cINSERM, U258, dDepartment of Internal Medicine, Broussais Hospital, Paris, France
                72696 J Vasc Res 2003;40:320–328
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 4, References: 33, Pages: 9
                Research Paper


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