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      Pravastatin normalises peripheral cardiac sympathetic hyperactivity in the spontaneously hypertensive rat

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          Abstract

          Hypertension is associated with heightened cardiac sympathetic drive whilst statins reduce angiotensin II (ATII) signalling, superoxide anion production and increase nitric oxide bioavailability, events that can potentially reduce peripheral cardiac sympathetic neurotransmission. We therefore investigated whether pravastatin alters peripheral cardiac sympathetic control in the spontaneously hypertensive rat (SHR). SHRs (16–18 weeks) had significantly ( p < 0.05) enhanced atrial 3H-norepinephrine ( 3H-NE) release to field stimulation compared to normotensive WKYs. 2-week pravastatin supplementation significantly reduced 3H-NE release to levels observed in the WKY. In-vivo, pravastatin lowered resting heart rate (HR) in the SHR despite not affecting arterial blood pressure or serum cholesterol. In SHR atria/right stellate ganglion preparations, the HR response to stellate stimulation (1, 3, and 5 Hz) was also significantly reduced by pravastatin whilst the HR response to exogenous NE (0.025–5 μmol) remained similar. The nitric oxide synthase (NOS) inhibitor l-NAME (1 mmol/l) increased 3H-NE release by similar amounts in atria from supplemented and non-supplemented SHRs, whilst Western blotting showed no difference in protein levels of nNOS, eNOS, guanylyl cyclase, or the NADPH oxidase subunits Gp91 and P40phox. Pravastatin significantly reduced cardiac ATII levels and angiotensin converting enzyme 1 and 2 expressions whilst protein levels of the ATII receptor (ATR 1) remained unchanged in the SHR. Immunohistochemistry co-localised ATR 1 with tyrosine hydroxylase positive neurons in the stellate ganglion. The ATR 1 antagonist Losartan (5 μmol) equalised release of 3H-NE to comparable levels in supplemented and non-supplemented SHRs. These results suggest 2-week pravastatin treatment reduces cardiac ATII, and prevents its facilitatory effect on NE release thus normalising cardiac sympathetic hyper-responsiveness in SHRs.

          Research Highlights

          ► Pravastatin lowers resting heart rate (HR) in spontaneously hypertensive rats (SHR) ► Cardiac norepinephrine release & tachycardia are reduced by pravastatin in SHRs ► Neuronal NO signalling & NADPH oxidase expression are unchanged by pravastatin ► The effect of pravastatin on sympathetic neurotransmission is reversed by losartan. ► Pravastatin reduces cardiac angiotensin 2 & angiotensin converting enzymes 1 & 2

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          Most cited references35

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          Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.

          Hemodynamics, plasma norepinephrine, and plasma renin activity were measured at supine rest in 106 patients (83 men and 23 women) with moderate to severe congestive heart failure. During follow-up lasting 1 to 62 months, 60 patients died (57 per cent); 47 per cent of the deaths were sudden, and 45 per cent were related to progressive heart failure. Statistically unrelated to the risk of mortality were cause of disease (60 patients had coronary disease, and 46 had cardiomyopathy), age (mean, 54.8 years), cardiac index (mean, 2.11 liters per minute per square meter of body-surface area), pulmonary wedge pressure (mean, 24.5 mm Hg), and mean arterial pressure (mean, 83.2 mm Hg). A multivariate analysis of the five significant univariate prognosticators--heart rate (mean, 84.4 beats per minute), plasma renin activity (mean, 15.4 ng per milliliter per hour), plasma norepinephrine (mean, 700 pg per milliliter), serum sodium (mean, 135.7 mmol per liter), and stroke-work index (mean, 21.0 g-meters per square meter)--found only plasma norepinephrine to be independently (P = 0.002) related to the subsequent risk of mortality. Norepinephrine was also higher in patients who died from progressive heart failure than in those who died suddenly. These data suggest that a single resting venous blood sample showing the plasma norepinephrine concentration provides a better guide to prognosis than other commonly measured indexes of cardiac performance.
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            Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators.

            Experimental evidence suggests that autonomic markers such as heart-rate variability and baroreflex sensitivity (BRS) may contribute to postinfarction risk stratification. There are clinical data to support this concept for heart-rate variability. The main objective of the ATRAMI study was to provide prospective data on the additional and independent prognostic value for cardiac mortality of heart-rate variability and BRS in patients after myocardial infarction in whom left-ventricular ejection fraction (LVEF) and ventricular arrhythmias were known. This multicentre international prospective study enrolled 1284 patients with a recent ( 105 ms, BRS >6.1 ms per mm Hg). The association of low SDNN or BRS with LVEF below 35% carried a relative risk of 6.7 (3.1-14.6) or 8.7 (4.3-17.6), respectively, compared with patients with LVEF above 35% and less compromised SDNN (> or = 70 ms) and BRS (> or = 3 ms per mm Hg). ATRAMI provides clinical evidence that after myocardial infarction the analysis of vagal reflexes has significant prognostic value independently of LVEF and of ventricular arrhythmias and that it significantly adds to the prognostic value of heart-rate variability.
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              Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives.

              Methodological refinements in the assessment of human sympathetic cardiovascular drive have allowed throughout the years to better define the role of the sympathetic nervous system in the pathophysiology of hypertension. Earlier studies have provided evidence that indirect markers of adrenergic drive, such as plasma or urinary norepinephrine as well as heart rate, often display an increase in the hypertensive state. Direct recording of efferent postganglionic muscle sympathetic nerve traffic via microneurography and regional norepinephrine spillover technique have conclusively documented the occurrence of an adrenergic overdrive in hypertension, showing that the sympathetic activation is directly related to the severity of the hypertensive state and is widespread to different cardiovascular districts. The present review will focus on some major features of the "neuroadrenergic hypothesis of hypertension." In particular it will examine the mechanisms responsible for the adrenergic overdrive, the relationships between the sympathetic activation and the metabolic disarray of frequent detection in the hypertensive state, and the participation of neuroadrenergic factors at the development of the hypertension-related target organ damage. Further issues addressed will be the contribution of the hyperadrenergic state to the different patterns of the 24-hour blood pressure profile as well as to the day/night blood pressure variability described in the hypertensive state and the behavior of the sympathetic function in the hypertensive states complicated by the presence of other cardiovascular or metabolic disease. Finally, the clinical and therapeutic implications of the neuroadrenergic abnormalities occurring in hypertension, as well as the areas worthy of future research, will be highlighted.
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                Author and article information

                Contributors
                Journal
                J Mol Cell Cardiol
                J. Mol. Cell. Cardiol
                Journal of Molecular and Cellular Cardiology
                Academic Press
                0022-2828
                1095-8584
                January 2011
                January 2011
                : 50
                : 1
                : 99-106
                Affiliations
                Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, OX1 3PT, UK
                Author notes
                [* ]Corresponding author. Tel.: +44 1865 272518. neilherring@ 123456doctors.org.uk
                [1]

                These authors contributed equally to the paper.

                Article
                YJMCC6920
                10.1016/j.yjmcc.2010.09.025
                3020274
                20933519
                fd5858a3-73aa-45e7-8c79-5ff7b54cf8c4
                © 2011 Elsevier Ltd.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 1 April 2010
                : 25 August 2010
                : 29 September 2010
                Categories
                Original Article

                Cardiovascular Medicine
                hypertension,statins,autonomic nervous system,angiotensin,nitric oxide
                Cardiovascular Medicine
                hypertension, statins, autonomic nervous system, angiotensin, nitric oxide

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