Mechanism of Fatty Acids Induced Suppression of Cardiovascular Reflexes in Rats

Abstract

A blunted baroreflex sensitivity (BRS), impaired heart rate variability (HRV), and high plasma nonesterified fatty acids (NEFA) are predictors of adverse cardiovascular outcomes. We tested the hypothesis that elevation of NEFA negatively impacts the cardiac baroreflex response and undertook spectral analyses and molecular studies to delineate the mechanism of action. We used two interventions to elevate serum NEFA: 1) overnight fasting (n ϭ 7) and 2) i.v. infusion of 1.2 ml/kg intralipid 20% ϩ heparin (I/H) over 10 min (n ϭ 9) in conscious unrestrained male rats. Elevated NEFA caused by fasting complemented by I/H infusion were associated with a concentration-dependent reduction in spontaneous BRS measured by spectral analysis [low-frequency ␣ and high-frequency ␣ (HF␣) indices] and sequence method and HRV measured by frequency domain as power of RR interval (RRI) spectra (low-frequency RRI and high-frequency RRI) and by time domain as standard deviation of beat-to-beat interval and root mean square of successive differences along with increase in blood pressure variability measured as standard deviation of mean arterial pressure and power of systolic arterial pressure spectra (low-frequency systolic arterial pressure). Because elevated NEFA suppressed the vagal component of the baroreflex response (HF␣), we tested the hypothesis that NEFA-evoked sequestration of myocardial muscarinic receptor (M2-mAChR) contributes to the reduced BRS. High NEFA level was accompanied by increased caveolar sequestration of cardiac M2-mAChRs without changing M2-mAChR protein expression. We report the first detailed analyses of NEFA's effect on the cardiac baroreflex and show that increased caveolar sequestration of cardiac M2-mAChRs constitutes a cellular mechanism for elevated NEFA-related deleterious cardiovascular outcomes.Sympathetic overactivity and depression of cardiac vagal function contribute to baroreflex dysfunction and may predispose to hypertension (Ketch et al., 2002), and these neural and hemodynamic abnormalities are associated with lifethreatening cardiac arrhythmias and sudden death (Hennersdorf and Strauer, 2001). Fluctuations in blood pressure (BP) and heart rate (HR) reflect the dynamic interplay of diverse physiological processes (Akselrod et al., 1985) and are acceptable measures for cardiovascular autonomic balance. Increased HR variability (HRV) and BP variability (BPV) and reduced HRV are predictors for mortality (Stein et al., 1994;Lombardi et al., 1996; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996;Palatini and Julius, 1997;Malliani and Montano, 2002). Spectral analysis of arterial BP and HR has provided new insight into the autonomic vascular and cardiac regulation (Cerutti et al., 1994). Analysis of BPV and HRV by the spectral approach, as well as by time domain techniques, represents a useful tool for the study of the mechanisms involved in cardiovascular regulation in both normal and diseased conditions (Parati et al., 1...

Mild chronic hypoxemia modifies expression of brain stem angiotensin peptide receptors and reflex responses in fetal sheep

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Role of Myocardial Contractility and Autonomic Control in the Hypotensive Response to a Limited Access Ethanol Paradigm in SHRs

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Acute elevation of plasma non-esterified fatty acids increases pulse wave velocity and induces peripheral vasodilation in humans in vivo

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