Received for publication March 14, 2005.
Revised June 1, 2005.
Accepted for publication June 1, 2005.

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 non-esterified fatty acids (NEFAs) are predictors of adverse cardiovascular outcomes. We tested the hypothesis that elevation of NEFAs negatively impacts the cardiac baroreflex response and undertook spectral analyses and molecular studies to delineate the mechanism of action. We employed two interventions to elevate serum NEFAs: (1) overnight fasting (n=7) and (2) i.v. infusion of 1.2 ml/Kg intralipid 20% + heparin (I/H) over 10 min (n=9) in conscious unrestrained male rats. Elevated NEFAs caused by fasting complemented by I/H infusion was associated with a concentration-dependent reduction in spontaneous BRS measured by spectral analysis (LF, HF indices) and sequence method (seq-BRS) and HRV measured by frequency domain as power of RRI spectra (LF_RRI and HF_RRI) and by time domain as standard deviation of beat-to-beat interval (SDRR) and root mean square of successive differences (rMSSD) along with increase in blood pressure variability (BPV) measured as standard deviation of mean arterial pressure (SD-MAP) and power of systolic arterial pressure spectra (LF_SAP). Because elevated NEFAs suppressed the vagal component of the baroreflex response (HF), we tested the hypothesis that NEFA-evoked sequestration of myocardial muscarinic receptor (m2-mAChRs) contribute to the reduced BRS. High NEFAs level was accompanied by increased caveolar sequestration of cardiac m2-mAChRs without changing m2-mAChRs protein expression. We report the first detailed analyses of NEFAs effect on the cardiac baroreflex and show that increased caveolar sequestration of cardiac m2-mAChRs constitutes a cellular mechanism for elevated NEFAs related deleterious cardiovascular outcomes.

Key words: Baroreflex sensitivity, Blood pressure variability, Heart rate variability, Intralipid, Muscarinic receptor, Nonesterified fatty acids