Mechanism of fatty acids induced suppression of cardiovascular reflexes in rats.
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 = 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 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 alpha and high-frequency alpha (HFalpha) 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 (HFalpha), 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.
Shaltout
Hossam A
HA
Department of Pharmacology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA.
Abdel-Rahman
Abdel A
AA
D000818:Animals; D017704:Baroreflex; D001794:Blood Pressure; D005215:Fasting / Q000097:blood; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000502:physiology*; D006339:Heart Rate; D006493:Heparin / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000502:physiology
D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D043585:Receptor, Muscarinic M2; D006493:Heparin