Endocrine Abstracts (2002) 3 OC29

Deleterious effect of non-esterified free fatty acids (NEFAs) on resistance artery endothelial function

CAR Sainsbury1,2,3, C Hillier3, N Sattar2, JR Petrie2 & JMC Connell1

1Department of Medicine and Therapeutics, Western Infirmary, Glasgow, UK; 2University Department of Medicine, Glasgow Royal Infirmary, Glasgow, UK; 3Department of Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK.

Elevated circulating concentrations of non-esterified free fatty acids (NEFAs) are observed in states of insulin resistance and may be associated with increased cardiovascular risk. We hypothesised that NEFAs directly impair endothelial NO bioavailability via increased oxidative stress, in addition to their proposed indirect effect via VLDL. The study was designed to investigate the effect of monounsaturated and saturated fatty acids on endothelium-dependent and -independent vascular relaxation. In addition, we investigated the effect of co-incubation of physiological concentrations of the antioxidant ascorbic acid. Third order mesenteric arteries were dissected from male 12-week old Wistar rats. Arteries were mounted on a wire myograph and a standard normalisation and start-up protocol was followed. Vessels were pre-incubated for 40 minutes with: 1) oleic acid [1.75x10-4M]; 2) palmitic acid [10-4M]; or, 3) vehicle (ethanol maximum concentration 0.5% in bath).

Vessels were preconstricted with 3x10-7M U-46619 (thromboxane A2 mimetic). Cumulative concentrationresponse curves were generated with carbachol [10-9M] to [10-5M] and S-nitroso-N-acetyl-penicillamine (SNAP) [10-9M] to [10-5M]. Dose response curves to carbachol were repeated following coincubation with palmitic acid [10-4M] and ascorbic acid [10-5M].

Incubation with palmitic acid [10-4M] and oleic acid [1.75x10-7M] impaired endothelium-dependent relaxation significantly (p=<0.05, paired t-test comparison of pD2 values) vs control vessels. No effect was noted upon endothelium-independent relaxation. Incubation with ethanol (vehicle) had no such effects.

Impairment of endothelium-dependent relaxation by palmitic acid was reversed following co-incubation with ascorbic acid at [10-5M] (p=ns).

At physiological concentrations, endothelial NO bioavailability is impaired following incubation with both palmitic acid (saturated) and oleic acid (monounsaturated). The impaired response with palmitic acid is abolished following co-incubation with the antioxidant ascorbic acid at physiological concentrations.

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