Cholesterol-independent endothelial dysfunction in virgin and pregnant rats fed a diet high in saturated fat

Abstract

1. Western diets high in saturated fat are associated with an increased incidence of cardiovascular diseases. In this study we have evaluated vascular endothelial function and oxidative stress in virgin rats fed a normal (VC) or high in saturated fat diet (VHF) (20 % lard and corn oil w/w) from weaning until adulthood, and throughout subsequent pregnancy (PC and PHF, respectively). 2. The saturated fat diet was associated with enhanced noradrenaline sensitivity in small mesenteric arteries from VHF rats (VHF vs. VC, P < 0.05) and blunted endothelium-dependent relaxation in VHF and PHF rats (VHF vs. VC, P < 0.001; PHF vs. PC, P < 0.05). Endothelial dysfunction was attributable to a reduced nitric oxide component of relaxation in VHF rats, and blunted prostacyclin and endothelium-derived hyperpolarizing factor components in PHF rats. 3. Other than plasma cholesterol, which was reduced in VHF and PHF rats, plasma lipids were normal. Fasting plasma insulin and glucose concentrations were raised in VHF rats (P < 0.05) and the plasma marker of oxidative stress, 8-iso PGF2alpha, was increased in PHF animals (P < 0.01). 4. These findings suggest that endothelial dysfunction induced by a saturated fat diet is cholesterol independent and likely to be of different mechanistic origin in virgin and pregnant rats.

Figure 1. Growth curves

Growth curves for female virgin rats fed a control (○; n = 21) or saturated fat diet (•; n = 23) from 7 until 98 days of age. Values are given as means ±s.e.m.*P < 0.05.

Figure 2. Concentration-response curves to noradrenaline in mesenteric small arteries

A, virgin rats fed a control (○; n = 10) or saturated fat diet (•; n = 10); B, pregnant rats fed a control (□; n = 9) or saturated fat diet (▪; n = 9). Values are given as means ±s.e.m. pEC₅₀: *P < 0.05.

Figure 3. Concentration-response curves to acetylcholine in mesenteric small arteries from virgin rats fed a control (○; n = 10) or saturated fat diet (•; n = 10)

A, without inhibitors. B, in the presence of 10 μm indomethacin. C, in the presence of 100 μm L-NAME, 10 μm indomethacin and 1 μm ODQ and also with the same inhibitors but in the presence of depolarizing 25 mM KCl to obviate the effects of endothelium-derived hyperpolarizing factor (EDHF) (▵, control diet; ▴, saturated fat diet). Values are given as means ±s.e.m. pEC₅₀: ***P < 0.001.

Figure 4. Plasma concentrations of 8-iso PGF_2α and PGF_2α

Plasma concentrations (pg (ml plasma)⁻¹) of 8-iso PGF_2α (A) and PGF_2α (B) from virgin (VC; n = 18) and pregnant (PC; n = 10) rats fed the control diet and virgin (VHF; n = 20) and pregnant (PHF; n = 10) rats fed the saturated fat diet. Values are given as means ±s.e.m.A:**P < 0.01, PHF vs. PC and ***P < 0.001, VHF vs. PHF; B:**P < 0.01, PC vs. VC and ***P < 0.001, PHF vs. VHF.

Figure 5. Concentration-response curves to acetylcholine in mesenteric small arteries from pregnant rats fed a control (□; n = 9) or saturated fat diet (▪; n = 9)

A, without inhibitors. B, in the presence of 10 μm indomethacin. C, in the presence of 100 μm L-NAME, 10 μm indomethacin and 1 μm ODQ and with the same inhibitors but in the presence of depolarizing 25 mM KCl to obviate the effects of EDHF (▿, control diet; ▾, saturated fat diet). Values are given as means ±s.e.m. Maximum relaxation: *P < 0.05.