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© Copyright 2004 The British Pharmacological Society

069P GKT, University of London
Winter Meeting December 2003

Temporal evolution of the renal endothelial dysfunction in hypercholesterolemic LDLR/- hAPOB+/+ mice
Marie-Eve Gendron, Louis P. Perrault, Eric Thorin. Montreal Heart Institute, Faculty of Medecine, Department of Surgery, Montreal, Quebec, Canada.

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Gendron M
Perrault LP
Thorin E

Vascular endothelial dysfunction (ED) represents an early marker of atherosclerosis in patients with cardiovascular risk factors such as hypercholesterolemia (HC). Similar ED has been reported to occur later in life during the healthy ageing process. Altered production in endothelium-derived relaxant factors (EDRF), namely nitric oxide (NO), the hyperpolarizing factor (EDHF) and prostacyclin (PGI2), could be involved in this ED. It is not known, however, which EDRF is targeted by HC. The aim of this study was to investigate the temporal evolution of the endothelial function in HC mice and the involvement of NO and PGI2 in this process.

To investigate the impact of HC on EDRF-dependent dilation of renal arteries induced by acetylcholine (ACh), young (3 month old; n=6, 32±1g), mature (6 m/o; n=6, 42±1g) and old (12-14 m/o; n=6, 51±2g) male mice lacking the expression of the LDL receptor (LDLR-/-) and over-expressing the human ApoB-100 (hApoB+/+) were used. These mice are HC and develop atherosclerotic lesions at 6 m/o (Sanan et al., 1998). Renal arteries were isolated and pressurised to 100 mm Hg in an arteriograph. Arteries were studied in no-flow condition and bathed at 37°C in oxygenated (12% O2, 5% CO2, 83% N2), pH 7.4 physiological salt solution. Endothelium-dependent dilations to ACh (1 nM- 30 µM) were obtained in vessels pre-contracted with phenylephrine (30 µM). Blockade of PGI2 and NO production was obtained by using indomethacin (indo, 10 µM) and L-NNA (10 µM). Values are mean ± SEM.

Table 1. Potency (pD2) and efficacy (Emax, diameter in %) of ACh in LDLR-/-; hApoB+/+ mice of 3, 6 and 12 m/o.

3 m/o
6 m/o
12 m/o
pD2
Emax
pD2
Emax
pD2
Emax
Control
6.4±0.2
93±4
6.2±0.1
61±102
5.7±0.22
64±122
+ indo
6.2±0.2
85±6
6.6±0.4
55±132
5.9±0.33
29±131,2
+ indo
+5.8±0.1
79±6
6.1±0.2
54±9
5.6±0.2
63±124
L-NNA

1: P<0.05 vs Control; 2: P<0.05 vs 3 m/o; 3: P<0.05 vs 6 m/o; 4: P<0.05 vs with indo (ANOVA, Fisher's F test).

In 3 m/o mice, ACh induced a maximal dilation via an indo- and L-NNA-insensitive factor, likely to be EDHF (Table 1). With maturation, only the efficacy of ACh was reduced (P<0.05) and remained insensitive to indo and L-NNA. With ageing (>12 m/o mice), vascular sensitivity to ACh decreased (P<0.05), whereas Emax was unchanged compared with 6 m/o mice. In the presence of indo, however, the maximal dilation to ACh was strongly reduced (P<0.05) but restored by L-NNA.

In renal arteries of HC mice, maturation decreased the efficacy of EDHF. It is followed by a reduction in the potency of ACh in ageing. However, both EDHF and the compensatory indo-sensitive factor, possibly PGI2, prevent further decrease in efficacy. Our data also suggest that basal NO reduces the efficacy of ACh in ageing, possibly by preventing EDHF release as previously reported (Thorin et al., 1998).

Sanan et al. (1998). Proc Natl Acad Sci USA, 95, 4544-4549.
Thorin et al. (1998). Circ Res, 82, 1323-1329.