Endothelium-dependent vasodilator effects of the PPAR β/δ agonist L-165041 in rat isolated aorta

Rosario Jimenez1, Manuel Sanchez1, Maria Jose Zarzuelo1, Miguel Romero1, Rocio Lopez-Sepulveda1, Francisco Perez-Vizcaino2, Juan Duarte1
1Universidad de Granada, Granada, Spain, 2Universidad Complutense de Madrid, Madrid, Spain

Peroxisome proliferator-activated receptor β/δ (PPAR β/δ) is a ligand-activated transcription factor that regulates at the transcriptional level the function of many target genes. PPAR β/δ agonists also inhibit platelet activation and aggregation acutely via a nongenomic mechanism (Ali et al., 2006). However, the acute effects of PPAR β/δ agonists in vascular tone have not yet been explored. In the present study, we have investigated the ability of a PPAR β/δ agonist L-165041 to relax aortic rings from male Wistar rats (250-300 g). The descending thoracic aorta was rapidly dissected, cut into rings and mounted in a conventional organ bath containing Krebs solution (composition in mmol/L: NaCl 118, KCl 4.75, NaHCO3 25, MgSO4 1.2, CaCl 2 2, KH 2PO4 1.2 and glucose 11) as previously described (Jimenez et al., 1999). Cumulative addition of the PPAR β/δ agonist L-165041 (10-7-10-5M) induced vascular relaxation in phenylephrine (10-7 M)-pre-contracted intact aortic rings (-log EC50 = 5.10±0.11, n=12), which was significantly (p<0.01, Students’ t test) reduced by both endothelial denudation and nitric oxide synthase (NOS) inhibition with NG-Nitro-L-Arginine methylester (L-NAME, 100 μM) (Figure 1A). This effect reached steady-state within approx. 15 min. The relaxation induced by L-165041 in aortic rings with functional endothelium pre-contracted with the thromboxane A2 analogue U-46619 (10-6 M) was significantly (p<0.01) reduced by removal of extracellular calcium and incubation with the intracellular calcium chelator BAPTA/AM (10-5M, Figure 1B). A time control experience was performed and tone was not lost. Moreover, the phosphatidyl-inositol (PI)-3 kinase inhibitor wortmannin (10-5 M) also inhibited the relaxant response (Figure 1B). In conclusion, the PPAR β/δ agonist L-165041 acutely caused vasodilation which was partially independent of endothelial-derived NO. Endothelial NOS activation seems to be related to both an increase in intracellular calcium and PI3-kinase phosphorylation.

Figure 1. Effects of L-165041 (mean ± sem) in rat isolated aorta with (+E) or without (-E) endothelium.

Ali, F.Y. et al. (2006) FASEB J., 20, 326-328.
Jimenez, R. et al. (1999) Br. J. Pharmacol., 127, 1539-1544.