The PPARβ agonist GW0742 improves endothelial- and cAMP-dependent relaxation in coronary arteries from type 1 diabetic rats

B Barreira1,3, L Moreno1,3, J Moral-Sanz1,3, E Moreno1,3, R Jimenez2, J Duarte2, F Perez-Vizcaino1,3, A Cogolludo1,2. 1Universidad Complutense Madrid, Pharmacology, Spain, 2Universidad de Granada, Pharmacology, Spain, 3Ciber Enfermedades Respiratorias, 28040, Spain

Activation of peroxisome proliferator-activated receptor β (PPARβ) exerts protective effects on obesity, insulin sensitivity and metabolic syndrome. We have found that the PPARβ agonist GW0742 reduces endothelial dysfunction in aortae from spontaneously hypertensive rats (Zarzuelo et al., 2011). Moreover, GW0742 improves the altered relaxation induced by the cAMP pathway in coronary arteries (CA) following short term exposure to high glucose (Moreno et al., 2012). The objective of the present study was to study the possible protective role of GW0742 on the endothelial-dependent and cAMP-dependent relaxations in CA from type 1 diabetic rats.

Male Wistar rats (270-315 g) were randomized to three experimental groups: control, diabetic and GW0742-treated diabetic. Diabetes was induced by a single intraperitoneal injection of streptozotocin (70 mg kg-1) and confirmed after three days. Animals were treated by gavage with vehicle (1 ml of 1% methylcellulose) or GW0742 (5 mg kg-1 per day, mixed in 1 ml of 1% methylcellulose) during 5 weeks. At the end of the treatment plasma insulin levels were measured. Rats were killed by cervical dislocation and the left main CA (250-400 μm internal diameter) were isolated. Vascular reactivity was assessed using isometric wire myographs. Statistical analysis for multiple comparisons was carried out by one-way analysis of variance followed by Dunnett’s posttest, a probability level of P<0.05 being regarded as significant.

The relaxant response induced by acetylcholine (Ach, 10-9 - 10-6 M) and the adenylate cyclase activator forskolin (3x10-9 - 3x10-7 M) was tested in arteries pretreated with serotonin (10-6 M). Maximal Ach-induced relaxation was reduced in diabetic vs control CA (44 ± 13% vs 101 ± 13% relaxation; n = 6-7, p<0.01), whereas treatment with GW0742 prevented this endothelial dysfunction (89 ± 4% relaxation; n = 6 p>0.05 vs control). Similarly, the relaxation induced by forskolin (3x10-7 M) was reduced in CA from diabetic (60 ± 16%; n = 4) as compared to control (119 ± 14%; n = 5; P<0.05) or GW0742-treated diabetic (118 ± 15%; n = 6; P<0.05) rats. In control rats, the relaxation induced by forskolin was not affected by the ATP-dependent K+ channel blocker glibenclamide (10-6 M; 119 ± 19%; n = 3) but attenuated by the Kv1 channel blocker DPO-1 (10-6 M). Thus, in the presence of this drug the relaxant responses induced by forskolin (3x10-7 M) were comparable in CA from control, diabetic and GW0742-treated diabetic (58 ± 7%, 51 ± 14% and 43 ± 14%, respectively; n = 3-5; P>0.05) rats. Finally, plasma insulin levels were similar in the GW0742-treated diabetic versus the diabetic group (1.07 ± 0.1 and 1.02 ± 0.09 ng/ml, respectively; n = 4).

In conclusion, activation of PPARβ prevents the reduced endothelial- and cAMP-dependent relaxation in CA from type 1 diabetic rats. This improvement is associated with the restoration of the Kv1 channel function.

Zarzuelo MJ et al., (2011). Hypertension 58:733-43.

Moreno L, et al., (2012). Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol9Issue3abst123P.

Supported by SAF2010-22066