2-furoyl-ligrlo-amide and Metabolic-Syndrome

Topics: Aging; Animals; Aorta; Cyclic GMP; Disease Models, Animal; Down-Regulation; Endothelium, Vascular; Gene Expression; Male; Metabolic Syndrome; Nitric Oxide; Nitroprusside; Oligopeptides; Oxidative Stress; Rats; Rats, Inbred Strains; Receptor, PAR-2; RNA, Messenger; Thiobarbituric Acid Reactive Substances; Thionucleotides; Trypsin; Vasodilation; Vasodilator Agents

Endothelium-dependent vasodilation via protease-activated receptor 2 (PAR2) is preserved in mesenteric arteries from SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome even though nitric oxide (NO)-mediated vasodilation is attenuated. Therefore, we examined the PAR2 mechanisms underlying metabolic syndrome-resistant vasodilation in SHRSP.ZF aortas with ageing. In isolated aortas, the PAR2 agonist 2-furoyl-LIGRLO-amide (2fly) caused vasodilation that was sustained in male SHRSP.ZF until 18 weeks of age, but was attenuated afterwards compared with age-matched Wistar-Kyoto rats (controls) at 23 weeks. In contrast, acetylcholine-induced vasodilation was impaired in SHRSP.ZF already at 18 weeks of age. Treatments of aortas with inhibitors of NO synthase and soluble guanylate cyclase abolished the sustained 2fly- and residual acetylcholine-induced vasodilation in SHRSP.ZF at 18 weeks of age. In the aortas of SHRSP.ZF, 8-bromo-cGMP-induced vasodilation, NO production and cGMP accumulation elicited by 2fly were not different from in the controls. PAR2 agonist increased phospho-Ser1177-eNOS protein content only in SHRSP.ZF aortas. These results indicate that vasodilation mediated by PAR2 is sustained even though NO-dependent relaxation is attenuated with ageing/exposure to metabolic disorders in large-caliber arteries from SHRSP.ZF. PAR2 stimulation of NO production via an additional pathway that targets phosphorylation of Ser1177-eNOS suggests a regulatory mechanism for sustaining agonist-mediated vasodilation in metabolic syndrome.

Topics: Acetylcholine; Age Factors; Animals; Aorta, Thoracic; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Male; Metabolic Syndrome; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroprusside; Oligopeptides; Phosphorylation; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, PAR-2; Signal Transduction; Vasodilation; Vasodilator Agents

Protease-activated receptor-2 (PAR2) activation causes vascular inflammation and vasodilation, but its role in metabolic syndrome (MetS) remains uncertain. Therefore, we examined whether the PAR2-induced vasodilation of SHRSP.Z-Lepr(fa)/IzmDmcr rats (SHRSP.ZF) is impaired and if so, whether administering telmisartan is protective. PAR2-activating peptide, 2-furoyl-LIGRLO-amide (2fly), relaxed the isolated superior and first-order branches of mesenteric arteries (MAs) from Wistar-Kyoto rats (WKY) and SHRSP.ZF. Superior-MA relaxation by 2fly was less in SHRSP.ZF than in WKY. Relaxation of first-order MAs by 2fly was the same in SHRSP.ZF and WKY. NO synthase inhibitor partially reduced 2fly-induced relaxation of superior and first-order MAs in SHRSP.ZF and WKY; inhibition of relaxation was proportionately larger in SHRSP.ZF. In SHRSP.ZF, nitroprusside-induced relaxation and the expression of soluble guanylyl cyclase decreased. In SHRSP.ZF, telmisartan reversed these abnormalities, and decreased blood pressure and serum levels of thiobarbituric acid reactive substances, an index of oxidative stress. Vasodilation via PAR2 activation was preserved in small-caliber MAs, in contrast to large-caliber MAs, even when MetS reduced NO-dependent relaxation mechanisms. NO and non-NO relaxing factor(s) contributed to PAR2-mediated relaxation in MAs, and the balance between factors may be altered to preserve vasodilation in MetS. Telmisartan prevented vascular dysfunction in MetS by protecting arteries against oxidative stress.

Topics: Animals; Benzimidazoles; Benzoates; Blood Pressure; Disease Models, Animal; Guanylate Cyclase; Male; Mesenteric Arteries; Metabolic Syndrome; Nitric Oxide; Nitroprusside; Oligopeptides; Oxidative Stress; Rats; Rats, Inbred WKY; Receptor, PAR-2; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Telmisartan; Thiobarbituric Acid Reactive Substances; Vasodilation