Pioglitazone alters the participation of cCyclooxygenase-2 produts and reactive oxygen species on vascular reactivity of hypertensive rats

Abstract

The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) is expressed in all major vascular cells, where it may play an important role in vascular disease. Thus, the PPARgamma agonists, glitazones, exert depressor action in both hypertensive subjects and various animal models, improve endothelium-dependent vasodilation, and reduce vascular contractility in response to various vasoconstrictors. In addition, glitazones have anti-inflammatory actions associated to interference with redox-sensitive transcription factors, such as NF-kappaB, involved in the transcription of several genes including COX-2. Objetive: To analyze the effect of chronic pioglitazone treatment on the vascular reactivity of mesenteric resistance arteries from spontaneously hypertensive (SHR) rats to phenylephrine as well as the role of prostanoids and reactive oxygen species in such effect. Methods: Mesenteric resistance arteries from 6- month old SHR rats untreated or treated with the PPARgamma activator pioglitazone (2.5 mg/Kg/day for 28 days) were used. Vascular reactivity was studied with wire myography and protein expression by western blot. Results: Pioglitazone did not lower blood pressure of SHR (control: 198.9±3.3; pioglitazone: 200±5.2 mmHg; P>0.05). Concentration-response curve to phenylephrine (0.1-30 microM) was similar in segments from untreated and pioglitazone-treated rats. Indomethacin (10 microM), the selective COX-2 inhibitor, NS 398 (1 microM), the TxA2 receptor antagonist, SQ 29,548 (1 microM) and the EP1 receptor antagonist, SC 19220 (10 µM) reduced the response to phenylephrine only in segments from treated rats, while the TxA2 synthase inhibitor, furegrelate (1 µM) did not modify this response in both treated and untreated rats. In addition, COX-2 expression was higher in mesenteric arteries from treated than untreated rats. Pioglitazone treatment abolished the inhibitory effect of the respective inhibitors of NADPH oxidase and xanthine oxidase inhibitor, apocynin (0.3 mM) and allopurinol (0.3 mM) on vasoconstrictor response to phenylephrine, and reduced the vascular levels of Cu/Zn- and Mn-SOD. On the other hand, the NO synthase inhibitor L-NAME (0.1 mM) potentiated the response to phenylephrine in segments from both untreated and treated rats. Conclusions: Chronic pioglitazone treatment of hypertensive rats increases mesenteric COX-2 expression, associated with increased participation of contractile prostanoids from COX-2 in vasoconstrictor responses to phenylephrine. On the other hand, the observed reduction of involvement of NADPH oxidase and xantine oxidase-derived reactive oxygen species in the contraction elicited by phenylephrine can explain the similar vasoconstrictor response to this agonist found in resistance arteries. In spite of this, the treatment reduced the expression of cytosolic and mitochondrial SOD; if pioglitazone regulates reactive oxygen species production needs to be elucidated