Fenofibrate and Pioglitazone Do Not Ameliorate the Altered Vascular Reactivity in Aorta of Isoproterenol-treated Rats

Abstract

Chronic stimulation of beta-adrenoceptors with isoproterenol induces alteration of vascular reactivity and increases local pro-inflammatory cytokines. We investigated whether fenofibrate and pioglitazone, PPAR-alpha and -gamma agonists, respectively, improve the changes in vascular reactivity induced by isoproterenol. Wistar rats received isoproterenol (0.3 mg x kg x day, SC) or vehicle (CT) plus fenofibrate (alpha, 100 mg x kg x day, PO), pioglitazone (gamma, 2.5 mg.kg.day, PO), or water for 7 days. In aortas, isoproterenol treatment enhanced the maximal response (Rmax) to phenylephrine (10 to 10 M) compared to CT as previously demonstrated. The effects of endothelium removal (E-) or L-NAME incubation (100 microM) on the phenylephrine response were smaller in isoproterenol-treated animals compared to CT while superoxide dismutase (SOD, 150 U/mL) significantly reduced the Rmax to phenylephrine to CT levels. Neither fenofibrate nor pioglitazone changed the effects induced by isoproterenol in aorta. E-, L-NAME, or SOD effects were similar between CTalpha and CT. However, pioglitazone per se increased Rmax to phenylephrine (CT: 59 +/- 4 versus CTgamma: 72 +/- 5 % of contraction to KCl). E- or L-NAME effects were reduced in CTgamma compared to CT, and SOD normalized the altered reactivity to phenylephrine in the CTgamma group. In conclusion, neither fenofibrate nor pioglitazone ameliorates the altered vascular reactivity present in aorta from isoproterenol-treated rats. Moreover, pioglitazone per se induced endothelial dysfunction and increased phenylephrine-induced contraction in aorta.

Isoproterenol Induces Vascular Oxidative Stress and Endothelial Dysfunction via a Giα-Coupled β2-Adrenoceptor Signaling Pathway

“…Together, these results reinforce our previous studies [7], [8], [26], suggesting that ISO treatment induces changes in vascular reactivity to phenylephrine that are associated with oxidative stress. Furthermore, we add new data that these adjustments seem to be dependent of the presence of functional vascular β 2 -AR.…”

“…However, little is known about the mechanisms associated with the effects of long-term β-AR activation in vascular cells. Previous studies suggested that ISO-induced β-AR overactivation leads to alterations in vascular tone depending on the vessel type [8], [9], [26], [29], [30]. In murine aortas, ISO treatment enhances the contractile response to the α 1 -adrenoceptor agonist phenylephrine and is associated with elevated ROS generation and impaired NO bioavailability [8], [30].…”

Pioglitazone treatment increases COX‐2‐derived prostacyclin production and reduces oxidative stress in hypertensive rats: role in vascular function

“…In MRA from SHR, pioglitazone treatment slightly improved the impaired ACh‐induced vasodilatation. Moreover, the phenylephrine contraction was similar in MRA from WKY and SHR, and remained unmodified after pioglitazone treatment; this result, which agrees with that found in isoprenaline‐treated rats (Fukuda et al ., 2008), apparently excludes an effect of the glitazone on vasoconstrictor responses.…”

Endothelial dysfunction in cardiovascular and endocrine-metabolic diseases: an update

“…The administration of isoproterenol, a non-selective β-adrenoceptor agonist, to laboratory animals for several days is used as a model of prolonged β-adrenoceptor stimulation. In the vasculature of these animals, we demonstrated that isoproterenol treatment increases the vasoconstrictor response to the α 1 -adrenoceptor agonist phenylephrine as well as to the serotonin (5-HT) agonist in rat (31) and mouse ( Figure 3A) aorta, although no changes in acetylcholine-induced relaxation were observed (31,32). In addition, endothelial removal and L-NAME incubation normalized the hyperreactivity to phenylephrine observed in aortas from isoproterenol-treated rats, indicating that persistent activation of β-adrenoceptors impairs basal endothelial-derived NO (31,32).…”