Decreased bioavailability of nitric oxide in aorta from ovariectomized senescent mice. Role of cyclooxygenase

• Published in: Experimental gerontology 2016-04, Vol.76, p.1-8
• Main Authors: Vidal-Gómez, Xavier, Novella, Susana, Pérez-Monzó, Isabel, Garabito, Manel, Dantas, Ana Paula, Segarra, Gloria, Hermenegildo, Carlos, Medina, Pascual
• Format: Article
• Language: English
• Subjects: Age Factors; Aging; Aging - metabolism; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - enzymology; Cyclooxygenase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Activation; Estradiol - pharmacology; Estrogen; Estrogen Replacement Therapy; Experimental menopause; Female; Menopause - metabolism; Mice; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Ovariectomy; Oxidative Stress; Prostaglandin-Endoperoxide Synthases - metabolism; Prostanoids; Receptors, Thromboxane - agonists; Receptors, Thromboxane - metabolism; Senescence-accelerated mice; Signal Transduction; Superoxides - metabolism; Thromboxane A2 - pharmacology; Vascular reactivity; Vasoconstriction - drug effects; Vasoconstrictor Agents - pharmacology
• ISSN: 0531-5565; 1873-6815
• DOI: 10.1016/j.exger.2016.01.006

This study investigates the effects of aging and/or ovariectomy on vascular reactivity to thromboxane A2 (TXA2) receptor stimulation with U46619, and the modulation by nitric oxide (NO) and cyclooxygenase (COX) in aorta from female senescence-accelerated mice (SAMP8) and from senescence resistant mice (SAMR1). Five-month-old female SAMR1 and SAMP8 were divided into three groups: sham-operated, ovariectomized and ovariectomized plus estradiol. Twenty-eight days after surgery, thoracic aortic rings were mounted for isometric recording of tension and concentration–response curves for U46619 (10−10–3×10−7M) were performed in the absence and in the presence of the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME, 10−4M) and/or COX inhibitor indomethacin (10−5M). Vascular superoxide production was detected by dihydroethidium staining on sections of thoracic aorta. NO bioavailability in response to U46619 was suppressed by estrogen withdrawn in young and senescent mice and was restored by the administration of estradiol. In the presence of indomethacin, contractions to U46619 decreased in all groups indicating an aging- and estrogen-dependent modulation of contractile prostanoids. The simultaneous incubation of L-NAME and indomethacin did not change the maximal responses and sensitivities to TXA2 in any group in comparison with untreated aortic segments. The superoxide generation induced by TXA2 was greater in aorta from SAMP8 than in SAMR1. Moreover, in ovariectomized groups superoxide production was further increased and treatment with 17β-estradiol reverted the effects of the ovariectomy. Inhibition of COX with indomethacin prevented the U46619-induced increase in superoxide formation. Our results indicate that NO bioavailability in response to TP receptor activation is both estrogen- and aging-dependent. TXA2 induced contractions are partially mediated by COX activation. Both aging and ovariectomy enhanced COX-dependent component of the TXA2-induced contraction. It is noteworthy that in the absence of estrogen, COX inhibition induces an increase of NO bioavailability. Therefore, in senescent female mice with an experimental menopause, TP-receptor stimulation is responsible for COX activation and enhanced superoxide generation, which may result in reduced NO bioavailability. These effects were reversed by estrogen administration. •NO induced by TP receptor activation is reduced by aging and estrogen deficiency.•COX modulates TXA2 contractions and