Endothelial Nitric Oxide Synthase-Independent Release of Nitric Oxide in the Aorta of the Spontaneously Hypertensive Rat

Abstract

In the aorta of male spontaneously hypertensive rats (SHR), but not in that of normotensive Wistar-Kyoto rats (WKY), contractions to phenylephrine obtained in the presence of L-NAME [inhibitor of nitric oxide synthase (NOS)] and indomethacin (inhibitor of cyclooxygenase) are inhibited by an unknown endothelium-derived factor. The present study aimed to identify the mechanism underlying this endothelium-dependent inhibition in the SHR aorta. Aortic rings of male SHR and WKY, with and without endothelium, were suspended in organ chambers in the presence of indomethacin and L-NAME for the measurement of isometric tension. Contractions to phenylephrine were smaller in SHR aortae with endothelium than in those without, but were similar in the two types of preparations of WKY aortae.The endothelium-dependent, NOS-independent inhibition of phenylephrine-induced contraction was abolished by oxyhemoglobin [extracellular NO scavenger], carboxy-PTIO (NO scavenger) and ODQ (inhibitor of soluble guanylyl cyclase). It was unmasked not only by indomethacin but also by apocynin (antioxidant), but inhibited by diphenyleneiodonium (inhibitor of flavoproteins including cytochrome P450 reductase). The cytochrome P450 reductase protein expression was similar in SHR and WKY aortae. However, the level of nitrate and nitrite, substrates of cytochrome P450 reductase, were higher in SHR than WKY plasma and aortae. Therefore, in SHR but not WKY aortae, eNOS-independent NO is formed by cytochrome P450 reductase.

Preservation of Endothelium-Dependent Relaxation in Atherosclerotic Mice with Endothelium-Restricted Endothelin-1 Overexpression

“…The hemecontaining proteins, myoglobin, hemoglobin, xanthine oxidase, and cytochrome P450 enzyme system, generate NO from nitrite and nitrate. Nitrite-and nitrate-dependent generation contributes to endothelium-dependent, eNOS-independent regulation of vascular tone (Zhao et al, 2013). S-Nitrosothiols, derived in part from S-nitrosoglutathione, have also been shown to be an eNOS-independent source of NO that could account for ACh-mediated NO release (Ng et al, 2007).…”

Sodium nitrite causes relaxation of the isolated rat aorta: By stimulating both endothelial NO synthase and activating soluble guanylyl cyclase in vascular smooth muscle

“…The role of eNOS in modulating responses to sodium nitrite was determined by the removal of the endothelium or incubation with the NOS inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME, 100 μM [25]). To determine the contribution of NO-formation to nitrite-induced relaxations, the rings were pre-incubated with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt (cPTIO, 100 μM [26]), a NO scavenger.…”

“…To determine the contribution of NO-formation to nitrite-induced relaxations, the rings were pre-incubated with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt (cPTIO, 100 μM [26]), a NO scavenger. To assess the contribution of guanyl cyclase, the rings were pre-incubated with the inhibitor of the enzyme 1H- [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 μM [25]). To investigate if the smooth muscle sensitivity of the arteries to NO differed between strains, the relaxation of the vascular rings was tested with the exogenous NO donor, sodium nitroprusside (SNP, 1 nM-100 μM).…”

Antispasmodic effects of yarrow (<i>Achillea millefolium l</i>.) extract in the isolated ileum of rat

“…Propranolol is a competitive antagonist which specifically competes with beta-adrenergic receptor stimulating agents for available beta-receptor sites (Pereira-Leite et al, 2013). NG-nitro-L-arginine methyl ester (L-NAME) is a non-selective inhibitor of nitric oxide synthesis (NOS) (Zhao et al, 2013). In this study, we investigated the effect of hydroalcoholic extract of floriated shoot of A. millefolium on the smooth muscle relaxation of isolated ileum in rats to find out their antispasmodic activity possibility.…”