S-nitrosothiols dilate the mesenteric artery more potently than the femoral artery by a cGMP and L-type calcium channel-dependent mechanism

Abstract

S-nitrosothiols (SNOs) are metabolites of NO with potent vasodilatory activity. Our previous studies in sheep indicated that intra-arterially infused SNOs dilate the mesenteric vasculature more than the femoral vasculature. We hypothesized that the mesenteric artery is more responsive to SNO-mediated vasodilation, and investigated various steps along the NO/cGMP pathway to determine the mechanism for this difference. In anesthetized adult sheep, we monitored the conductance of mesenteric and femoral arteries during infusion of S-nitroso-l-cysteine (L-cysNO), and found mesenteric vascular conductance increased (137 ± 3%) significantly more than femoral conductance (26 ± 25%). Similar results were found in wire myography studies of isolated sheep mesenteric and femoral arteries. Vasodilation by SNOs was attenuated in both vessel types by the presence of ODQ (sGC inhibitor), and both YC-1 (sGC agonist) and 8-Br-cGMP (cGMP analog) mediated more potent relaxation in mesenteric arteries than femoral arteries. The vasodilatory difference between mesenteric and femoral arteries was eliminated by antagonists of either protein kinase G or L-type Ca(2+) channels. Western immunoblots showed a larger L-type Ca(2+)/sGC abundance ratio in mesenteric arteries than in femoral arteries. Fetal sheep mesenteric arteries were more responsive to SNOs than adult mesenteric arteries, and had a greater L-Ca(2+)/sGC ratio (p = 0.047 and r = -0.906 for correlation between Emax and L-Ca(2+)/sGC). These results suggest that mesenteric arteries, especially those in fetus, are more responsive to SNO-mediated vasodilation than femoral arteries due to a greater role of the L-type calcium channel in the NO/cGMP pathway.

Nitrite potentiates the vasodilatory signaling of S-nitrosothiols

“…The surgical procedures have been reported before [37; 39] and are described in the SI. The conductance and blood flow of the infused femoral artery, mean arterial blood pressure, and heart rate were recorded.…”

Hemodynamic Effects of Glutathione-Liganded Binuclear Dinitrosyl Iron Complex: Evidence for Nitroxyl Generation and Modulation by Plasma Albumin

“…Wire Myography. Ovine mesenteric arterial rings (2-mm diameter and 5 mm long) were denuded of endothelium (verified with 1 mM acetylcholine) and mounted in organ bath chambers as previously described (Liu et al, 2016b). Following preconstriction with 10 mM serotonin, dose-response curves were measured for study drugs including glut-BDNIC, glut-MDNIC, PROLI-NONOate (NO • donor; Cayman Chemical, Ann Arbor, MI), GSNO, and Angeli's salt (AS; HNO donor; Cayman Chemical).…”

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

“…Free •NO is a highly reactive uncharged radical with a half-life of ~1–5 second in vivo (Kelm and Schrader, 1990), and will often establish a stable RSNO equilibrium with GSH in the form of GSNO (Wink and Mitchell, 1998). •NO, and by extension, GSNO, plays a critical role in smooth muscle relaxation (Bradley et al , 1998; Tomita et al , 2002; Buxton, 2004 Ricciardolo et al , 2004; Liu et al , 2016) cardiopulmonary regulation (Rastaldo et al, 2007; Sears et al, 2004; Tamargo et al, 2010a) neuronal signaling (Shahani and Sawa, 2011), as well as dozens of other intra/extracellular functions (Pa´ L Pacher, Josehph S. Beckman, 1995; Salvador Moncada, 1994). The dysregulation of •NO production and metabolism can lead to drastic changes in protein S-nitrosation (Foster et al, 2009, 2003), an important posttranslational modification, and can have numerous other downstream consequences.…”