Functional role of the soluble guanylyl cyclase α1 subunit in vascular smooth muscle relaxation☆

Nimmegeers, Sofie; Sips, Patrick; Buys, Emmanuel; Brouckaert, Peter; Voorde, Johan Van de

doi:10.1016/j.cardiores.2007.06.002

Cited by 48 publications

(49 citation statements)

References 32 publications

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“…These findings were supported by previous reports about vasorelaxation induced by NO or NO donors (3,45). Furthermore, the present study also shows that the presence of ODQ, CHT, or BaCl 2 (1 μM) further inhibited relaxations to FLNT, indicating that FLNT activates K Ca and K IR independently of the sGC/ cGMP pathway.…”

Section: Discussionsupporting

confidence: 81%

Involvement of Guanylate Cyclase and K+ Channels in Relaxation Evoked by Ferulate Nitrate in Rat Aorta Artery

Wang¹,

Xu²,

Wang³

et al. 2012

J Pharmacol Sci

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Abstract. Vasorelaxant properties of N-2-(ferulamidoethyl)-nitrate (ferulate nitrate, FLNT), a newly synthesized nitrate, were compared with those of isosorbide dinitrate, nicorandil, nitroglycerin, and 8-bromoguanosine 3,5-cyclic monophosphate (8-Br-cGMP) in rat aorta pre-contracted by phenylephrine. FLNT produced vasorelaxation in a concentration-dependent manner (0.1 -100 μM). The degree of relaxation induced by FLNT was similar to that induced by isosorbide dinitrate. In addition, removal of endothelium did not affect the relaxant effect of FLNT. FLNT caused a rightward shift of the cumulative concentration-response curves of phenylephrine and reduced the maximal efficacy of contraction. 1H-[1,2,4]Oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 μM) and K + -channel blockers charybdotoxin (CHT, 0.1 μM) and BaCl 2 (1 μM) reduced the relaxant effect of FLNT in the endothelium-denuded arteries, whereas glibenclamide (1 μM) and 4-aminopyridine (1 mM) failed to influence FLNT-induced vasorelaxation. Furthermore, in the presence of ODQ, both CHT (0.1 μM) and BaCl 2 (1 μM) still significantly reduced the relaxation evoked by FLNT. Pretreatment of vessels with hydroxocobalamin, a nitric oxide scavenger, abolished the FLNT effect. These findings demonstrate that FLNT induces relaxation of the rat aorta rings endothelium-independently. Furthermore, we demonstrated that FLNT-induced vasorelaxation is related to its stimulation of soluble guanylate cyclase and activation of K + channels.

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Section: Discussionsupporting

confidence: 81%

Involvement of Guanylate Cyclase and K+ Channels in Relaxation Evoked by Ferulate Nitrate in Rat Aorta Artery

Wang¹,

Xu²,

Wang³

et al. 2012

J Pharmacol Sci

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“…Activity of the RAAS modulates endothelium-dependent vascular reactivity. We previously reported that vascular smooth muscle relaxation in response to endothelium-derived NO was severely attenuated in aortic and femoral rings isolated from sGCα 1 -/-S6 mice (19). In an independent study, the ability of acetylcholine to induce vasorelaxation in isolated carotid arteries was attenuated in sGCα 1 -/-B6 mice (27).…”

Section: Figurementioning

confidence: 94%

“…Two isoforms of each subunit have been identified (α 1 , α 2 , β 1 , β 2 ), but only sGCα 1 β 1 and sGCα 2 β 1 appear to function in vivo (16). Although the sGCα 1 β 1 heterodimer is the most abundant sGC isoform in the cardiovasculature (17), low levels of cGMP, generated by sGCα 2 β 1 , are sufficient to mediate many of NO's cardiovascular effects (15,(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Buys¹,

Raher²,

Kirby³

et al. 2012

J. Clin. Invest.

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Nitric oxide (NO) plays an essential role in regulating hypertension and blood flow by inducing relaxation of vascular smooth muscle. Male mice deficient in a NO receptor component, the α1 subunit of soluble guanylate cyclase (sGCα 1 ), are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension. Using linkage analyses, we discovered a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) in the context of sGCα 1 deficiency. This region is syntenic with previously identified blood pressure-related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS). Further, we found that RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα 1 -deficient mice. These data identify the RAAS as a blood pressure-modifying mechanism in a setting of impaired NO/cGMP signaling. IntroductionSystemic arterial hypertension is one of the most widespread public health problems in the developed world and the most prevalent modifiable risk factor for cardiovascular disease (CVD) in both women and men (1). The pathogenesis of essential hypertension is multifactorial, and in the vast majority of cases the etiology of hypertension is unknown. Although major advances in the treatment of hypertension have decreased CVD-related deaths over the last decade (2), many of the molecular mechanisms underlying the development of hypertension remain elusive. Genome-wide association studies (GWAS) suggest that there is a substantial heritable component to blood pressure (3, 4). Although GWAS have identified several loci associated with blood pressure in human beings, including loci containing genes that either regulate cGMP levels (4-7) or the renin-angiotensin-aldosterone system (RAAS) (8), many of the genetic factors determining blood pressure and how these factors interact remain to be identified.Renal abnormalities, such as decreased urinary sodium excretion in response to increasing renal perfusion pressure, and increased activity of the RAAS are generally considered to be a major contributor to the development of high blood pressure (9). However, other studies support the idea that hypertension can arise from primary vascular abnormalities (10, 11). The ability of NO to relax vascular smooth muscle and its essential role in the regulation of blood flow are well characterized (12, 13). Ample evidence suggests that altered NO signaling is involved in the pathogenesis of hypertension (14).One of the primary receptors for NO is soluble guanylate cyclase (sGC), a heme-containing enzyme that generates cGMP. The

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“…Because of the unusual flow patterns seen during the IS superfusion experiments, vasocontractile effect of IS on the vessel was studied using a wire myograph as described by Nimmegeers et al 82 Briefly, three female Wistar rats were used. After cervical dislocation, the thoracic aorta and femoral artery were carefully removed from each animal and transferred to cooled Krebs-Ringer bicarbonate (KRB) solution.…”

Section: Studies Of Vasoactive Effect Of Is In Vitromentioning

confidence: 99%

Protein-Bound Uremic Toxins Stimulate Crosstalk between Leukocytes and Vessel Wall

Pletinck

Glorieux

Schepers

et al. 2013

Journal of the American Society of Nephrology

100

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Leukocyte activation and endothelial damage both contribute to cardiovascular disease, a major cause of morbidity and mortality in CKD. Experimental in vitro data link several protein-bound uremic retention solutes to the modulation of inflammatory stimuli, including endothelium and leukocyte responses and cardiovascular damage, corroborating observational in vivo data. However, the impact of these uremic toxins on the crosstalk between endothelium and leukocytes has not been assessed. This study evaluated the effects of acute and continuous exposure to uremic levels of indoxylsulfate (IS), p-cresylsulfate (pCS), and p-cresylglucuronide (pCG) on the recruitment of circulating leukocytes in the rat peritoneal vascular bed using intravital microscopy. Superfusion with IS induced strong leukocyte adhesion, enhanced extravasation, and interrupted blood flow, whereas pCS caused a rapid increase in leukocyte rolling. Superfusion with pCS and pCG combined caused impaired blood flow and vascular leakage but did not further enhance leukocyte rolling over pCS alone. Intravenous infusion with IS confirmed the superfusion results and caused shedding of heparan sulfate, pointing to disruption of the glycocalyx as the mechanism likely mediating IS-induced flow stagnation. These results provide the first clear in vivo evidence that IS, pCS, and pCG exert proinflammatory effects that contribute to vascular damage by stimulating crosstalk between leukocytes and vessels.

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Functional role of the soluble guanylyl cyclase α1 subunit in vascular smooth muscle relaxation☆

Cited by 48 publications

References 32 publications

Involvement of Guanylate Cyclase and K+ Channels in Relaxation Evoked by Ferulate Nitrate in Rat Aorta Artery

Involvement of Guanylate Cyclase and K+ Channels in Relaxation Evoked by Ferulate Nitrate in Rat Aorta Artery

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Protein-Bound Uremic Toxins Stimulate Crosstalk between Leukocytes and Vessel Wall

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