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Depletion, Nitric Oxide leads to Impaired, Vasodilation
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Nitric oxide (NO) is a critical endothelium-derived hyperpolarising factor (EDHF), responsible for relaxation of vascular smooth muscle and vasodilation. The primary regulator of endothelial vasodilator function via NO is vascular shear; the frictional force exerted on the vascular wall during the flow of blood through the vessel. Vascular shear opens calcium channels on endothelial cells, and leads to the calcium-dependent activation of eNOS and thus NO production. NO then diffuses to the underlying vascular smooth muscle, where it activates soluble guanylate cyclase, causing an increase in cyclic guanosine monophosphate (cGMP), potassium ion efflux, hyperpolarization and smooth muscle relaxation (Giles et al. 2012).
Depletion of vascular NO bioavailability causes an imbalance in the maintenance of vascular tone, which shifts in favour of vasoconstriction, and hence elevates blood pressure (Kojda et al. 1999). Under oxidative stress, decreased NO bioavailability results in impaired endothelium-dependent vasodilation (Silva et al., 2012).
Evidence Collection Strategy
Evidence Supporting this KER
Vasodilation is caused by the relaxation of vascular smooth muscle cells within the walls of blood vessels, which is regulated through a number of mechanisms, including cyclic GMP-dependent hyperpolarization and relaxation via NO. Thus, alterations to NO levels have an influence on vasodilation (Silva et al., 2012). Many animal studies demonstrated that inhibition of NO via eNOS inhibitors impaired acetylcholine-induced endothelium-dependent vasodilation, providing strong biological plausibility for this key event relationship.
Constitutively active AKT, which has been shown to phosphorylate and activate eNOS, increased resting vessel diameter in a rabbit femoral artery model, but infusion with eNOS inhibitor L-NAME reversed this effect (Luo et al., 2000). Dominant negative AKT, which prevents eNOS activation, also blocked vasodilation in response to the endothelium-dependent agonist acetylcholine (ACh) in rabbit arteries and mouse aortas. Since acetylcholine induces endothelium-dependent vasodilation, the assumption is that when eNOS inhibitors blocks Ach-induced vasodilation, NO production is decreased and vasodilation is impaired. L-NAME abolished endothelium-dependent relaxations induced by ACh in aortas of wild-type and hph-1 mice (Li et al., 2007). ACh induced a dose-dependent endothelium-dependent relaxation in rat small mesenteric arteries, but the NO-dependent component of ACh-induced relaxation was decreased in L-NAME-treated rats (Paulis et al., 2008). After L-NAME cessation, the NO-dependent component was restored to above control levels. L-NAME diminished eNOS activity by 66% and its cessation restore NOS activity to control levels in rat aortas. Another study showed that L-NAME caused a mild but significant decrease in vasodilation in rat thoracic aorta (Sélley et al., 2014).
Uncertainties and Inconsistencies
While the effect of NO depletion on impaired vasodilation is clear, the NO pathway does not appear to be solely responsible for this phenomenon. Vascular tone is a balance between relaxation and constriction factors. Studies have shown that when NO bioavailability is decreased, COX-mediated pro-inflammatory factors such as prostaglandins (Kellogg et al. 2005, Lüscher and Vanhoutte 1986) and Endothelin-1 (Taddei et al. 2003) contribute to a shift in vascular tone towards vasoconstiction. The review by Silva et al. (2012) discusses the roles of various pathways and their effects on vascular tone. The relative contribution of these mechanisms towards vascular tone is currently unknown.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This relationship between NO depletion and impaired vasodilation was shown in humans (Li et al. 1993, Heitzer et al. 2000), rabbits (Luo et al. 2000), mice (Luo et al. 2000, Wang et al. 2008) and rats (Paulis et al. 2008, Li et al. 1993, Sélley et al. 2014, Chen et al. 2010).
Bode-Böger SM, Böger RH, Galland A, Tsikas D, Frölich JC. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamicrelationship. Br J Clin Pharmacol. 1998, 46(5):489-97.
Carnevale R, Sciarretta S, Violi F et al. Acute Impact of Tobacco vs Electronic Cigarette Smoking on Oxidative Stress and Vascular Function. Chest. (2016) 150(3):606-12.
Chen, C.-A., Wang, T.-Y., Varadharaj, S., Reyes, L.A., Hemann, C., Talukder, M.A.H., Chen, Y.-R., Druhan, L.J., and Zweier, J.L. (2010). S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468, 1115–1118.
Giles TD, Sander GE, Nossaman BD et al. Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial-derived hyperpolarizing factors, and prostaglandins. J Clin Hypertens (2012) 14(4):198-205.
Heitzer T, Brockhoff C, Mayer B, Warnholtz A, Mollnau H, Henne S, Meinertz T, Münzel T. Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase. Circ Res. 2000, 86(2):E36-41.
Kellogg DL Jr, Zhao JL, Coey U, Green JV. Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin. J Appl Physiol (1985). 2005, 98(2):629-32.
Kojda G, Laursen JB, Ramasamy S et al. Protein expression, vascular reactivity and soluble guanylate cyclase activity in mice lacking the endothelial cell nitric oxide synthase: contributions of NOS isoforms to blood pressure and heart rate control. Cardiovasc Res. (1999) 42(1):206-13.
Li, J., Zhou, Z., Jiang, D.-J., Li, D., Tan, B., Liu, H., and Li, Y.-J. (2007). Reduction of NO- and EDHF-mediated vasodilatation in hypertension: role of asymmetric dimethylarginine. Clin. Exp. Hypertens. N. Y. N 1993 29, 489–501.
Lüscher T. F., Vanhoutte P. M. (1986). Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 8, 344–348
Luo, Z., Fujio, Y., Kureishi, Y., Rudic, R.D., Daumerie, G., Fulton, D., Sessa, W.C., and Walsh, K. (2000). Acute modulation of endothelial AKT/PKB activity alters nitric oxide–dependent vasomotor activity in vivo. J. Clin. Invest. 106, 493–499.
Paulis, L., Zicha, J., Kunes, J., Hojna, S., Behuliak, M., Celec, P., Kojsova, S., Pechanova, O., and Simko, F. (2008). Regression of L-NAME-induced hypertension: the role of nitric oxide and endothelium-derived constricting factor. Hypertens. Res. Off. J. Jpn. Soc. Hypertens. 31, 793–803.
Sander M, Chavoshan B, Victor RG. A large blood pressure-raising effect of nitric oxide synthase inhibition in humans. Hypertension. (1999) 33(4):937-42.
Sélley, E., Kun, S., Szijártó, I.A., Laczy, B., Kovács, T., Fülöp, F., Wittmann, I., and Molnár, G.A. (2014). Exenatide induces aortic vasodilation increasing hydrogen sulphide, carbon monoxide and nitric oxide production. Cardiovasc. Diabetol. 13, 69.
Silva, B.R., Pernomian, L., and Bendhack, L.M. (2012). Contribution of oxidative stress to endothelial dysfunction in hypertension. Front. Physiol. 3, 441.
Taddei S., Ghiadoni L., Virdis A., Versari D., Salvetti A. (2003). Mechanisms of endothelial dysfunction: clinical significance and preventive non-pharmacological therapeutic strategies. Curr. Pharm. Des. 9, 2385–2402
Taylor BA, Zaleski AL, Dornelas EA et al. The impact of tetrahydrobiopterin administration on endothelial function before and after smoking cessation in chronic smokers. Hypertens Res. (2016) 39(3):144-50.
Wang, S., Xu, J., Song, P., Wu, Y., Zhang, J., Chul Choi, H., and Zou, M.-H. (2008). Acute inhibition of guanosine triphosphate cyclohydrolase 1 uncouples endothelial nitric oxide synthase and elevates blood pressure. Hypertension 52, 484–490.