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Relationship: 958
Title
Depletion, Nitric Oxide leads to Impaired, Vasodilation
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Peptide Oxidation Leading to Hypertension | adjacent | High | Moderate | Frazer Lowe (send email) | Not under active development | Under Development |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| 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
Biological Plausibility
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).
Empirical Evidence
Include consideration of temporal concordance here
There is moderate empirical support for depletion of NO leading to impaired vasodilation based on several studies measuring decreased NO and vasodilation following a number of perturbations. In rat small mesenteric arteries, treatment with L-NAME for five weeks decreased NO-dependent relaxation from 28% to 7.5%, while diminishing eNOS activity by 66% (Paulis et al, 2008). In rat aortic rings, BCNU treatment for 4 hours caused a dose-dependent decrease in NO production (control: 100%, 25 μM: 61%, 80 μM: 36%), and also decreased vasodilation from 69% control to 37% (at 80 μM) (Chen et al., 2010). Similarly, treatment with 10 mM DAHP for 24 hours caused a decrease in both NO (from 100% to 61%) and vasodilation (from 87% to 42%) (Wang et al., 2008).
In humans, application of L-NAME and/or NG-monomethyl-L-arginine (L-NMMA) resulted in elevated mean arterial pressure via impairment of NO-mediated vasodilation. Application of both drugs compounded the effect (Sander et al. 1999). BH4 administration reversed NO depletion by L-NMMA and improved forearm venous blood flow in chronic smokers (Heizter et al. 2000). In human skin, acetylcholine-mediated vasodilation was shown to be modulated by NO and impaired by the eNOS inhibitor; L-NAME (Kellogg et al. 2005). Intravenous infusion of the eNOS substrate L-arginine was shown to decrease blood pressure and total peripheral resistance. The onset and the duration of the vasodilator effect of L-arginine and its effects on endogenous NO production closely corresponded to the plasma concentration half-life of l-arginine, and was associatedwith a concomminant elevation of urinary nitrate and cyclic GMP excretion (Bode-Böger et al. 1998). Finally, in chronic smokers with impaired flow-mediated dilation (FMD; 5.6±3.0% vs. 8.1±3.7% for non-smokers P<0.01), administration of the essential eNOS cofactor; BH4, improved FMD in both cohorts (6.6±3.3% vs. 9.8±3.2%; P<0.01) and smoking cessation for 1 week also improved FMD (from 5.0±2.9 to 7.8±3.2%;P<0.01). This data indicates that improvement in arterial vasodilation was partially improved by BH4 administration (Taylor et al. 2016). Another study by Carnevale et al. (2016) in which current smokers switched to an e-cigarette product for 1 week showed significant reductions in FMD impairment compared to baseline, which was associated with improvement in levels of 8-iso-prostagladin F2α (a biomarker of oxidative stress).
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
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
In rat aortic rings, BCNU treatment for 4 hours caused a dose-dependent decrease in NO production (control: 100%, 25 μM: 61%, 80 μM: 36%), and also decreased vasodilation from 69% control to 37% (at 80 μM) (Chen et al., 2010). Similarly, treatment with 10 mM DAHP for 24 hours caused a decrease in both NO (from 100% to 61%) and vasodilation (from 87% to 42%) (Wang et al., 2008).
Hence, it appears that a decrease of 40% NO relative to baseline conditions appears sufficient to impact vasodilation since the experiments show that NO decreases to near 60% after applying the stressors. The studies used several perturbations that were able to modulate NO production and vasodilation simultaneously including L-NAME, DAHP and BCNU. The evidence is qualitative however.
Furthermore, as NO is a highly volatile substance, researchers are not able to treat models/subjects with specific doses to observe the corresponding biological effects. NO donors such as sodium nitroprusside and glyceryl trinitrate are often used to generate NO in humans and animal studies, however this is indepedent of the vascular endothelium. More stable metabolites of NO are often measured in vivo to estimate NO turnover e.g. Nitrate/nitrite, however the conversion kinetics of NO to these metabolites is unclear and hence limited to qualitative comparisons. An example is the study by Bode-Böger et al. (1998) which investigated the pharmacokinetics of the eNOS substrate L-arginine and its subsequent effects upon vasodilation (measured using total peripheral resistance and blood pressure as surrogate endpoints). Plasma l-arginine levels increased to (mean±s.e.mean) 6223±407 (range, 5100–7680) and 822±59 (527–955) μmol l−1 after intravenous infusion of 30 g and 6 g l-arginine, respectively, and to 310±152 (118–1219) μmol l−1 after oral ingestion of 6 g l-arginine. Oral bioavailability of l-arginine was 68±9 (51–87)%. Clearance was 544±24 (440–620), 894±164 (470–1190), and 1018±230 (710–2130) ml min−1, and elimination half-life was calculated as 41.6±2.3 (34–55), 59.6±9.1 (24–98), and 79.5±9.3 (50–121) min, respectively, for 30 g i.v., 6 g i.v., and 6 g p.o. of l-arginine. Blood pressure and total peripheral resistance were significantly decreased after intravenous infusion of 30 g l-arginine by 4.4±1.4% and 10.4±3.6%, respectively, but were not significantly changed after oral or intravenous administration of 6 g l-arginine. l-arginine (30 g) also significantly increased urinary nitrate and cyclic GMP excretion rates by 97±28 and 66±20%, respectively. After infusion of 6 g l-arginine, urinary nitrate excretion also significantly increased, (nitrate by 47±12% [P<0.05], cyclic GMP by 67±47% [P=ns]), although to a lesser and more variable extent than after 30 g of l-arginine. The onset and the duration of the vasodilator effect of l-arginine and its effects on endogenous NO production closely corresponded to the plasma concentration half-life of l-arginine, as indicated by an equilibration half-life of 6±2 (3.7–8.4) min between plasma concentration and effect in pharmacokinetic-pharmacodynamic analysis, and the lack of hysteresis in the plasma concentration-versus-effect plot.
Response-response Relationship
Time-scale
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).
References
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.