Depletion, Nitric Oxide leads to Impaired, Vasodilation

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).

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.

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).