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Hypertension. 2007;49:563-568
Published online before print January 22, 2007, doi: 10.1161/01.HYP.0000256764.86208.3d
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(Hypertension. 2007;49:563.)
© 2007 American Heart Association, Inc.

Original Articles

Asymmetrical Dimethylarginine Inhibits Shear Stress–Induced Nitric Oxide Release and Dilation and Elicits Superoxide-Mediated Increase in Arteriolar Tone

Janos Toth; Anita Racz; Pawel M. Kaminski; Michael S. Wolin; Zsolt Bagi; Akos Koller

From the Department of Pathophysiology (J.T., A.R., A.K.), Semmelweis University, Budapest, Hungary; the Department of Physiology (J.T., P.M.K., M.S.W., A.K.), New York Medical College, Valhalla; and the Division of Clinical Physiology (Z.B.), Institute of Cardiology, University of Debrecen, Debrecen, Hungary.

Correspondence to Akos Koller, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail koller{at}nymc.edu


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
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L-arginine is the substrate used by NO synthase to produce the vasodilator NO. However, in several human diseases, such as hyperhomocysteinemia, diabetes mellitus, and hypertension, there is an increase in serum levels of methylated L-arginines, such as asymmetrical dimethylarginine (ADMA), which cannot be used by NO synthase to produce NO. Yet, the functional consequence of increased levels of ADMA on the vasomotor function of resistance vessels has not been delineated. We hypothesized that elevated levels of exogenous ADMA inhibit NO mediation of flow/shear stress–dependent dilation of isolated arterioles. In the presence of indomethacin, isolated arterioles from rat gracilis muscle ({approx}165 µm at 80 mm Hg) were incubated with ADMA (10–4 mol/L), which eliminated the dilations to increases in intraluminal flow (control: from 164±5.4 to 188±3.8 µm versus ADMA: from 171±6.1 to 173±6.3 µm at 20 µL/min). ADMA did not affect dilations to nifedipine (10–6 mol/L; control: 63.4±2%, ADMA: 65.8±3%) or 8-bromo cGMP (10–4 mol/L; control: 51.2±2.1%, ADMA: 49.3±3.4%). In addition, ADMA elicited significant constriction of arterioles (from 173±17 µm to 138±16 µm at 80 mm Hg), which was prevented by previous incubation of arterioles with polyethylene-glycol (PEG) superoxide dismutase (SOD; 120 U/mL, control: 155±11 µm versus ADMA: 150±14 µm). Correspondingly, ADMA increased PEG-SOD reversible manner the production of vascular superoxide assessed by lucigenin-enhanced chemiluminescence and ethidium bromide fluorescence. Thus, increased levels of ADMA in various diseases could inhibit the regulation of arteriolar resistance by shear stress–induced release of NO and elicit superoxide-mediated increase in basal tone, both of which favor the development of hypertension.


Key Words: ADMA • flow-dependent dilation • superoxide • nitric oxide • arteriolar tone


*    Introduction
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 *Introduction
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The production of the important signaling molecule NO is regulated and modulated by several physiological and pathological mechanisms.1 It has been well established that L-arginine is the physiological substrate of NO synthase (NOS) to produce the vasodilator substance NO.1 Supporting this conclusion, we have found previously that exogenous L-arginine increases the synthesis of NO and augments NO-mediated arteriolar vasodilation.2 In 1992, Vallance et al3 described that >10 mg of methylated L-arginines, such as asymmetrical dimethylarginine (ADMA), is excreted in urine in 24 hours indicating that these forms of L-arginine exist in vivo. Further studies revealed that in several human diseases, such as hyperhomocysteinemia,4 diabetes mellitus,5 hypertension,6 coronary artery disease,7 peripheral arterial occlusive disease,8 and pulmonary hypertension,9 and as result of smoking,10 there is an increase in the serum level of methylated L-arginines, such as ADMA. The pathological importance of these findings is underscored by the biochemical mechanism showing that NOS cannot use ADMA to produce NO.3 Interestingly, a significant positive correlation between age and ADMA levels in a random population sample11 was shown to be associated with impaired dilation of the brachial artery after release of occlusions, which could be significantly improved by oral L-arginine supplementation.12 These studies suggest a strong correlation between elevated levels of ADMA and vascular diseases associated with reduced synthesis of NO. Thus ADMA can be viewed as an endogenous inhibitor of NOS.13

One of the important roles of arterial microvessels in skeletal muscle is the local regulation of tissue blood flow and peripheral vascular resistance by the flow/shear stress–sensitive vascular mechanisms, which is mediated in part by endothelium-derived NO. Previous studies have shown that other methylated L-arginines, such as N{omega}-nitro-L-arginine-methyl-ester and N{omega}-nitro-L-arginine, inhibit flow-dependent dilation of arterioles, however the effect of ADMA,2,14,15 the most abundant inhibitor of NOS present in vivo, especially in pathologic conditions,16 on the regulation of arteriolar tone is not known.

We hypothesized that elevated concentrations of ADMA inhibit NO mediation of flow/shear stress–dependent dilation of skeletal muscle arterioles. To avoid the potential contribution of other factors present in skeletal muscle tissue in vasomotor responses, we have used isolated gracilis muscle arterioles and investigated the effects of exogenous ADMA on their vasomotor function.


*    Methods
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 *Methods
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Animals
Experiments were carried out in isolated arterioles of male Wistar rats (n=35, weighing {approx}150 g). Animals were housed in an animal care facility, were fed standard rat chow, and had free access to tap water. All of the protocols were approved by the Institutional Animal Care and Use Committee. Rats were anesthetized with an intraperitoneal injection of pentobarbital sodium (50 mg/kg), and segments of gracilis muscle were removed; animals were then euthanized by an additional injection of pentobarbital sodium (150 mg/kg), followed by a bilateral pneumothorax.

Isolation of Gracilis Skeletal Muscle Arterioles
With the use of microsurgery instruments and an operating microscope, gracilis arterioles ({approx}1.5 mm in length) were isolated15 and transferred into an organ chamber containing 2 glass micropipettes filled with physiological salt solution composed of (in mM) 110 NaCl, 5.0 KCl, 2.5 CaCl2, 1.0 MgSO4, 1.0 KH2PO4, 5.5 glucose, and 24.0 NaHCO3 equilibrated with a gas mixture of 10% O2/5% CO2 balanced with nitrogen at pH 7.4. Both perfusate and bath solutions were continuously saturated with this gas mixture to mimic the in vivo level of PO2. Vessels were cannulated at both ends, and micropipettes were connected with silicon tubing to adjustable physiological salt solution reservoirs. Inflow and outflow pressures were set to 80 mm Hg and measured by a pressure servo control system (Living System Instrumentation). Temperature was set at 37°C by a temperature controller (YSI Tele Thermometer). The internal diameters at the midpoint of the isolated arterioles were measured by videomicroscopy with a microangiometer (Texas A&M University System). Changes in arteriolar diameter and intraluminal pressure were recorded continuously with a chart recorder and in digital form with a PowerLab system (ADInstruments Ltd) connected to a computer and analyzed with PowerLab and Sigma Plot software. Perfusate flow was measured with a ball flowmeter (Omega).

Flow-Induced Responses
Changes in diameter of arterioles were obtained in response to step increases in intraluminal flow (from 0 to 20 µL/min) in the presence of a constant intravascular pressure (80 mm Hg).15 Each flow rate was maintained for 5 to 10 minutes to allow the vessel to reach a steady-state diameter. To exclude the potential contribution of prostaglandins, all of the experiments were performed in the presence of indomethacin (2.5x10–5 mol/L). Flow-induced changes in arteriolar diameter were measured in control conditions and after incubation of ADMA (10–4 mol/L).

Agonist-Induced Responses
Acetylcholine was used to demonstrate that the endothelium of arterioles is intact. Acetylcholine (10–7 mol/L) elicited dilation from 129±12 µm to 166±14 µm, a change that corresponds with data obtained previously.17 Responses of the arterioles to the cell-permeable activator of cGMP-dependent protein kinase analog 8-bromoguanosine cGMP (10–6–10–4 mol/L) and the calcium channel blocker nifedipine (6x10–8 to 10–6 mol/L) added to the tissue bath were obtained before and after administration of ADMA (10–4 mol/L).

Assessment of Vascular Superoxide Level
Vascular superoxide production was assessed in isolated femoral artery samples by the lucigenin chemiluminescence method18 in the absence or presence of PEG-SOD (120 U/mL). Also, hydroethidine was used to localize superoxide production in gracilis arterioles.18 In brief, cells are permeable to hydroethidine, which, in the presence of superoxide, is oxidized to fluorescent ethidium bromide that is trapped by intercalation with DNA. Vessels were exposed to hydroethidine (10–6 mol/L) in the presence of physiological salt solution, ADMA (10–4 mol/L), and ADMA+PEG-SOD.

Statistical Analysis of Data
Peak constrictions of arterioles in response to ADMA are expressed as a percentage of the baseline diameter at an intraluminal pressure of 80 mm Hg. Peak dilations of arterioles are expressed as changes in arteriolar diameter as a percentage of the maximal dilation of the vessel, defined as the passive diameter at 80 mm Hg intraluminal pressure in a Ca2+-free physiological salt solution containing 10–3 mol/L EGTA and 10–4 mol/L sodium nitroprusside. Wall shear stress (WSS) values were calculated according to the formula WSS=4{eta}Q/{pi}r3, where {eta} is the viscosity of the perfusate (0.007 poise at 37°C), Q is the perfusate flow, and r is the vessel radius. Statistical analyses were performed by 2-way ANOVA for repeated measures followed by the Tukey’s posthoc test or Student’s t test, as appropriate. P<0.05 was considered statistically significant. All of the data are expressed as mean±SE.


*    Results
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 *Results
down arrowDiscussion
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Flow-Induced Responses Versus ADMA
Original records of diameter as a function of time shows that, in control conditions, step increases in intraluminal flow (5, 10, 15, and 20 µL/min) elicited substantial dilations of an isolated arteriole from 162 µm to 176 µm (Figure 1A). After returning flow to 0, the diameter of arteriole returned to the control level. In the presence of ADMA (10–4 mol/L), the basal diameter of arteriole became reduced, and step increases in flow did not elicit dilation (Figure 1A). Summary data (Figure 1B) show that increases in intraluminal flow elicited substantial dilations of arterioles in control conditions (22.7±2.35%) that were completely eliminated by the presence of ADMA. Calculation of WSS indicated that increases of WSS elicited dilations in control conditions; however, in the presence of ADMA, the dilations were completely eliminated, and WSS reached high levels (Figure 1C).


Figure 1
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  		Figure 1. Original records (A) and summary data showing changes in diameter of skeletal muscle arterioles in control and in the presence of ADMA (10–4 mol/L) as a function of intraluminal flow (B) or WSS (C). Data are mean±SEM. *P<0.05 vs control; n=8.

Basal Arteriolar Tone Versus ADMA
Isolated gracilis muscle arterioles developed an active tone in response to the presence of intraluminal pressure of 80 mm Hg without the use of any vasoactive agent (active diameter: 149.6±13.9 µm versus passive diameter: 218.4±9.6 µm; P<0.05). Original records and summary data show that ADMA elicited a substantial, concentration-dependent decrease in the diameter of isolated gracilis muscle arteriole as a function of time (Figure 2A). The maximum decrease in diameter occurred at 15 minutes, to 10–4 mol/L ADMA (19.6±7.3%). Compared with control, the basal arteriolar diameters (Figure 2B) were significantly different in the presence of ADMA (control: 149.6±13.9 µm versus ADMA 127.4±10.44 µm). The presence of PEG-SOD abolished the constrictor effect of ADMA on basal diameter (Figure 2A and 2B). The non–NO-mediated dilations to 8-bromo-cGMP and calcium channel antagonist nifedipine, however, were not affected by the presence of ADMA (Figure 2C and 2D).


Figure 2
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  		Figure 2. Original records (A) and summary data (B) show the effect of increasing concentrations of ADMA on the basal diameter of skeletal muscle arterioles (n=9) in the presence and absence of PEG-SOD. Effect of increasing concentration of 8-bromo cGMP (C) and nifedipine (D) on the diameter of isolated arterioles in control conditions and in the presence of ADMA (10–4 mol/L). Data are mean±SEM. *P<0.05 vs control.

Assessment of Vascular Superoxide Production in the Presence of ADMA
Representative fluorescent photomicrographs of ethidium bromide (EB) fluorescence of hydroethidine–stained control and ADMA incubated gracilis arteriolar sections (Figure 3 indicate a substantially enhanced hydroethidine staining in ADMA-incubated vessels as compared with control. Additional incubation with PEG-SOD decreased the fluorescence in the arteriolar wall. To further assess and quantify differences in the level of superoxide anion, lucigenin-enhanced chemiluminescence of femoral arteries was used, because the tissue amount of gracilis arterioles is not sufficient to detect oxidant production by this method. We have found that lucigenin chemiluminescence was significantly higher in vessels incubated with ADMA (121±9 counts per minute per tissue millimeter squared) compared with that of control (78±4 counts per minute per tissue millimeter squared), and, in the presence of ADMA, PEG-SOD significantly decreased arterial lucigenin chemiluminescence close to the control levels (Figure 3, bottom).


Figure 3
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  		Figure 3. Ethidium bromide fluorescence of gracilis arteriole and summary data (n=6) of lucigenin chemiluminescence of sections of isolated rat femoral arterial branches in control conditions in the presence of ADMA (10–4 mol/L)and pretreatment with PEG-SOD. Data are mean±SEM. *P<0.05 vs control.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The salient findings of the present study are that in isolated gracilis muscle arterioles, asymmetrical dimethyl L-arginine: (1) inhibited the mediation of flow/shear stress–induced dilations by endogenously generated NO, whereas it did not affect dilations to nifedipine and 8 bromo-cGMP; (2) superoxide dismutase reversed the observed ADMA-elicited reduction in basal diameter; and (3) ADMA elicited vascular oxidative stress, indicated by increased ethidium bromide fluorescence and lucigenin-enhanced chemiluminescence.

Regulation of tissue blood flow and peripheral resistance is an important function of microvessels, primarily those of skeletal muscles arterioles. One of the key local mechanisms regulates blood flow by sensing changes in WSS during increases in blood flow.19 Previous studies have shown in skeletal muscle arterioles that increases in WSS, via increases in intraluminal flow, stimulate the synthesis and release of NO.14,15 It has been shown that L-arginine is the substrate of NOS, and NOS can be stimulated by administration of L-arginine resulting in arteriolar dilation. Methylated L-arginine, N{omega}-nitro-L-arginine, N{omega}-monomethyl-L-arginine, and N{omega}-nitro-L-arginine-methyl-ester have been shown to inhibit NOS with the consequent elimination of NO-mediated dilations of vessels. These forms of methylated L-arginine, however, are not readily available in vivo.20,21 Importantly, methylation of L-arginine released from proteins occurs in animals and humans in vivo. In several human diseases, such as hyperhomocysteinemia,4,22 diabetes mellitus,5,6,23 and hypertension,24 there is an increase in the serum level of methylated L-arginines, such as ADMA. Because in vitro biochemical studies show that ADMA inhibits NOS,3,25 it was logical to hypothesize that ADMA inhibits flow-dependent dilations of arterioles, which are known to be mediated by NO.

The normal concentration of ADMA in plasma is in the range of 0.355±0.066 µmol/L,26 which, however, becomes elevated in diseases associated with oxidative stress, as well as nitrosative stress, because these conditions decrease the activity of the ADMA demethylating enzyme, dimethylarginine dymethylaminohydrolase.27 For instance, in rats, intravenous administration of homocysteine (10 mg/kg per day for 4 weeks) increased the serum ADMA level (from 1 to 2 µmol/L),28 whereas in rats with type 2 diabetes, the level of ADMA significantly increases from the control 0.5 µmol/L to 1.5 µmol/L as the disease progresses.6 In obese subjects with high body mass index (≥26 kg/m2), the plasma concentration of ADMA is significantly higher (1.44 compared with 1.31 µmol/L) than in lean subjects with low body mass index (<26 kg/m2), whereas the L-arginine/ADMA ratio is lower (obese: 66 versus lean: 89). Also, several studies have shown that plasma concentration of ADMA is significantly higher in smokers as compared with nonsmokers.29 Recent studies measuring intracellular levels of ADMA in red blood cells showed that they are at 40.61±7.15 µmol/L.30 Importantly, a 5-fold increase in methylarginine concentration has been shown in endothelial cells when they were exposed to methylarginines added to the culture medium.31 This level of methylarginines is probably attributable to the arginine transport system referred to as the Y+ transporter. In human endothelial cells, the Michaelis constant for transport of methylated L-arginines is {approx}70 µmol/L, and the maximum velocity is in the range of 2 µmol per milligram of protein per minute.32 It is likely, however, that in the intracellular environment, ADMA compartmentalizes reaching high concentrations in localized regions and that removal of ADMA might also be a slow process. Collectively, one can logically assume that ADMA levels can reach high local concentrations under certain pathologic conditions.32,33 These concentrations of ADMA can inhibit NOS,13,25 resulting in the consequent pathologic regulation of vascular tone. Thus, present experiments were performed in the presence of 10–6 to 10–4 mol/L concentrations of ADMA to mimic potential in vivo conditions.31,34

Interestingly, there is an absence of studies showing that ADMA interferes with NO-mediated regulation of WSS in resistance arterioles. Therefore, we have used isolated arterioles to elucidate the effect of ADMA on dilator responses elicited by increasing flow/WSS. Previous studies showed that increases in intraluminal flow elicit the corelease of prostaglandins and NO in gracilis arterioles by increasing in WSS.15 Thus, to exclude the contribution of prostaglandins, we performed the experiments in the presence of indomethacin. Original traces of diameter and summary data show substantial dilation of arterioles as a function of intraluminal flow and that the presence of ADMA eliminated flow-induced dilations (Figure 1A and 1B). Calculation of WSS also showed that, in the presence of ADMA, increases in shear stress did not elicit dilation. Thus, these conditions result in an elevated level of shear stress (Figure 1C). The pathologic importance of this finding is underscored by our previous studies revealing that, in arterioles of spontaneously hypertensive rats, the level of WSS is high during increased flow conditions, which corresponds with an increased level of peripheral vascular resistance19 in this model of hypertension.

The findings of this study also indicate that ADMA inhibits only the NO-mediation of flow/shear stress–induced dilation, because dilations to 8-bromo cGMP and nifedipine were not affected by ADMA (Figure 2C and 2D). We interpreted these findings to mean that ADMA does not affect the signaling pathways downstream from cGMP and, in general, the dilator capacity of arteriolar smooth muscle.

The functional significance of vascular oxidative stress is further indicated by our finding that ADMA elicited significant constriction of arterioles, as shown by original traces and summary data (Figure 2A and 2B). This reduction in diameter by ADMA could also be prevented by previous incubation of arterioles with PEG-SOD, suggesting that superoxide is involved in the development of increased tone in the presence of ADMA.

To provide further evidence for the presence of oxidative stress, we have measured the effect of ADMA on dihydroethidine fluorescence18 in gracilis arterial sections. These studies showed that ADMA increased dihydroethidine fluorescence (Figure 3). Also, the presence of ADMA significantly increased lucigenin-enhanced chemiluminescence18 (Figure 3 bottom), which was significantly reduced toward control levels in the presence of PEG-SOD. Biochemical studies using the purified enzyme showed that NOS may become "uncoupled" in the absence of the NOS substrate L-arginine when electrons flowing from the reductase domain to the oxygenas domain are diverted to molecular oxygen rather than to L-arginine, resulting in production of superoxide rather than NO.35 Thus, our findings suggest that the primary substance released in the presence of ADMA eliciting increases in basal tone is superoxide.36

Arteriolar dysfunction is a key factor in the development of cardiovascular diseases, such as hypertension,37 atherothrombosis,38 and peripheral vascular disease.39 Thus, understanding the mechanisms responsible for the reduced availability of NO and increased production of superoxide in the presence of ADMA has the potential to identify novel therapeutic targets and modalities aiming to improve the regulation of arteriolar resistance by local mechanisms.

Perspectives
Elevated levels of ADMA in various cardiovascular and renal diseases likely impair the regulation of arteriolar resistance by shear stress-dependent release of NO. In addition, elevated levels of ADMA elicit superoxide release increasing arteriolar tone. Both changes favor the development of disturbed tissue blood flow, increased shear stress, and increased peripheral resistance, thus, hypertension. Our findings provide support for the clinical use of L-arginine supplementation and antioxidants, which may correct the adverse effect of high levels of ADMA present in pathologic conditions. In addition, alternative enzymatic mechanisms regulating the level of methylated L-arginine, such as protein arginine methyltransferase and dimethylarginine dymethylaminohydrolase, may also represent potential therapeutic targets when the transport and availability of L-arginine or demethylation of ADMA is not optimal.40,41


*    Acknowledgments
 
Sources of Funding

This work was supported by National Institute of Heart grants HL-46813, HL-43023, HL-31069, and HL-66331; American Heart Association North East Affiliate grant 0555897T; Hungarian National Scientific Research Founds/OTKA-T48376, F-048837 and Health Science Council/ETT 364/2006, 454/2006.

Disclosures

None.

Received September 19, 2006; first decision October 5, 2006; accepted December 17, 2006.


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