(Hypertension. 1997;29:1186-1191.)
© 1997 American Heart Association, Inc.
Articles |
Chronic Dietary L-Arginine Prevents Endothelial Dysfunction Secondary to Environmental Tobacco Smoke in Normocholesterolemic Rabbits
From the Vascular Research Laboratory, Division of Cardiology, University of California, San Francisco.
Correspondence to William W. Parmley, MD, Division of Cardiology, University of California, San Francisco, Moffit Hospital Room 1186, San Francisco, CA 94143-0124. E-mail parmley{at}cardio.ucsf.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Our goal was to determine whether environmental tobacco smoke causes endothelial dysfunction in the absence of hypercholesterolemia and whether such an effect can be prevented by supplementation with L-arginine. Environmental tobacco smoke exposure is associated with an increase in coronary artery disease events and mortality. We have previously demonstrated that environmental tobacco smoke causes endothelial dysfunction and atherosclerosis in rabbits with diet-induced hypercholesterolemia and atherosclerosis and that chronic dietary L-arginine supplementation prevents this. The effects of L-arginine supplementation (2.25% solution ad libitum) and environmental tobacco smoke (smoking chambers for 10 weeks) were examined with a 2x2 design in 32 rabbits fed a normal diet. Acetylcholine, calcium ionophore A23187, and nitroglycerin-induced vasorelaxation were assessed in aortic rings precontracted with phenylephrine. Endothelial L-arginine levels were measured by chromatography. Chronic L-arginine supplementation increased serum (P<.001) and endothelial (P=.003) L-arginine levels. Environmental tobacco smoke reduced endothelium-dependent acetylcholine-induced relaxation, and L-arginine blocked this adverse effect (P=.04). Environmental tobacco smoke tended to increase phenylephrine-induced contraction (P=.06). Neither environmental tobacco smoke nor L-arginine influenced A23187-induced relaxation nor endothelium-independent nitroglycerin-induced relaxation. Endothelial dysfunction secondary to environmental tobacco smoke may occur in the absence of diet-induced hypercholesterolemia and atherosclerosis. Chronic dietary supplementation with a nitric oxide donor such as L-arginine offsets the endothelial dysfunction associated with environmental tobacco smoke in normocholesterolemic rabbits, possibly through substrate loading of the nitric oxide pathway.
Key Words: arginine • endothelium • aorta • tobacco smoke pollution
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Environmental tobacco smoke (ETS) exposure is associated with an increase in coronary artery disease events and mortality.1 2 3 4 5 6 7 We have previously demonstrated in hypercholesterolemic rabbits that ETS causes atherogenesis,8 and similar results have been reported in cockerels.9 We have also shown that in rabbits with diet-induced hypercholesterolemia, ETS causes endothelial dysfunction and that this deleterious effect is prevented by dietary L-arginine supplementation.10 11 However, it is unclear whether ETS alone causes endothelial dysfunction in the absence of other cardiovascular risk factors.
L-Arginine is the substrate for endothelial nitric oxide synthase, which converts L-arginine into nitric oxide and citrulline.12 Endothelial production of nitric oxide is a major determinant of resting artery tone12 13 14 and possesses antiplatelet15 16 and antiatherogenic properties that preserve normal arterial structure.17 18
In the present study, using direct measurements of arterial function, we sought to determine the effect of ETS exposure alone on endothelial function in rabbits on a normal low-cholesterol diet and to establish whether chronic dietary L-arginine supplementation preserves endothelial function in the presence of ETS.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Protocol
The study protocol was approved by the Committee for Animal Research of the University of California at San Francisco and was performed in accordance with the recommendations of the American Association for Accreditation of Laboratory Animal Care. Thirty-two rabbits were randomized into four groups of eight rabbits each; L-arginine, ETS, ETS/L-arginine, and control. Animals were fed a regular rabbit chow diet. Three animals in the L-arginine group died from an undiagnosed condition during the course of the study.
Rabbits were housed in individual cages. Rabbits randomized to ETS exposure (ETS and ETS/Arg groups) were placed in ETS exposure chambers (BioClean, DuoFlo, model H 5500, Lab Products Inc) that measured 1.92x1.92x0.97 m (3.58 m3) and accommodated eight rabbits at a time. Rabbits were exposed to sidestream smoke from Marlboro filter cigarettes (four cigarettes every 15 minutes for 6 hours per day, 5 days per week) using a smoking machine (Heinr, Borgwald GmbH, RM 1/G) for 10 weeks, from week 3 to week 13. Three fans in the exposure chambers were adjusted to ensure good mixing of the air within them. At the end of the 6-hour exposure period, the exhaust fan on the BioClean unit was turned on and rapidly lowered the level of ETS pollution in the exposure chamber to background levels corresponding to those of the non-ETS–exposed animals until the next day when the BioClean unit was turned off and the smoking machine was turned on again. Rabbits randomized to non-ETS groups (control and L-arginine) were housed in separate cages in the same type of exposure chamber in another room but without a smoking machine. Rabbits randomized to L-arginine groups (ETS/L-arginine and L-arginine) received L-arginine in their drinking water (2.25% wt/vol solution of L-arginine ad libitum).
After 10 weeks of exposure to ETS (or control conditions), rabbits were killed by lethal injection with pentobarbital (130 mg/kg body wt IV). Ring segments (3 to 4 mm in diameter and 5 to 7 mm in length) were rapidly excised starting from the ascending thoracic aorta for organ bath studies of vascular reactivity. Rings were taken from the same position in the aorta for each study.
At the time of death, blood was taken for measurement of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, nicotine, cotinine, and L-arginine.
Vascular Reactivity Studies
Each ring was suspended horizontally between two parallel
stainless steel wires for measurement of isometric tension in
individual organ baths (Radnotti Glass Technologies Inc) containing
Krebs' solution composed of (mmol/L) NaCl 118.3, KCl 4.7,
CaCl2 2.5, MgSO4 1.2,
K2PO4 1.2, and glucose 11.1, bubbled with 95%
O2 and 5% CO2. Bath temperature was maintained
at 37°C. The isometric tension generated by the ring segment was
measured with Radnotti high-sensitivity isometric transducers (TRN001)
and recorded continuously by an eight-channel MacLab/8e
recording system on MacLab Chart v3.3 (both from Analog Digital
Instruments, Inc) recording software.
Ring segments were stabilized at 4 g resting tension for 60 minutes before being studied. For measurement of responsiveness to phenylephrine and calculation of the dose needed for precontraction, phenylephrine in increasing doses (from 10-9 to 10-4 mol/L) was added to each organ bath. For each ring, the dose needed to achieve half-maximal contraction (ED50Phe) was calculated. After the phenylephrine contraction series, the baths were washed out three times with fresh Krebs' solution, and the rings were allowed to stabilize for 1 hour.
For determination of endothelium-derived nitric oxide–mediated vasorelaxation, aortic rings were exposed to acetylcholine. Acetylcholine induces vasorelaxation by release of nitric oxide that is coupled to muscarinic receptor stimulation.19 Acetylcholine was added to the organ baths in increasing doses (from 10-9 to 10-4.5 mol/L) after the rings had been precontracted by the ED50Phe and stable tension had developed. At the end of the acetylcholine series, the baths were washed out twice with fresh Krebs' solution and the rings allowed to stabilize at baseline tension.
For measurement of endothelium-derived nitric oxide–mediated vasorelaxation induced by a non–receptor-dependent mechanism,20 aortic rings were exposed to the calcium ionophore A23187 in increasing doses (from 10-9 to 10-4.5 mol/L) after the rings had been precontracted by the ED50Phe and stable tension had developed.
For determination of maximal endothelium-independent relaxation, a single dose of nitroglycerin (10-5 mol/L) was added to the organ baths at the end of the A23187 series. As our primary purpose in this experiment was to study endothelium-dependent relaxation, endothelium-independent relaxation was examined only to document that the maximal range of vasorelaxation was similar in the different animal groups and therefore that the differences noted in endothelium-dependent relaxation were unrelated to differences in smooth muscle responsiveness. We therefore used a protocol similar to that previously described in in vivo studies by Linder et al21 and in vitro studies by Sudhir et al22 in which a single, near-maximal concentration of sodium nitroprusside was used to study endothelium-dependent relaxation.
Vascular reactivity experiments were performed by an investigator who was blinded to rabbit treatment group.
Drugs
Phenylephrine, acetylcholine, and the calcium
ionophore A23187 were purchased from Sigma Chemical Co.
Nitroglycerin was purchased from Solopak Laboratories
Inc. Distilled water was used as the solvent for all agents other than
A23187, which was dissolved in dimethyl sulfoxide to create a stock
solution of A23187 that was then sequentially diluted with
water.
Endothelial L-arginine levels were measured by elution of the endothelial layer of segments of aorta and assay of the eluted solution for L-arginine from each animal of each group. After careful removal of adipose tissue, a segment of aorta 4 to 6 cm long was infused over 4 to 5 seconds with 5 mL distilled water containing 1% Triton X-100 detergent to hydrolyze the endothelial cell layer, as previously described.23 The recovered eluate was frozen and later assayed chromatographically with a Beckman 6300 Amino Acid Analyzer, which detects the colored ninhydrin derivatives of most amino acids at 570 nmol/L.24 The recovered L-arginine level was standardized for the aorta surface area using commercially available software to planimeter a photographed image of the aortic segment, cut open longitudinally.
Monitoring ETS Exposure Inside the Chambers
Carbon monoxide and total particulates were measured as
described in previous studies.8
Biochemical Analysis
Total serum cholesterol and triglyceride
levels were determined by automated enzymatic methods (Coulter DART
cholesterol reagent using the DACOS and DACOS XL
analyzers), and HDL cholesterol concentrations were
measured after precipitation of other lipoprotein classes with dextran
and magnesium ions (HDL cholesterol precipitant, catalog
No. 236141, CIBA Corning Diagnostics Corp).
Statistical Analysis
Relaxation of aortic rings is expressed as percentage change of
net developed tension (Measured Tension-Baseline
Tension)/(Precontracted Tension-Baseline Tension), EC50,
and slope (calculated by the Hill equation). A curve of best fit was
calculated for each ring using the equation for the Hill coefficient
with Kaleidagraph, version 3.0 (Synergy Software), which calculated the
EC50 and slope. Response to phenylephrine was
expressed as change in tension (from baseline) (grams) and recorded
and analyzed as above.
The effects of ETS and L-arginine on vascular reactivity were evaluated with a general linear model ANOVA (GLM-ANOVA, Minitab Version 10.2, GLM procedure), which is a suitable model to analyze groups of differing size. This form of ANOVA allows for statistical description of the principal effects of two (or more) factors: in our study, these were ETS (present or absent) and L-arginine (present or absent). GLM-ANOVA also allows for determination of the interaction of the factors (ETS and L-arginine).25 Testing the significance of the interaction term (ETSxarginine interaction) specifically permitted us to test whether the effect of ETS exposure was modified by the presence of L-arginine beyond purely additive effects.
Animal weights, food ingestion, and cholesterol measurements were similarly analyzed with a general linear model ANOVA. For air particulate matter, carbon monoxide exposure, and L-arginine ingestion measurements, data were collected on only the two ETS-exposed or two L-arginine–supplemented groups, so a t test was used to compare the two groups.
A value of P<.05 was considered significant. Data in profile plots are cell (raw) means and SEM. All results are expressed as mean±SEM.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Data
ETS marginally influenced food intake (P=.06) but not body weight (PETS=.91); L-arginine reduced both food intake (PArg=.002) and body weight (PArg=.02) (Table 1
).
|
The carbon monoxide, particulate matter exposure, serum nicotine, and
serum cotinine levels of the two ETS-exposed groups (ETS and ETS/Arg)
were similar (Table 1
).
The L-arginine–supplemented groups (Arg and ETS/Arg) consumed similar amounts of L-arginine (P=.21). L-Arginine supplementation increased serum L-arginine levels (PArg<.001). ETS did not influence serum L-arginine levels (PETS=.61), and there was no ETSxL-arginine interaction.
ETS did not affect total cholesterol
(PETS=.42) or HDL cholesterol
(PETS=.20) but did increase
triglyceride levels (PETS=.02).
L-Arginine did not affect total cholesterol
(PArg=.10), triglyceride
(PArg=.23), or HDL cholesterol
(PArg=.11) levels. There were no significant
ETSxarginine interactions affecting cholesterol, HDL
cholesterol, or triglyceride measurements
(Table 2).
|
Vascular Reactivity Studies
Relaxation
Acetylcholine dose-response curves are plotted in Fig 1a.
|
There was a significant ETSxL-arginine interaction,
indicating that L-arginine attenuated an ETS-induced
impairment in maximal acetylcholine-induced
endothelium-dependent relaxation
(PETSxArg=.04). ETS
exposure reduced the slope of the acetylcholine dose-response curve
(PETS=.047), but L-arginine did not
influence the slope (PArg=.84,
PETSxArg=.83) (Fig 1b, Table 3).
|
ETS and L-arginine supplementation had no significant
effects on A23187-induced endothelium-dependent
relaxation (Fig 2a and 2b, Table 4).
|
|
ETS and L-arginine supplementation had no significant
effects on nitroglycerin-induced
endothelium-independent relaxation (Fig 3).
|
Contraction
Mean dose-response curves to phenylephrine are plotted
in Fig 4a. ETS tended to increase
phenylephrine-induced tension development
(PETS=.057). There was no L-arginine
effect (PArg=.64) or ETSxL-arginine
interaction
(PETSxArg=.82) (Fig 4b).
|
L-Arginine Levels
Serum and eluted aortic L-arginine levels are reported
in Table 1. Chronic supplementation with dietary
L-arginine increased both serum L-arginine
(PArg<.001) and recovered
endothelial eluted L-arginine
(PArg=.003) (Fig 5a and 5b).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The major findings of this study were that ETS alone causes endothelial dysfunction of rabbit aorta and that chronic supplementation with L-arginine blocked this adverse effect. We have previously shown that in hypercholesterolemic atherosclerotic rabbit aorta, ETS causes a significant additive impairment of endothelial function8 11 in addition to the effects of hypercholesterolemia. We designed the present study to test whether ETS, in the absence of any other factor known to impair endothelial function (in particular, hypercholesterolemia), caused endothelial dysfunction.
ETS exposure is associated with increased coronary and cardiac mortality.1 2 3 4 5 6 7 Few data have been available concerning the effect of passive smoking on vascular reactivity in humans. Noninvasive, cross-sectional studies suggest impairment of endothelium-mediated relaxation in the peripheral vasculature in people with ETS exposure.26 The endothelial nitric oxide pathway is believed to be an important physiological regulator of arterial tone12 13 14 and also to retard the development of coronary artery disease.17 18 Nitric oxide inhibits several pathophysiological phenomena that may participate in the development of atherosclerotic vascular disease, such as monocyte adhesion and neointima formation,27 28 and platelet aggregation.15 16 Thus, reduced endothelial nitric oxide may precede and be permissive of the development of atherosclerotic vascular disease.29 30
In the present study, we also have demonstrated that chronic L-arginine supplementation for at least 10 weeks prevents ETS-induced endothelial dysfunction. This effect may have been due to the higher endothelial L-arginine stores in L-arginine–supplemented animals, which may substrate load the nitric oxide synthase pathway and override the defect caused by ETS. However, our study is not able to define the site of the abnormality or abnormalities of L-arginine metabolism. The eluted L-arginine was recovered from dissolution of whole endothelial cells, and possibly from the extracellular milieu. Our results thus apply to total endothelial L-arginine and do not enable us to comment on the distribution of L-arginine among intracellular and extracellular compartments. Nor are we able to comment on factors that alter L-arginine uptake via transporter systems31 32 or that may influence the stability of synthesized nitric oxide, such as N-nitroso derivatives of hydroxy-L-arginine.33 34
As L-arginine selectively attenuated ETS-mediated impairment of vasorelaxation induced by acetylcholine, but not A23187, the effect of ETS might be mediated via muscarinic receptors on the endothelium or vascular smooth muscle. The fact that arginine failed to normalize the ETS-induced increase in phenylephrine-induced constriction may suggest that differences in nitric oxide activity do not underlie the differences in phenylephrine-induced constriction. Alternatively, this observation may suggest that the magnitude of benefit available from L-arginine supplementation is not sufficient to counteract the deleterious effect of ETS.
The effect of ETS to reduce the slope of the dose-response curves to acetylcholine (PETS=.047) indicates that ETS reduces the sensitivity of the vessel to acetylcholine.35 An ETS-induced rightward shift (which also would have suggested reduced sensitivity of the vessel to acetylcholine35 ) was not seen in this study. This may have been due to large variance in our acetylcholine EC50 data that obscured such a finding.
Our results also suggest a tendency for ETS to cause increased adrenoreceptor-mediated constriction. Thus, ETS would appear to induce an imbalance of vascular tone via both diminished relaxation and increased constriction. Active tobacco smoking is a risk factor for coronary spasm.36 37 Disturbed coronary vasomotor tone, including spasm, is believed to participate in acute ischemic syndromes,38 such as Prinzmetal's angina,39 and myocardial infarction.30 Disturbed coronary tone may also favor progression of atherosclerosis.40
In the present study only male rabbits were studied; therefore, the results cannot be extrapolated to female rabbits.
Even in the absence of other factors that induce endothelial dysfunction, 10 weeks of ETS exposure alone causes impairment of endothelial function that is preventable by chronic L-arginine supplementation. ETS induces abnormalities of the endothelial nitric oxide pathway in the absence of atherosclerosis, which may precede and possibly contribute to atherogenesis.
Received July 12, 1996; first decision September 5, 1996; accepted October 29, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Glantz SA, Parmley WW. Passive smoking and heart disease: epidemiology, physiology, and biochemistry. Circulation. 1991;83:1-12.
2.
Glantz SA, Parmley WW. Passive smoking and
heart disease: mechanisms and risk. JAMA. 1995;273:1047-1053.
3.
Steenland K. Passive smoking and the risk of
heart disease. JAMA. 1992;267:94-99.
4. Wells AJ. Passive smoking as a cause of heart disease. J Am Coll Cardiol. 1994;24:546-554.[Abstract]
5. Wells A. An estimate of adult mortality in the United States from passive smoking. Environ Int. 1988;14:249-265.
6.
Taylor AE, Johnson DC, Kazemi H. Environmental
tobacco smoke and cardiovascular disease: a position
paper from the Council on Cardiopulmonary and Critical Care,
American Heart Association. Circulation. 1992;86:699-702.
7. Health Effects of Exposure to Environmental Tobacco Smoke. Final draft for scientific, public, and SRP review. Sacramento, Calif: California Environmental Protection Agency; Office of Environmental Health Hazard Assessment; February 1997.
8. Zhu BQ, Sun YP, Sievers RE, Isenberg WM, Glantz SA, Parmley WW. Passive smoking increases experimental atherosclerosis in cholesterol-fed rabbits. J Am Coll Cardiol. 1993;21:225-232.[Abstract]
9.
Penn A, Snyder CA. Inhalation of sidestream
cigarette smoke accelerates development of
arteriosclerotic plaques.
Circulation. 1993;90:1820-1825.
10. Sun Y, Zhu B, Sievers R, Glantz S, Deedwania P, Parmley W. L-arginine preserves endothelial dependent relaxation during environmental tobacco smoke in lipid fed rabbits. Circulation. 1994;90(suppl I):I-459. Abstract.
11. Hutchison S, Ibarra M, Chou T, Sievers R, Chatterjee K, Glantz S, Deedwania P, Parmley W. L-arginine restores normal endothelium-mediated relaxation in hypercholesterolemic rabbits exposed to tobacco smoke. J Am Coll Cardiol. 1996;27(suppl A):39A:701-1. Abstract.
12. Moncada S. The 1991 Ulf von Euler Lecture. The L-arginine:nitric oxide pathway. Acta Physiol Scand. 1992;145:201-227.[Medline] [Order article via Infotrieve]
13. Luscher TF. Endothelium-derived vasoactive factors and regulation of vascular tone in human blood vessels. Lung. 1990;168(suppl):27-34.
14. Muramatsu K, Numaguchi K, Egashira K, Takahashi T, Kasuya H, Takeshita A. Effects of N-nitro-L-arginine on coronary artery tone and reactive hyperemia after brief coronary occlusion in conscious dogs. Coron Artery Dis. 1994;5:815-820.[Medline] [Order article via Infotrieve]
15.
de Graaf J, Banga JD, Moncada S, Palmer RM, de Groot
PG, Sixma JJ. Nitric oxide functions as an inhibitor
of platelet adhesion under flow conditions.
Circulation. 1992;85:2284-2290.
16. Abrams J. Mechanisms of action of the organic nitrates in the treatment of myocardial ischemia. Am J Cardiol. 1992;70:30B-42B.[Medline] [Order article via Infotrieve]
17.
Cooke JP. Enhanced endothelial
adhesiveness in hypercholesterolemia is
attenuated by L-arginine. Circulation. 1994;89:2176-2182.
18. Wang BY, Singer AH, Tsao PS, Drexler H, Kosek J, Cooke JP. Dietary arginine prevents atherogenesis in the coronary artery of the hypercholesterolemic rabbit. J Am Coll Cardiol. 1994;23:452-458.[Abstract]
19.
Jaiswal N, Lambrecht G, Mutschler E, Tacke R, Malik
KU. Pharmacological characterization of the vascular muscarinic
receptors mediating relaxation and contraction in rabbit aorta.
J Pharmacol Exp Ther. 1991;258:842-850.
20.
Sellke FW, Kagaya Y, Johnson RG, Shafique T, Schoen FJ,
Grossman W, Weintraub RM. Endothelial modulation
of porcine coronary microcirculation perfused via immature
collaterals. Am J Physiol. 1992;262:H1669-H1675.
21.
Linder L, Kiowski W, Buhler FR, Luscher TF.
Indirect evidence for release of endothelium-derived
relaxing factor in human forearm circulation in vivo: blunted response
in essential hypertension. Circulation. 1990;81:1762-1767.
22.
Sudhir K, Kurtz TW, Yock PG, Connolly AJ, Morris
RJ. Potassium preserves endothelial function and
enhances aortic compliance in Dahl rats.
Hypertension. 1993;22:315-322.
23.
Li K, Rouleau JL, Andries LJ, Brutsaert DL.
Effect of dysfunctional vascular endothelium on
myocardial performance in isolated papillary muscles.
Circ Res. 1993;72:768-777.
24. Spackman D, Stein W, Moore S. Automatic recording apparatus for use in the chromatography of amino acids. Anal Chem. 1958;30:1190-1206.
25. Glantz SA, Slinker BK. Regression with two or more independent variables. In: Primer of Applied Regression and Analysis of Variance. New York, NY: McGraw-Hill, Inc; 1990:50-109.
26.
Celemajer D, Adams MLR, Clarkson P, Robinson J,
McCredie R, Donald A, Deanfield JE. Passive smoking and impaired
endothelium-dependent arterial dilatation
in healthy young adults. N Engl J Med. 1996;334:150-154.
27. Tsao PS, McEvoy LM, Drexler H, Butcher EC, Cooke JP. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation. 1994;89:2176-2182.
28.
Cayatte AJ, Palacino JJ, Horten K, Cohen RA.
Chronic inhibition of nitric oxide production accelerates
neointima formation and impairs endothelial
function in hypercholesterolemic rabbits.
Arterioscler Thromb. 1994;14:753-759.
29.
McLenachan JM, Vita J, Fish DR, Treasure CB, Cox DA,
Ganz P, Selwyn AP. Early evidence of endothelial
vasodilator dysfunction at coronary branch points.
Circulation. 1990;82:1169-1173.
30.
Maseri A, Davies G, Hackett D, Kaski JC.
Coronary artery spasm and vasoconstriction: the case for a
distinction. Circulation. 1990;81:1983-1991.
31.
Durante W, Liao L, Iftikhar I, O'Brien WE, Schafer
AI. Differential regulation of L-arginine transport
and nitric oxide production by vascular smooth muscle and
endothelium. Circ Res. 1996;78:1075-1082.
32.
Sobrevia L, Cesare P, Yudilevich DL, Mann GE.
Diabetes-induced activation of system y+ and nitric oxide synthase in
human endothelial cells: association with membrane
hyperpolarization. J Physiol
(Lond). 1995;489:183-192.
33. Zembowicz A, Chlopicki S, Radziszewski W, Vane JR, Gryglewski RJ. NG-hydroxy-L-arginine and hydroxyguanidine potentiate the biological activity of endothelium-derived relaxing factor released from the rabbit aorta. Biochem Biophys Res Commun. 1992;189:711-716.[Medline] [Order article via Infotrieve]
34. Zembowicz A, Swierkosz TA, Southan GJ, Hecker M, Vane JR. Potentiation of the vasorelaxant activity of nitric oxide by hydroxyguanidine: implications for the nature of endothelium-derived relaxing factor. Br J Pharmacol. 1992;107:1001-1007.[Medline] [Order article via Infotrieve]
35. Martin GR, Giles H. Pharmacological principles for analyzing responses of vascular smooth muscle. In: Garland CJ, Angus JA, eds. Pharmacology of Vascular Smooth Muscle. New York, NY: Oxford University Press; 1996.
36.
Sugiishi M, Takatsu F. Cigarette smoking is a
major risk factor for coronary spasm.
Circulation. 1993;87:76-79.
37.
Caralis DG, Deligonul U, Kern MJ, Cohen JD.
Smoking is a risk factor for coronary spasm in young
women. Circulation. 1992;85:905-909.
38. Nakamura M. Experimental induction of spasm, sudden progression of organic stenosis and intramural hemorrhage in the epicardial coronary arteries. Basic Res Cardiol. 1991;2:159-172.
39. Meller J, Pichard A, Dack S. Coronary arterial spasm in Prinzmetal's angina: a proved hypothesis. Am J Cardiol. 1976;37:938-940.[Medline] [Order article via Infotrieve]
40.
Kuga T, Tagawa H, Tomoike H, Mitsuoka W, Egashira S,
Ohara Y, Takeshita A, Nakamura M. Role of coronary
artery spasm in progression of organic coronary
stenosis and acute myocardial infarction in a swine model:
importance of mode of onset and duration of coronary artery
spasm. Circulation. 1993;87:573-582.
This article has been cited by other articles:
 |
|
 |
|
  J. Barnoya and S. A. Glantz Cardiovascular Effects of Secondhand Smoke: Nearly as Large as Smoking Circulation, May 24, 2005; 111(20): 2684 - 2698. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. L. Gornik and M. A. Creager Arginine and Endothelial and Vascular Health J. Nutr., October 1, 2004; 134(10): 2880S - 2887S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Hutchison, R. E. Sievers, B.-Q. Zhu, Y.-P. Sun, D. J. Stewart, W. W. Parmley, and K. Chatterjee Secondhand Tobacco Smoke Impairs Rabbit Pulmonary Artery Endothelium-Dependent Relaxation Chest, December 1, 2001; 120(6): 2004 - 2012. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Woo, P. Chook, H. C. Leong, X. S. Huang, and D. S. Celermajer The impact of heavy passive smoking on arterial endothelial function in modernized Chinese J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1228 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Hutchison, K. Sudhir, R. E. Sievers, B.-Q. Zhu, Y.-P. Sun, T. M. Chou, K. Chatterjee, P. C. Deedwania, J. P. Cooke, S. A. Glantz, et al. Effects of L-Arginine on Atherogenesis and Endothelial Dysfunction due to Secondhand Smoke Hypertension, July 1, 1999; 34(1): 44 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Tangphao, S. Chalon, A. M Coulston, H. Moreno Jr, J. R Chan, J. P Cooke, B. B Hoffman, and T. F Blaschke L-arginine and nitric oxide-related compounds in plasma: comparison of normal and arginine-free diets in a 24-h crossover study Vascular Medicine, February 1, 1999; 4(1): 27 - 32. [Abstract] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||