JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2003; 42:71-77, doi:10.1016/S0735-1097(03)00505-9
© 2003 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Binggeli, C.
Right arrow Articles by Noll, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Binggeli, C.
Right arrow Articles by Noll, G.

CLINICAL RESEARCH: PROTEAN EFFECTS OF STATINS

Statins enhance postischemic hyperemia in the skin circulation of hypercholesterolemic patients

A monitoring test of endothelial dysfunction for clinical practice?

Christian Binggeli, MD*, Lukas E. Spieker, MD*, Roberto Corti, MD*, Isabella Sudano, MD, PhD*, Vesna Stojanovic, MD*, Daniel Hayoz, MD{dagger}, Thomas F. Lüscher, MD, FACC, FESC, FRCP* and Georg Noll, MD, FESC*,*

* CardioVascular Center, Division of Cardiology, University Hospital, Zürich, Switzerland
{dagger} Division of Hypertension and Vascular Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Manuscript received September 11, 2002; revised manuscript received December 21, 2002, accepted January 9, 2003.

* Reprint requests and correspondence: Dr. Georg Noll, Division of Cardiology, University Hospital, CH-8091 Zürich, Switzerland.
karnog{at}usz.unizh.ch


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The present study aims to investigate whether laser Doppler flowmetry can be used to monitor improvements in vascular function during statin therapy.

BACKGROUND: Endothelial dysfunction is an early feature of atherosclerosis in hypercholesterolemic patients and can be improved by statins. There are several methods to assess endothelial function in vivo, none of them being feasible in everyday practice.

METHODS: Skin perfusion, measured by laser Doppler flowmetry, was assessed at rest and during reactive hyperemia. Nineteen hypercholesterolemic patients (age 42 to 73 years, total cholesterol 5.4 to 9.6 mmol/l) were studied before and during statin therapy. To further investigate the mechanisms, postischemic skin hyperemia was measured before and after intradermal injection of the nitric oxide synthase inhibitor L-NAME and its inactive isoform D-NAME (0.5 µmol/10 µl each). On a separate day, the healthy volunteers were reexamined before and 2 h after 1,000 mg aspirin.

RESULTS: Postischemic skin blood flow was markedly reduced in hypercholesterolemic patients (45 ± 11%) compared with healthy controls (238 ± 20%, p < 0.0001) and improved after statin therapy (113 ± 15%, p = 0.0005 vs. pre-treatment). In the healthy volunteers, the hyperemic responses were not significantly different after L-NAME and D-NAME. Aspirin reduced hyperemia from 274 ± 49% to 197 ± 40% (p = 0.025).

CONCLUSIONS: Reactive hyperemia of the skin microcirculation can be easily and reproducibly assessed by laser Doppler flowmetry. Vasodilator prostaglandins are the major mediators of postischemic skin hyperemia, which is impaired in hypercholesterolemic patients and can be enhanced by cholesterol-lowering therapy. Thus, laser Doppler flowmetry may represent a tool to assess and monitor vascular function during therapy in everyday practice.

Abbreviations and Acronyms
  D-NAME
  N-omega-nitro-D-arginine methyl ester
  HDL
  high-density lipoprotein
  LDL
  low-density lipoprotein
  L-NAME
  N-omega-nitro-L-arginine methyl ester
  NO
  nitric oxide
  PGI2
  prostacyclin

Hypercholesterolemia is an important cardiovascular risk factor (1–3), and lipid-lowering therapy with statins reduces morbidity and mortality in the primary and secondary prevention of cardiovascular disease (4–8). Hypercholesterolemia is associated with reduced endothelium-dependent responses in the forearm and coronary circulation (9–11). These changes can, in part, be normalized by statins (12,13). The mechanisms by which statins improve endothelium-dependent vasodilation are not completely understood, but increasing evidence suggests that, besides the lipid lowering properties of statins, direct vascular effects are also responsible for the reduction of morbidity and mortality.

Nitric oxide (NO) and prostacyclin (PGI2), synthesized and released by the vascular endothelium, play an important role in the control of the vascular tone and structure (14–16); NO is produced by the enzymatic conversion of L-arginine to L-citrulline by NO synthase and possesses vasodilating, antithrombotic, and anti-proliferative properties (17); PGI2, with similar biological characteristics, is synthesized by cyclooxygenase from arachidonic acid (18). Both mediators are released from endothelial cells in response to shear stress during increased blood flow (19–22). Atherosclerotic changes in blood vessels are thought to be partly due to endothelial dysfunction with an imbalance between endothelium-derived vasodilators and vasoconstrictors (23).

Reactive hyperemia is a reflection of an increased requirement of blood flow after temporary occlusion of arterial blood supply and is a result of myogenic and several metabolic factors, for example, adenosine, ATP-sensitive potassium channels, pH, pO2, prostaglandins, and NO (24–30). Previous clinical studies investigated reactive hyperemia mainly by means of ultrasonography or venous occlusion plethysmography in the forearm (28,31,32). It has been shown that the skin blood flow correlates poorly with large vessel blood flow (blood flow mainly to the underlying muscle), but that it reflects the endothelium-dependent regulation of small skin vessels and is correlated to other established methods to test endothelial function such as plethysmography and laser-Doppler flowmeter (33–35). Reactive hyperemia measured in the radial artery after proximal limb occlusion is reduced in hypercholesterolemic patients (36) and improved by lipid-lowering therapy. The contribution of NO and PGI2 and the influence of statins to reactive hyperemia of the skin has not been investigated yet. In the clinical setting, the skin circulation has the advantage that it is easily accessible also in everyday practice and, hence, is an excellent candidate as a surrogate circulation for clinical monitoring.

The objective of this study was to investigate the value of laser Doppler flowmetry for the assessment of vascular function as an easily practicable surrogate of existing techniques.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Measurement of skin blood flow.   A laser Doppler flowmeter (PF 3, Perimed, Sweden) with a probe holder was used to assess skin blood flow. This method has been previously described and validated. Red laser light is guided to the skin through fiberoptics. There it is partly absorbed, partly reflected, and recorded by a second fiberoptic bundle. Circulating red cells cause a Doppler shift, whereas tissue does not. The signal intensity, thus, depends on velocity and the concentration of red cells. The sample volume approximates 1 mm2. Absolute blood flow depends on the sample volume, and, because the sample volume is not constant, absolute blood flow cannot be calculated. The system gives arbitrary perfusion units (37). The laser probe was placed close to the wrist, distal from a blood pressure cuff loosely placed around the arm. Skin temperature was measured next to the probe in nine subjects. Stable baseline conditions were recorded for 5 min. Then the cuff was inflated to suprasystolic pressure for 4.5 min. After release of the cuff, skin reactive hyperemia was recorded. The signal was digitally recorded (Centris, Apple Computer, Cupertino, California) using a modified commercial data acquisition software (LabView, National Instruments, Austin, Texas) and an analog/digital board (National Instruments). Because basal as well as peak skin blood considerably depends on the precise location of the measurement, flow was normalized to baseline and expressed as percent increase. Pilot experiments revealed that the mean flow between 30 and 60 s after cuff deflation discriminated best between before and during statin treatment (data not shown).

Experimental protocols.   All experiments were performed in a quiet, air-conditioned room with room temperature of 22°C to avoid changes in skin blood flow induced by different ambient temperatures. Measurements were started after a period of 20 min. All participants gave informed consent, and the study was approved by the local ethics committee.

Effects of statin therapy.   A total of 19 hypercholesterolemic patients (age 42 to 73 years; 2 female, 17 males; total cholesterol, 5.4 to 9.6 mmol/l) were studied before and during therapy with atorvastatin (n = 8), simvastatin (n = 4), cerivastatin (n = 6), or pravastatin (n = 1). Concomitant medication consisted of acetyl salicylic acid (100 mg daily, n = 11), beta-blockers (n = 9), calcium antagonists (n = 3), vasodilators (n = 1), anticoagulants (n = 2), angiotensin-converting enzyme inhibitors (n = 4), diuretics (n = 5), digoxin (n = 1), or amiodarone (n = 1) and was not altered during the study. The control group consisted of 12 young, healthy nonsmokers, age 28 ± 1 year, five females, seven males.

Correlation between plasma lipid levels and skin reactive hyperemia.   Sixteen healthy normo- or hypercholesterolemic volunteers (age, 31 to 70 years) with a wide range of plasma cholesterol levels (low-density lipoprotein [LDL] cholesterol, 1.8 to 9.6 mmol/l; high-density lipoprotein [HDL] cholesterol, 0.9 to 2.5 mmol/l) were additionally studied to investigate a possible correlation between plasma lipid levels and skin reactive hyperemia (all without any medication and all normotensive nonsmokers).

Study of the mechanisms of skin reactive hyperemia.   In six healthy normotensive subjects (age, 26 to 40 years; 3 males, 3 females), the mechanisms of skin reactive hyperemia as measured by laser Doppler flowmetry were investigated. The NO synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME) and its inactive isoform D-NAME (Clinalfa, Läufelfingen, Switzerland) were injected strictly intradermally into the left and right forearm skin (solutions of 0.5·10–6 mol, injection volume 10 µl each), respectively, through 30G needles (Omnican, Braun, Melsungen, Germany), as described previously by our group (38,39). If there was visible spreading outside the produced wheal, the injection site was excluded. After a resting period of 40 min, the laser Doppler probe was placed on the center of the flare, 4 to 5 mm from the injection site. After recording of a stable baseline, arterial blood flow was occluded for 4.5 min. After release of the arterial occlusion, reactive hyperemia was recorded.

On a separate day, the effects of acetylsalicylic acid (aspirin, 1 g orally; Aspirin, Bayer AG, Leverkusen, Germany) was studied. Before and 2 h after oral administration of the drug, skin reactive hyperemia was measured as described.

Reproducibility of the method.   To test the reproducibility of the method, hyperemia was measured in six healthy volunteers again after 13 ± 5 weeks, under the same conditions.

Statistical analysis.   All results are presented as means ± SEM. The effects of the drugs were evaluated with paired Student t test; intergroup differences were evaluated by unpaired t tests (StatView 4.5, Abacus Concepts, Berkeley, California [38]). A value of p < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Skin reactive hyperemia and plasma cholesterol levels.   There was a significant inverse association between LDL and postischemic skin blood flow (Fig. 1) (r = –0.62, p = 0.01). Total cholesterol plasma levels, but not triglycerides, were also significantly correlated to postischemic skin blood flow (r = –0.52, p = 0.029).



View larger version (16K):
[in this window]
[in a new window]
  		Figure 1 Relation between maximal blood flow during reactive hyperemia of the skin and plasma levels of low-density lipoprotein (LDL) cholesterol. There was a significant inverse correlation between skin blood flow and LDL cholesterol.

 
Skin reactive hyperemia and statins.   Patients were examined before and after a mean of 6 ± 0.8 weeks of lipid-lowering therapy. Total cholesterol was reduced from 7.1 ± 0.4 to 4.8 ± 0.3 mmol/l (p < 0.0001). Hyperemic blood flow was markedly impaired in patients with hypercholesterinemia (45 ± 11%) compared with healthy controls (238 ± 20%, p < 0.0001). Hyperemic skin blood flow increased from 45 ± 11% to 113 ± 15% of baseline during statin therapy (p = 0.0005). Total cholesterol was lowered by 33% as expected (n = 11) (Figs. 2 and 3). Skin temperature was comparable before and during statin therapy (31.8 ± 0.4°C and 32.2 ± 0.4°C, p = NS, n = 9).



View larger version (23K):
[in this window]
[in a new window]
  		Figure 2 Skin blood flow during reactive hyperemia in normocholesterolemic and hypercholesterolemic subjects and before and during therapy with a statin (changes normalized to baseline flow). Hyperemic skin blood flow in hypercholesterolemic patients is reduced compared with healthy controls, *p < 0.0001 versus healthy volunteers and can markedly be increased by statin therapy, {dagger}p = 0.0005 versus before treatment.

 


View larger version (19K):
[in this window]
[in a new window]
  		Figure 3 Scattergram: individual patients undergoing cholesterol lowering. Total cholesterol was reduced by statins in every patient and postischemic blood flow increased in every patient.

 
Mechanisms of skin reactive hyperemia.   Hyperemic blood flow after oral administration of 1,000 mg aspirin was blunted (197 ± 40% vs. 274 ± 49%, p = 0.025) (Fig. 4A).



View larger version (14K):
[in this window]
[in a new window]
  		Figure 4 (A) Skin blood flow during reactive hyperemia before and after cyclooxygenase inhibition with aspirin (percent change from baseline). Hyperemic skin blood flow is markedly reduced after oral administration of aspirin (*p = 0.025). (B) Skin blood flow during reactive hyperemia after intracutaneous administration of L-NAME, an inhibitor of nitric oxide synthase, and control (D-NAME), respectively (percent change from baseline). There is no significant difference in hyperemic skin blood flow.

 
The hyperemic response was not significantly different after intradermal injection of the NO synthase inhibitor L-NAME (238 ± 37%) and its inactive isoform D-NAME (192 ± 49%, respectively) (p = 0.32) (Fig. 4B).

Reproducibility.   Postischemic hyperemia was tested again after 13 ± 5 weeks in six of the healthy controls and proofed to be comparable (243 ± 36% and 229 ± 32%, p = NS). The control measurement was 4% lower (range, –17% to 36%). The coefficient of variation was 21%.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study shows that, in patients with hypercholesterolemia, postischemic skin blood flow is correlated to plasma cholesterol levels and that lipid-lowering therapy with statins markedly increases the postischemic flow response as measured by laser Doppler flowmetry. Vasodilator prostaglandins are the major physiologic mediators of postischemic skin hyperemia, which is impaired in hypercholesterolemic patients and enhanced by cholesterol-lowering therapy.

Reactive hyperemia, cholesterol, and statins.   Plasma cholesterol levels correlate with morbidity and mortality (1–3). The present study found an association between skin reactive hyperemia and plasma cholesterol levels. Statins are beneficial in the secondary prevention of cardiovascular events (4–8). This appears only in part to be due to their lipid-lowering property; indeed, the evidence is growing that statins also influence the formation of endothelial mediators (13,40). The present results show that the marked increase of skin blood flow during statin therapy is presumably due to increased bioavailability of vasodilator prostaglandins. Skin temperature might influence post-ischemic skin blood flow. However, this was monitored closely in our study and cannot explain the improvement of reactive hyperemia. Furthermore, the changes observed were very marked and consistent; indeed, there was not a single patient whose flow decreased during statin therapy.

Reactive hyperemia and prostaglandins.   Reactive hyperemia denotes increased blood flow after temporary occlusion of arterial blood flow and is a result of myogenic and several metabolic factors, for example, adenosine, ATP-sensitive potassium channels, pH, pO2, prostaglandins, and NO (25–30,41); PGI2, a vasodilator prostaglandin produced from arachidonic acid by constitutive cyclooxygenase in endothelial cells, is mainly released in response to shear-stress (22,42,43). The present results demonstrate that vasodilator prostaglandins—most probably PGI2—are essential mediators of reactive hyperemia in the human skin. The release of vasodilator prostaglandins is likely to be a result of increased shear stress generated by increased blood flow during reactive hyperemia. In addition, our findings show that prostaglandins contribute to the maintenance of basal skin blood flow. This does not invalidate the clinical use of aspirin because the low doses inhibit platelets but have minimal effects on prostacyclin and is in line with previous studies investigating the effects of prostaglandins on skin blood flow (44–48).

Reactive hyperemia and NO.   Nitric oxide is synthesized by the vascular endothelium by the enzymatic conversion of L-arginine to L-citrulline by NO synthase, which can be inhibited by L-NAME (17). A major stimulus for NO release is shear stress (19–22); NO plays an essential role in the control of vascular tone and structure and exerts vasodilating, anti-thrombotic, and antiproliferative properties (23).

It has been demonstrated that NO importantly contributes to flow-mediated dilation of large human arteries (28,31). In contrast, the present results exclude a major role of NO in reactive hyperemia of the skin microcirculation, because skin reactive hyperemia could not be inhibited by pharmacologic inhibition of NO synthase. Similarly, others found that dermal vasodilation in response to acetylcholine is mediated predominantly by prostanoids rather than NO (49). However, NO did contribute to basal skin blood flow in our subjects, as also shown by previous studies (50,51).

Relevance of the study.   Laser Doppler measurement of skin reactive hyperemia could potentially represent a simple, noninvasive method to study flow-mediated release of endothelial mediators in patients with cardiovascular disease. Even before morphologic evidence of atherosclerotic changes in the vessel wall, endothelial dysfunction can evolve in response to injury by cardiovascular risk factors (e.g., diabetes mellitus) (52), leading to impaired flow-dependent vasodilation (36,53–56). Impaired flow-mediated arterial dilation has also been demonstrated in a number of disease states, for example, coronary artery disease and congestive heart failure (57,58). In fact, a lower peak blood flow during skin reactive hyperemia has been found in diabetic patients compared with controls (59). In contrast, arterial hypertension (which also causes endothelial dysfunction) (60) does not seem to be associated with altered skin reactive hyperemia (59,61).

Statin therapy has been shown to improve endothelial function, as assessed by acetylcholine infusion to the coronary and forearm circulation (12,13,62). Because the vasodilator effects of acetylcholine in the skin are mediated rather by vasodilator prostaglandins than NO (49) and skin reactive hyperemia largely depends on vasodilator prostaglandins as shown in the present study, laser Doppler flowmetry of the skin may serve as a simple, noninvasive tool to assess endothelial function in daily practice.

Study limitations.   The present study is limited by the fact that it is not randomized and placebo-controlled. However, the observed differences were large, and the reproducibility of the method as shown in this study is acceptable. The present study is descriptive, and no data can be given on a possible relationship between these findings and prognosis yet. A further limitation is that intracutaneous injection leads to a small trauma and subsequent release of vasoactive substances (e.g., potassium, bradykinin, and substance P). These mediators may influence skin blood flow and could confound the hyperemic response. However, by injecting D-NAME—the inactive isoform of the NO synthase inhibitor L-NAME—as a control, we have tried to eliminate these factors as much as possible. Another limiting factor is the regulation of skin blood flow by systems other than the endothelium, for example, the sympathetic nervous system (63). By performing the experiments in an air-conditioned and quiet room, confounding influences, for example, noise and changing temperature, have been minimized.

Conclusions.   Assessment of skin reactive hyperemia by laser Doppler flowmetry is an easy and reproducible method to assess and monitor vascular function. Vasodilator prostaglandins are the major mediators of postischemic skin hyperemia, which is impaired in hypercholesterolemic patients and can be enhanced by cholesterol-lowering therapy. Because laser Doppler flowmetry is a simple noninvasive method for measuring skin blood flow during reactive hyperemia, it may be clinically used to test and monitor vascular function in patients before and during therapeutic interventions.


   Acknowledgments
 
The authors gratefully acknowledge the assistance of Rosy Hug and Susanne Aerne.


   Footnotes
 
Supported by grants from the Swiss National Research Foundation (Grant Nr. 52690 to G.N.).


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Multiple Risk Factor Intervention Trial Group. Risk factor changes and mortality results: Multiple Risk Factor Intervention trial research group. JAMA. 1982;248:1465–1477[Abstract]
  2. Sempos CT, Cleeman JI, Carroll MD, et al. Prevalence of high blood cholesterol among U.S. adults: an update based on guidelines from the second report of the National Cholesterol Education Program Adult Treatment Panel. JAMA. 1993;269:3015–3023[CrossRef][Medline]
  3. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart study: implications for treatment. Circulation. 1992;85:37–45[Abstract/Free Full Text]
  4. The Scandinavian Simvastatin Survival Study. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389[CrossRef][Medline]
  5. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–1357[Abstract/Free Full Text]
  6. West of Scotland Coronary Prevention study: identification of high-risk groups and comparison with other cardiovascular intervention trials. Lancet 1996;348:1339–42
  7. Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia: report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med. 1990;323:946–955[Abstract]
  8. Frick MH, Elo O, Haapa K, et al. Helsinki Heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–1245[Abstract]
  9. Chowienczyk PJ, Watts GF, Cockcroft JR, Ritter JM. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet. 1992;340:1430–1432[CrossRef][Medline]
  10. Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 1991;83:391–401[Abstract/Free Full Text]
  11. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991;338:1546–1550[CrossRef][Medline]
  12. Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995;332:481–487[Abstract/Free Full Text]
  13. John S, Schlaich M, Langenfeld M, et al. Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolemic patients: a randomized, placebo-controlled, double-blind study. Circulation. 1998;98:211–216[Abstract/Free Full Text]
  14. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–376[CrossRef][Medline]
  15. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526[CrossRef][Medline]
  16. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2:997–1000[Medline]
  17. Moncada S, Higgs EA. Endogenous nitric oxide: physiology, pathology and clinical relevance. Eur J Clin Invest. 1991;21:361–374[Medline]
  18. Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976;263:663–665[CrossRef][Medline]
  19. Pohl U, Holtz J, Busse R, Bassenge E. Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension. 1986;8:37–44[Abstract/Free Full Text]
  20. Rubanyi GM, Romero JC, Vanhoutte PM. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol. 1986;250:H1145–1149[Medline]
  21. Cooke JP, Rossitch E Jr, Andon NA, Loscalzo J, Dzau VJ. Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest. 1991;88:1663–1671[Medline]
  22. Topper JN, Cai J, Falb D, Gimbrone MA Jr. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci USA. 1996;93:10417–10422[Abstract/Free Full Text]
  23. Lüscher TF, Vanhoutte PM. The Endothelium: Modulator of Cardiovascular Function. Boca Raton, FL: CRC Press; 1990.
  24. Sparks HV Jr, Belloni FL. The peripheral circulation: local regulation. Annu Rev Physiol. 1978;40:67–92[CrossRef][Medline]
  25. Lansman JB, Hallam TJ, Rink TJ. Single stretch-activated ion channels in vascular endothelial cells as mechanotransducers? Nature. 1987;325:811–813[CrossRef][Medline]
  26. Carlsson I, Wennmalm A. Effect of different prostaglandin synthesis inhibitors on post-occlusive blood flow in human forearm. Prostaglandins. 1983;26:241–252[CrossRef][Medline]
  27. Banitt PF, Smits P, Williams SB, Ganz P, Creager MA. Activation of ATP-sensitive potassium channels contributes to reactive hyperemia in humans. Am J Physiol. 1996;271:H1594–1598[Medline]
  28. Joannides R, Haefeli WE, Linder L, et al. Nitric oxide is responsible for flow-dependent dilation of human peripheral conduit arteries in vivo. Circulation. 1995;91:1314–1319[Abstract/Free Full Text]
  29. O’Leary DS, Dunlap DC, Glover KW. Role of endothelium-derived relaxing factor in hindlimb reactive and active hyperemia in conscious dogs. Am J Physiol. 1994;266:R1213–1219[Medline]
  30. Olesen SP, Clapham DE, Davies PF. Haemodynamic shear stress activates a K+ current in vascular endothelial cells. Nature. 1988;331:168–170[CrossRef][Medline]
  31. Tagawa T, Imaizumi T, Endo T, Shiramoto M, Harasawa Y, Takeshita A. Role of nitric oxide in reactive hyperemia in human forearm vessels. Circulation. 1994;90:2285–2290[Abstract/Free Full Text]
  32. Engelke KA, Halliwill JR, Proctor DN, Dietz NM, Joyner MJ. Contribution of nitric oxide and prostaglandins to reactive hyperemia in human forearm. J Appl Physiol. 1996;81:1807–1814[Abstract/Free Full Text]
  33. Saumet JL, Dittmar A, Leftheriotis G. Non-invasive measurement of skin blood flow: comparison between plethysmography, laser-Doppler flowmeter and heat thermal clearance method. Int J Microcirc Clin Exp. 1986;5:73–83[Medline]
  34. Saumet JL, Kellogg DL Jr, Taylor WF, Johnson JM. Cutaneous laser-Doppler flowmetry: influence of underlying muscle blood flow. J Appl Physiol. 1988;65:478–481[Abstract/Free Full Text]
  35. Johnson JM, Taylor WF, Shepherd AP, Park MK. Laser-Doppler measurement of skin blood flow: comparison with plethysmography. J Appl Physiol. 1984;56:798–803[Abstract/Free Full Text]
  36. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115[CrossRef][Medline]
  37. Stern MD. In vivo evaluation of microcirculation by coherent light scattering. Nature. 1975;254:56–58[CrossRef][Medline]
  38. Wenzel RR, Noll G, Luscher TF. Endothelin receptor antagonists inhibit endothelin in human skin microcirculation. Hypertension. 1994;23:581–586[Abstract/Free Full Text]
  39. Wenzel RR, Duthiers N, Noll G, Bucher J, Kaufmann U, Luscher TF. Endothelin and calcium antagonists in the skin microcirculation of patients with coronary artery disease. Circulation. 1996;94:316–322[Abstract/Free Full Text]
  40. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998;101:2711–2719[Medline]
  41. Carlsson I, Sollevi A, Wennmalm A. The role of myogenic relaxation, adenosine and prostaglandins in human forearm reactive hyperaemia. J Physiol. 1987;389:147–161[Abstract/Free Full Text]
  42. Koller A, Kaley G. Prostaglandins mediate arteriolar dilation to increased blood flow velocity in skeletal muscle microcirculation. Circ Res. 1990;67:529–534[Abstract/Free Full Text]
  43. Okahara K, Sun B, Kambayashi J. Upregulation of prostacyclin synthesis-related gene expression by shear stress in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 1998;18:1922–1926[Abstract/Free Full Text]
  44. Goldyne ME, Winkelmann RK. In vitro effects of prostaglandin E2 on cutaneous vascular smooth muscle in the dog and in man. J Invest Dermatol. 1973;60:258–262[Medline]
  45. Juhlin L, Michaelsson G. Cutaneous vascular reactions to prostaglandins in healthy subjects and in patients with urticaria and atopic dermatitis. Acta Derm Venereol. 1969;49:251–261[Medline]
  46. Parker JL, Daugherty RM Jr., Emerson TE Jr.. Vascular responses of skin and skeletal muscle to prostaglandin A1 infusions. Am J Physiol. 1974;227:1109–1115[Free Full Text]
  47. Kingston WP, Greaves MW. Actions of prostaglandin E2 metabolites on skin microcirculation. Agents Actions. 1985;16:13–14[CrossRef][Medline]
  48. Harper EI, Beck JS, Spence VA, Brown RA. Effect of histamine and prostaglandin E2 on the microcirculation in the skin. Agents Actions. 1988;24:102–108[CrossRef][Medline]
  49. Noon JP, Walker BR, Hand MF, Webb DJ. Studies with iontophoretic administration of drugs to human dermal vessels in vivo: cholinergic vasodilatation is mediated by dilator prostanoids rather than nitric oxide. Br J Clin Pharmacol. 1998;45:545–550[CrossRef][Medline]
  50. Goldsmith PC, Leslie TA, Hayes NA, et al. Inhibitors of nitric oxide synthase in human skin. J Invest Dermatol. 1996;106:113–118[CrossRef][Medline]
  51. Wenzel RR, Zbinden S, Noll G, Meier B, Luscher TF. Endothelin-1 induces vasodilation in human skin by nociceptor fibres and release of nitric oxide. Br J Clin Pharmacol. 1998;45:441–446[CrossRef][Medline]
  52. Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med. 1989;320:1025–1030[Abstract]
  53. Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest. 1996;97:22–28[Medline]
  54. Sorensen KE, Celermajer DS, Georgakopoulos D, et al. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J Clin Invest. 1994;93:50–55[Medline]
  55. Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans: effects of age, atheroscle-rosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993;92:652–662[Medline]
  56. Zeiher AM, Schachinger V, Minners J. Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. Circulation. 1995;92:1094–1100[Abstract/Free Full Text]
  57. Schroeder S, Enderle MD, Ossen R, et al. Noninvasive determination of endothelium-mediated vasodilation as a screening test for coronary artery disease: pilot study to assess the predictive value in comparison with angina pectoris, exercise electrocardiography, and myocardial perfusion imaging. Am Heart J. 1999;138:731–739[CrossRef][Medline]
  58. Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation. 1996;93:210–214[Abstract/Free Full Text]
  59. Tur E, Yosipovitch G, Bar-On Y. Skin reactive hyperemia in diabetic patients: a study by laser Doppler flowmetry. Diabetes Care. 1991;14:958–962[Abstract]
  60. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22–27[Abstract]
  61. Orlandi C, Rossi M, Finardi G. Evaluation of the dilator capacity of skin blood vessels of hypertensive patients by laser Doppler flowmetry. Microvasc Res. 1988;35:21–26[CrossRef][Medline]
  62. Stroes ES, Koomans HA, de Bruin TW, Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet. 1995;346:467–471[CrossRef][Medline]
  63. Hagbarth KE, Hallin RG, Hongell A, Torebjork HE, Wallin BG. General characteristics of sympathetic activity in human skin nerves. Acta Physiol Scand. 1972;84:164–176[Medline]



This article has been cited by other articles:


Home page
 J. Appl. Physiol.Home page
F. Khan
Commentary on Viewpoint: The human cutaneous circulation as a model of generalized microvascular function
J Appl Physiol, July 1, 2008; 105(1): 385 - 385.
[Full Text] [PDF]

Home page
 J. Physiol.Home page
S. Lorenzo and C. T. Minson
Human cutaneous reactive hyperaemia: role of BKCa channels and sensory nerves
J. Physiol., November 15, 2007; 585(1): 295 - 303.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. S. Medow, I. Taneja, and J. M. Stewart
Cyclooxygenase and nitric oxide synthase dependence of cutaneous reactive hyperemia in humans
Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H425 - H432.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
B. J. Wong and C. T. Minson
Neurokinin-1 receptor desensitization attenuates cutaneous active vasodilatation in humans
J. Physiol., December 15, 2006; 577(3): 1043 - 1051.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
G. R. McCord, J.-L. Cracowski, and C. T. Minson
Prostanoids contribute to cutaneous active vasodilation in humans
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R596 - R602.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
T. Gori
Olive Oil and Ischemic Reactive Hyperemia in Hypercholesterolemic Patients
J. Am. Coll. Cardiol., July 18, 2006; 48(2): 414 - 414.
[Full Text] [PDF]

Home page
 CirculationHome page
G. F. Mitchell, J. A. Vita, M. G. Larson, H. Parise, M. J. Keyes, E. Warner, R. S. Vasan, D. Levy, and E. J. Benjamin
Cross-Sectional Relations of Peripheral Microvascular Function, Cardiovascular Disease Risk Factors, and Aortic Stiffness: The Framingham Heart Study
Circulation, December 13, 2005; 112(24): 3722 - 3728.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
G. F. Mitchell, H. Parise, J. A. Vita, M. G. Larson, E. Warner, J. F. Keaney Jr, M. J. Keyes, D. Levy, R. S. Vasan, and E. J. Benjamin
Local Shear Stress and Brachial Artery Flow-Mediated Dilation: The Framingham Heart Study
Hypertension, August 1, 2004; 44(2): 134 - 139.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
D. M. Herrington, W. V. Brown, L. Mosca, W. Davis, B. Eggleston, W. G. Hundley, and J. Raines
Relationship Between Arterial Stiffness and Subclinical Aortic Atherosclerosis
Circulation, July 27, 2004; 110(4): 432 - 437.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
C. T. Minson and B. J. Wong
Reactive hyperemia as a test of endothelial or microvascular function?
J. Am. Coll. Cardiol., June 2, 2004; 43(11): 2147 - 2147.
[Full Text] [PDF]

Home page
 CirculationHome page
P. P. Dimitrow, J. T. Kuvin, and R. H. Karas
Noninvasive Assessment of Coronary Endothelium-Dependent Vasomotion * Response
Circulation, February 10, 2004; 109 (5): e37 - e37.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Binggeli, C.
Right arrow Articles by Noll, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Binggeli, C.
Right arrow Articles by Noll, G.

HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK