CLINICAL STUDIES
Improvement in endothelial function by angiotensin-converting enzyme inhibition in non–insulin-dependent diabetes mellitus
Gerard O’Driscoll, MB, BCh, BAO, FRACPa,
Daniel Green, PhD ,
Andrew Maiorana, MSc,
Kim Stanton, MB, BS, FRACP*,
Frances Colreavy, MB, BCh, BAO, FFARCSIa and
Roger Taylor, MB, BS, FRACP
a Departments of Cardiology and Endocrinology, Royal Perth Hospital, Nedlands, Australia
* Department of Diabetes, Royal Perth Hospital, Nedlands, Australia
Department of Human Movement, The University of Western Australia, Nedlands, Australia
Department of Medicine, The University of Western Australia, Nedlands, Australia
Manuscript received August 18, 1998;
revised manuscript received January 5, 1999,
accepted January 21, 1999.
Reprint requests and correspondence: Dr. Danny Green, Department of Human Movement, The University of Western Australia, Nedlands 6907, Western Australia, Australia
brevis{at}cyllene.uwa.edu.au
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Abstract
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OBJECTIVES
The aim of this study was to assess the effect of angiotensin-converting enzyme (ACE) inhibition with enalapril on forearm endothelial function in subjects with type II diabetes mellitus.
BACKGROUND
Endothelial function is depressed in the presence of conventional risk factors for atherosclerosis, and various therapies, such as lipid-lowering therapy in hypercholesterolemia, can improve endothelial-mediated vasodilation. ACE inhibition has improved such function in several conditions including type I diabetes, but there is no evidence for a beneficial effect in type II diabetes.
METHODS
The influence of enalapril (10 mg twice daily for 4 weeks) on endothelium-dependent and -independent vasodilator function was determined in 10 type II diabetic subjects using a double-blinded placebo-controlled crossover protocol. Forearm blood flow was measured using strain-gage plethysmography and graded intrabrachial infusion of acetylcholine (ACh), NG-monomethyl-L-arginine (LNMMA) and sodium nitroprusside (SNP).
RESULTS
Enalapril increased the response to the endothelium-dependent vasodilator, ACh (p < 0.02) and the vasoconstrictor response to the nitric oxide (NO) synthase inhibitor, LNMMA (p < 0.002). No difference was evident in the response to SNP.
CONCLUSIONS
In type II diabetic subjects without evidence of vascular disease, the ACE inhibitor enalapril improved stimulated and basal NO-dependent endothelial function. The study extends the spectrum of beneficial effects demonstrated to result from ACE inhibition in diabetes.
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Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme | | ACh | = acetylcholine | | FBF | = forearm blood flow | | FVR | = forearm vascular resistance | | LNMMA | = NG-monomethyl-L-arginine | | NO | = nitric oxide | | SNP | = sodium nitroprusside | | TREND | = Trial on Reversing Endothelial Dysfunction |
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The importance of the endothelium in maintaining a healthy vasculature has been increasingly recognized, particularly with respect to its numerous nitric oxide (NO)-mediated functions. Impaired endothelium-dependent vasodilation, which is largely dependent upon NO, has been found not only in the presence of overt vascular disease but also in association with conventional risk factors for vascular disease (1), and many studies have documented improvement with appropriate interventions.
In non–insulin-dependent, type II diabetic subjects, NO-related dilator endothelial function has usually (2–5), although not invariably (6), been found to be depressed, while results have been inconsistent in type I diabetics (7–10). In the latter, we recently documented that local intrabrachial administration of the angiotensin-converting enzyme (ACE) inhibitor, enalaprilat, produced an acute increase in the vasodilator response to the NO-dependent dilator acetylcholine (ACh), while the response to the endothelium-independent dilator, sodium nitroprusside (SNP), was unaltered (11). Although no improvement in endothelium-dependent flow-mediated dilatation, assessed by ultrasound, was found after oral enalapril administration to type I diabetics in a recent study (12), in our study, one month of oral enalapril produced further improvement in the endothelium-dependent response (11). Angiotensin-converting enzyme inhibitors are becoming more frequently used in both type I and type II diabetics, largely because of their beneficial effect on renal function and albuminuria (13–17). However, whether ACE inhibition improves endothelial function in type II diabetics is unclear. A substantial dose of perindopril failed to improve the forearm blood flow response to the endothelium-dependent dilator methacholine in one study (18), although postischemic hyperemic blood flow was increased. The recent Trial on Reversing Endothelial Dysfunction (TREND) study of quinapril in patients with coronary artery disease included 9 (14%) type II diabetics in the placebo treated group, and 13 (20%) in the group treated with quinapril for six months (19). Coronary endothelial function improved in the entire group treated with quinapril, without distinction between clinical subgroups, suggesting that there was benefit in the type II diabetic patients, although this question was not specifically addressed. However, since strategies to improve vascular and endothelial function in type II diabetics are of considerable clinical importance, the question deserved further study. We therefore examined the effect of ACE inhibition with enalapril therapy of four weeks duration using a placebo-controlled crossover design. Forearm blood flow, and hence resistance vessel function, was assessed by plethysmography, with intraarterial infusion of ACh used to examine endothelium-dependent dilation, SNP to examine endothelium-independent dilation, and the competitive inhibitor of NO synthase, NG-monomethyl-L-arginine (LNMMA), to examine resting NO-related dilated tone.
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Methods
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Subjects.
Ten male subjects (60 ± 3 years) with type II diabetes mellitus, without evidence of microvascular or macrovascular complications, were recruited. They undertook a screening program consisting of a medical history and examination, hematologic and biochemical profile, including measurement of blood glucose, glycated hemoglobin, serum electrolytes, urea and creatinine, uric acid, liver function and serum lipids. The following were excluded: smokers, those with renal impairment or proteinuria, hepatic impairment, gout or hyperuricemia, more than mild hypercholesterolemia or hypertension (see Table 1). Although one patient was receiving lipid-lowering therapy, none were taking vitamin supplements, ACE inhibitors or any other medication known to affect endothelial function other than that for diabetes. One subject was taking no medications, while 5 were on metformin alone, 3 on metformin and gliclazide and 1 on metformin and glipizide. Medications remained unchanged during the study. None had significant microalbuminuria on quantitative assessment (24-h excretion using nephelometric method) or significant retinopathy (full-field photography). The mean glycated hemoglobin at entry was 7.8 ± 0.6% (SE) (normal range = 4.3–6.0%), indicating moderate to good glycemic control. Mean body mass index was 28.4 ± 1.2 kg/m2. The study protocol was approved by Royal Perth Hospital Ethics Committee and subjects gave written informed consent.
Study design.
The effect of four weeks of enalapril therapy was studied using a randomized, double-blind, placebo-controlled crossover protocol. Subjects were randomized in equal numbers to receive enalapril 10 mg twice daily (Renitec; Merck, Sharp & Dohme, Australia) or a similarly packaged placebo. Forearm vascular function was studied after four weeks, following which crossover of therapy occurred with re-study four weeks later. The procedures were conducted, on average, 4 h after the study medication and, for individual subjects, at the same time of the day for the repeat study after crossover. Subjects were required to refrain from drinking alcohol or caffeine-containing beverages for 12 h before the procedure. At each visit the biochemical and hematologic parameters were repeated. There were no adverse side effects.
Protocol.
Investigations were conducted in a quiet, climate-controlled laboratory with subjects lying supine and both forearms supported above heart level. A 20-gauge arterial cannula (Arrow, Reading, Pennsylvania) was introduced into the brachial artery of the nondominant arm under local anesthesia with <2 ml of 1% lidocaine (Astra Pharmaceuticals, Australia) to transduce pressure, for the infusion of drugs or physiologic saline and for sampling of arterial blood. Forearm blood flow (FBF; ml/100 ml forearm/min) was measured simultaneously in both arms by gallium/indium strain-gauge (SG24; Medasonics, Mountain View, California) plethysmography. Wrist cuffs, connected to a flow-regulated source of compressed air, and arm cuffs, connected to a rapid inflation device (E20; D.E. Hokanson, Bellevue, Australia), were placed on each limb. Output from the strain-gauges passed through an amplifier (SPG 16; Medasonics) and was sampled by an on-line microcomputer at 75 Hz before being displayed on a monitor in real time. A software program coordinated the acquisition, storage and display of data as well as inflation and deflation of the arm cuffs, ensuring that blood flow measures were synchronized with cuff inflation during recording periods. Intraarterial pressure was measured continuously (Transpac; Abbot Laboratories, Illinois) throughout the study. Drug infusions were administered using a constant rate infusion pump (IVAC 770; IVAC Corporation, California).
Baseline measurements started at least 25 min after cannulation of the brachial artery. Blood flow measurements were taken by inflating the wrist cuffs to 220 mm Hg, to exclude the hands from the circulation, and by rapidly inflating the upper arm cuffs to 45 mm Hg for 10 out of every 15 s throughout the baseline and drug infusion periods. Output from the strain-gauges was stored, and the average of the last five flow measurements from each period was used for analysis. Between infusions, the cuffs were deflated, allowing at least 15 min for forearm blood flow to recover from the preceding infusion before further baseline measures were recorded.
All solutions were prepared aseptically from sterile stock solutions or ampules immediately before infusion into the brachial artery. ACh (Miochol; Johnson & Johnson, Australia) was infused at 10, 20 and 40 µg/min, each for 3 min, followed by SNP (David Bull Laboratories, Australia) at 2, 4 and 8 µg/min, each for 3 min and then LNMMA (Clinalfa, Switzerland) at 2, 4 and 8 µmol/min, each for 5 min.
Analysis.
Although the low doses of drugs infused in the study produce negligible systemic effects and showed no effect on blood pressure or heart rate, it is still desirable to exclude an alteration in overall hemodynamics as a cause of the flow changes seen in the infused forearm. Thus, FBF was measured simultaneously in both arms, although only one arm was infused, and the noninfused arm served as a control. As in earlier studies (11,20), FBF in the infused arm is described as a ratio to that in the noninfused arm. Changes in these ratios during ACh and SNP infusions are expressed as percentage changes from the baseline immediately preceding each drug administration. In addition, vascular resistance was calculated in the infused arm as the ratio of mean arterial pressure to FBF and expressed as mmHg per ml/100 ml tissue/min.
Results are expressed as means ± SE. The responses after ACE inhibition were compared with placebo responses using two-way analysis of variance with repeated measures performed on the three dose levels of ACh, SNP and LNMMA. A p < 0.05 was considered significant.
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Results
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There was no difference in blood glucose, glycated hemoglobin or serum lipids between enalapril and placebo treatment (Table 1). Blood pressure at the time of FBF measurement was lower during enalapril therapy (p < 0.001), while heart rate was not significantly altered.
Absolute FBF data recorded in the infused and noninfused limbs at baseline and during the infusion of ACh, SNP and LNMMA at three dose levels, during placebo and enalapril administration, are presented in Table 2. The baseline FBF values preceding each drug were not different, indicating adequate washout periods between infusions. Although the responses to ACh and LNMMA were, on average, augmented after enalapril administration, the difference from placebo was not significant. Acetylcholine reduced forearm vascular resistance (FVR) more, on average, after enalapril therapy than after placebo, although this did not achieve statistical significance (p = 0.054). Enalapril significantly augmented the FVR response to LNMMA (p < 0.01), while the response to SNP was unchanged.
However, as described in Methods, it is optimal to analyze the data in terms of FBF ratios, which is the ratio of flow in the infused arm to that in the noninfused arm, and to refer these to the similarly derived baseline ratios preceding each set of drug infusions. Uncorrected ratios at the three dose levels of ACh were significantly greater after enalapril than placebo administration (p < 0.02) and are presented in Table 3, while the responses to SNP and LNMMA were not different. Figures 1–3 present the percentage changes in these ratios from their baselines, in response to ACh, SNP and LNMMA. The vasodilator response to ACh was significantly augmented after enalapril therapy (p < 0.02; Fig. 1), while the response to the endothelium-independent dilator, SNP, was unchanged (Fig. 2). The NO-dependent vasoconstrictor response to LNMMA was increased (p < 0.002, Fig. 3).
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Table 3 FBF Ratios During Graded Infusions of ACh, and During the Preceding Baselines, After Enalapril and Placebo Treatments
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Figure 1 FBF response to three doses of ACh after placebo (open circles) or enalapril (filled squares) administration for four weeks. FBF is expressed as the percentage change in the ratio of infusion arm to noninfusion arm flows relative to the baseline period preceding the administration of ACh. Values are means ± SE. Vasodilation to ACh was significantly increased (p < 0.02).
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Figure 2 FBF response to three doses of SNP after placebo (open circles) or enalapril (filled squares) administration for four weeks. FBF is expressed as the percentage change in the ratio of infusion arm to noninfusion arm flows relative to the baseline period preceding the administration of SNP. Values are means ± SE. The responses to the endothelium-independent vasodilator, SNP, were unchanged by enalapril therapy.
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Figure 3 FBF response to three doses of LNMMA after placebo (open circles) or enalapril (filled squares) administration for four weeks. FBF is expressed as the percentage change in the ratio of infusion arm to noninfusion arm flows relative to the baseline. Values are means ± SE. The endothelium, NO-dependent vasoconstrictor responses to LNMMA were significantly augmented by enalapril therapy (p < 0.002).
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Discussion
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Principle findings and comparison with previous studies.
The results of this study indicate that enalapril therapy given orally for four weeks to type II diabetics significantly improved endothelial function. Vasodilation in response to ACh, largely mediated through NO, was increased and vasoconstriction to the NO synthase inhibitor, LNMMA, was also augmented, the latter indicating greater resting NO-dependent dilation. These findings extend our previous observation of improvement in endothelial function, in terms of the response to ACh, in type I diabetics treated with enalapril for four weeks (11). LNMMA was not given in that study to test resting NO dilator tone. However, intrabrachial co-infusion of enalaprilat with ACh augmented the ACh response, indicating that the response is almost certainly due to a local vascular effect of ACE inhibition and not primarily to a systemic effect, for example, associated with hypotension. This contention is supported by the observation that captopril improved endothelial function in hypertensives whereas nifedipine did not (21) and, indirectly, by the observation that lisinopril improved capillary permeability and reduced urinary albumin loss more than did atenolol in hypertensive type II diabetics (17).
In contrast to the present findings, an earlier study found no beneficial effect on endothelial function, tested with methacholine, when perindopril was given for six months to type II diabetics (18). However, ACE inhibition has been reported to improve endothelial function in patients with heart failure (22,23), hypertension (21), coronary artery disease (19) and even normal subjects (24). It is therefore not surprising that it does so in diabetics but, because of the prevalence of type II diabetes and the predisposition to vascular disease, this was considered important to document.
Mechanisms responsible for endothelial dysfunction in diabetes.
Most of our patients were being treated on hypoglycemic drugs, which may improve NO-mediated endothelial function (25). However, such drugs are commonly used in type II diabetics and it was ensured that they remained unchanged throughout the study. It was not an aim of the study to compare endothelial function in type II diabetic and normal subjects; although there are negative studies (6), there is substantial evidence that endothelial function is depressed in type II diabetics (2–5). The responsible mechanisms are unknown and the possibilities have been discussed by others (2), with emphasis on strong evidence from diabetic animal studies for inactivation of NO by oxygen-derived free radicals, such as superoxide anions, or by advanced glycosylation products. There is also evidence that insulin stimulates the production of NO through the insulin receptor and that the effector pathway has some commonality with that for glucose transport, as demonstrated in cultured human vascular endothelial cells (26). Presumably, lack of insulin production or resistance to the action of insulin in the clinical diabetic states would, therefore, depress NO production. It seems that, in vivo, either an influence of insulin on NO production, or on its inactivation or effectiveness, could explain the relationships between insulin, diabetes and NO-related vasoactivity, as recently summarized (11).
Potential mechanisms responsible for ACE effect.
Although we have demonstrated improved basal and stimulated endothelial function in type II diabetes with ACE inhibition, this study does not elucidate mechanisms. Several possibilities exist. If greater quenching of NO by superoxide anions contributes substantially to the defect in diabetes, it would be analogous to that which is implicated in the endothelial dysfunction in hypercholesterolemia and probably in other conditions (27). The generation of such oxygen-derived free radicals may be dependent upon xanthine oxidase or upon membrane-bound vascular oxidases (27), and one possible mechanism for the beneficial effect of ACE inhibition could relate to the latter (28). Angiotensin II increases the activity of these oxidases along with the production of superoxide, an effect inhibited by selective blockade of angiotensin type I receptors (27–29). Angiotensin-converting enzyme inhibition could act through this oxidase system. Additionally, the inhibition of angiotensin II production could lead to increased activity of NO synthase, and production of NO, through an effect on protein kinase C (28). An alternate possibility is that inhibition of the breakdown of bradykinin by kininase II, which is synonymous with ACE, plays a role in the beneficial response to the enzyme inhibitor since bradykinin stimulates the endothelial production of NO (30–32). Whether the preservation of endogenous bradykinin is important is unclear, but the coronary vasodilation resulting from the intracoronary administration of bradykinin, in humans, is decreased by local infusion of LNMMA and increased by enalaprilat, indicating that the largely NO-dependent dilation induced by bradykinin is potentiated by enzyme inhibition (30).
Other interventions studied for their effect on the endothelial dysfunction of diabetes help little to elucidate mechanisms. The substantial improvement in vasodilation to intraarterial methacholine resulting from local vitamin C infusion in type II diabetics was not seen in normal subjects and tends to implicate oxidants in the defect (33). However, vitamin C also improves the endothelium-dependent posthyperemic response in the brachial artery of patients with coronary artery disease (34). Further, tetrahydrobiopterin, a cofactor for NO synthase, and an antioxidant, improves endothelial function in both experimental diabetes (35) and in hypercholesterolemia (36), as does the administration of fish oil in these clinical conditions (37,38). Yet, tetrahydrobiopterin might play a particular role in diabetes since its concentration is reduced in the diabetic rat (39) and its metabolism is dependent upon the oxidant state (35,36). In summary, a number of interventions improve endothelial function in diverse conditions associated with depressed endothelial function; the oxidant state is likely to be important in the various pathologies associated with endothelial dysfunction and to relate to the effect of ACE inhibition.
Conclusion and implications.
Whatever the mechanism, improvement in endothelial function in type II diabetes by ACE inhibition is potentially of considerable clinical relevance in the management of this disease. It has been known for some time that ACE inhibition in this common form of diabetes preserves renal function and reduces albuminuria (13–17). In fact, these renal manifestations and the improvement in endothelial function, demonstrated here in terms of the NO dilator response, are probably closely related. It is likely that there would be commensurate benefit in other NO-related functions such as the regulation of vascular smooth muscle proliferation, and adhesion and interaction of platelets and monocytes with vessel walls, all processes integral to the development of atherosclerosis.
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Footnotes
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This study was supported by the Raine Foundation of The University of Western Australia, Nedlands, Australia. Enalapril and placebo were supplied by Merck, Sharpe and Dohme (Australia).
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E. Gkaliagkousi, A. Shah, and A. Ferro
Review: Pharmacological and non-pharmacological treatment of endothelial dysfunction: relevance to diabetes
The British Journal of Diabetes & Vascular Disease,
January 1, 2007;
7(1):
5 - 10.
[Abstract]
[PDF]
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J.-H. Oak and H. Cai
Attenuation of Angiotensin II Signaling Recouples eNOS and Inhibits Nonendothelial NOX Activity in Diabetic Mice
Diabetes,
January 1, 2007;
56(1):
118 - 126.
[Abstract]
[Full Text]
[PDF]
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J. R. Grubb, A. Dejam, J. Voell, W. C. Blackwelder, P. A. Sklar, J. A. Kovacs, R. O. Cannon, H. Masur, and M. T. Gladwin
Lopinavir-Ritonavir: Effects on Endothelial Cell Function in Healthy Subjects
The Journal of Infectious Disease,
June 1, 2006;
193(11):
1516 - 1519.
[Abstract]
[Full Text]
[PDF]
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I. L Williams, P. J Chowienczyk, S. B Wheatcroft, A. G Patel, R. A Sherwood, A. M Shah, and M. T Kearney
Divergent effects of angiotensin-converting enzyme inhibition on blood pressure and endothelial function in obese humans
Diabetes and Vascular Disease Research,
May 1, 2006;
3(1):
34 - 38.
[Abstract]
[PDF]
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T. S. Hermann, W. Li, H. Dominguez, N. Ihlemann, C. Rask-Madsen, A. Major-Pedersen, D. B. Nielsen, K. W. Hansen, M. Hawkins, L. Kober, et al.
Quinapril Treatment Increases Insulin-Stimulated Endothelial Function and Adiponectin Gene Expression in Patients with Type 2 Diabetes
J. Clin. Endocrinol. Metab.,
March 1, 2006;
91(3):
1001 - 1008.
[Abstract]
[Full Text]
[PDF]
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J. B. Meigs, C. J. O'Donnell, G. H. Tofler, E. J. Benjamin, C. S. Fox, I. Lipinska, D. M. Nathan, L. M. Sullivan, R. B. D'Agostino, and P. W.F. Wilson
Hemostatic Markers of Endothelial Dysfunction and Risk of Incident Type 2 Diabetes: The Framingham Offspring Study
Diabetes,
February 1, 2006;
55(2):
530 - 537.
[Abstract]
[Full Text]
[PDF]
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S. Watanabe, T. Tagawa, K. Yamakawa, M. Shimabukuro, and S. Ueda
Inhibition of the Renin-Angiotensin System Prevents Free Fatty Acid-Induced Acute Endothelial Dysfunction in Humans
Arterioscler Thromb Vasc Biol,
November 1, 2005;
25(11):
2376 - 2380.
[Abstract]
[Full Text]
[PDF]
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Y. Taniyama, H. Hitomi, A. Shah, R. W. Alexander, and K. K. Griendling
Mechanisms of Reactive Oxygen Species-Dependent Downregulation of Insulin Receptor Substrate-1 by Angiotensin II
Arterioscler Thromb Vasc Biol,
June 1, 2005;
25(6):
1142 - 1147.
[Abstract]
[Full Text]
[PDF]
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D. R. Morgan, L. J. Dixon, C. G. Hanratty, S. M.T. Hughes, W. J. Leahey, K. P. Rooney, G. D. Johnston, and G. E. McVeigh
Impaired endothelium-dependent and -independent vasodilation in elderly patients with chronic heart failure
Eur J Heart Fail,
December 1, 2004;
6(7):
901 - 908.
[Abstract]
[Full Text]
[PDF]
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D. J Green, A. Maiorana, G. O'Driscoll, and R. Taylor
Effect of exercise training on endothelium-derived nitric oxide function in humans
J. Physiol.,
November 15, 2004;
561(1):
1 - 25.
[Abstract]
[Full Text]
[PDF]
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K. Watts, P. Beye, A. Siafarikas, E. A. Davis, T. W. Jones, G. O'Driscoll, and D. J. Green
Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents
J. Am. Coll. Cardiol.,
May 19, 2004;
43(10):
1823 - 1827.
[Abstract]
[Full Text]
[PDF]
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F. Andreozzi, E. Laratta, A. Sciacqua, F. Perticone, and G. Sesti
Angiotensin II Impairs the Insulin Signaling Pathway Promoting Production of Nitric Oxide by Inducing Phosphorylation of Insulin Receptor Substrate-1 on Ser312 and Ser616 in Human Umbilical Vein Endothelial Cells
Circ. Res.,
May 14, 2004;
94(9):
1211 - 1218.
[Abstract]
[Full Text]
[PDF]
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J. B. Meigs, F. B. Hu, N. Rifai, and J. E. Manson
Biomarkers of Endothelial Dysfunction and Risk of Type 2 Diabetes Mellitus
JAMA,
April 28, 2004;
291(16):
1978 - 1986.
[Abstract]
[Full Text]
[PDF]
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F. B. Hu, J. B. Meigs, T. Y. Li, N. Rifai, and J. E. Manson
Inflammatory Markers and Risk of Developing Type 2 Diabetes in Women
Diabetes,
March 1, 2004;
53(3):
693 - 700.
[Abstract]
[Full Text]
[PDF]
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R. T. Hurst and R. W. Lee
Increased Incidence of Coronary Atherosclerosis in Type 2 Diabetes Mellitus: Mechanisms and Management
Ann Intern Med,
November 18, 2003;
139(10):
824 - 834.
[Abstract]
[Full Text]
[PDF]
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A. K. Trauernicht, H. Sun, K. P. Patel, and W. G. Mayhan
Enalapril Prevents Impaired Nitric Oxide Synthase-Dependent Dilatation of Cerebral Arterioles in Diabetic Rats
Stroke,
November 1, 2003;
34(11):
2698 - 2703.
[Abstract]
[Full Text]
[PDF]
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J. H. Walsh, G. Yong, C. Cheetham, G. F. Watts, G. J. O'Driscoll, R. R. Taylor, and D. J. Green
Effects of exercise training on conduit and resistance vessel function in treated and untreated hypercholesterolaemic subjects
Eur. Heart J.,
September 2, 2003;
24(18):
1681 - 1689.
[Abstract]
[Full Text]
[PDF]
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F. Locatelli, B. Canaud, K.-U. Eckardt, P. Stenvinkel, C. Wanner, and C. Zoccali
The importance of diabetic nephropathy in current nephrological practice
Nephrol. Dial. Transplant.,
September 1, 2003;
18(9):
1716 - 1725.
[Abstract]
[Full Text]
[PDF]
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J. H. Walsh, W. Bilsborough, A. Maiorana, M. Best, G. J. O'Driscoll, R. R. Taylor, and D. J. Green
Exercise training improves conduit vessel function in patients with coronary artery disease
J Appl Physiol,
July 1, 2003;
95(1):
20 - 25.
[Abstract]
[Full Text]
[PDF]
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J. T. Kuvin and R. H. Karas
Clinical Utility of Endothelial Function Testing: Ready for Prime Time?
Circulation,
July 1, 2003;
107(25):
3243 - 3247.
[Full Text]
[PDF]
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H. Tezcan, D. Yavuz, A. Toprak, I. Akpmar, M. Koc, O. Deyneli, and S. Akalm
Effect of angiotensin-converting enzyme inhibition on endothelial function and insulin sensitivity in hypertensive patients
Journal of Renin-Angiotensin-Aldosterone System,
June 1, 2003;
4(2):
119 - 123.
[Abstract]
[PDF]
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P. O. Bonetti, L. O. Lerman, and A. Lerman
Endothelial Dysfunction: A Marker of Atherosclerotic Risk
Arterioscler Thromb Vasc Biol,
February 1, 2003;
23(2):
168 - 175.
[Abstract]
[Full Text]
[PDF]
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A. Kjaer, C. Meyer, F. S. Nielsen, H.-H. Parving, and B. Hesse
Dipyridamole, Cold Pressor Test, and Demonstration of Endothelial Dysfunction: A PET Study of Myocardial Perfusion in Diabetes
J. Nucl. Med.,
January 1, 2003;
44(1):
19 - 23.
[Abstract]
[Full Text]
[PDF]
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F. Enseleit, T.F. Luscher, and F. Ruschitzka
Angiotensin-converting enzyme inhibition and endothelial dysfunction: focus on ramipril
Eur. Heart J. Suppl.,
January 1, 2003;
5(suppl_A):
A31 - A36.
[Abstract]
[PDF]
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S. P Marso
Review: The pathogenesis of type 2 diabetes and cardiovascular disease
The British Journal of Diabetes & Vascular Disease,
September 1, 2002;
2(5):
350 - 356.
[Abstract]
[PDF]
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J. Davies and A. Struthers
Review: The potential benefits of aldosterone antagonism in Type 2 diabetes mellitus
Journal of Renin-Angiotensin-Aldosterone System,
September 1, 2002;
3(3):
150 - 155.
[Abstract]
[PDF]
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D. Green, C. Cheetham, L. Mavaddat, K. Watts, M. Best, R. Taylor, and G. O'Driscoll
Effect of lower limb exercise on forearm vascular function: contribution of nitric oxide
Am J Physiol Heart Circ Physiol,
September 1, 2002;
283(3):
H899 - H907.
[Abstract]
[Full Text]
[PDF]
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E. Nicolaides and C. J. Jones
Review: Type 2 diabetes -- implications for macrovascular mechanics and disease
The British Journal of Diabetes & Vascular Disease,
January 1, 2002;
2(1):
9 - 12.
[Abstract]
[PDF]
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Y. Arad, D. Newstein, F. Cadet, M. Roth, and A. D. Guerci
Association of Multiple Risk Factors and Insulin Resistance With Increased Prevalence of Asymptomatic Coronary Artery Disease by an Electron-Beam Computed Tomographic Study
Arterioscler Thromb Vasc Biol,
December 1, 2001;
21(12):
2051 - 2058.
[Abstract]
[Full Text]
[PDF]
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R D Rakhit and M S Marber
Nitric oxide: an emerging role in cardioprotection?
Heart,
October 1, 2001;
86(4):
368 - 372.
[Full Text]
[PDF]
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A. Maiorana, G. O'Driscoll, C. Cheetham, L. Dembo, K. Stanton, C. Goodman, R. Taylor, and D. Green
The effect of combined aerobic and resistance exercise training on vascular function in type 2 diabetes
J. Am. Coll. Cardiol.,
September 1, 2001;
38(3):
860 - 866.
[Abstract]
[Full Text]
[PDF]
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R. J. Woodman, D. A. Playford, G. F. Watts, C. Cheetham, C. Reed, R. R. Taylor, I. B. Puddey, L. J. Beilin, V. Burke, T. A. Mori, et al.
Improved analysis of brachial artery ultrasound using a novel edge-detection software system
J Appl Physiol,
August 1, 2001;
91(2):
929 - 937.
[Abstract]
[Full Text]
[PDF]
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A. Asberg, K. Midtvedt, T. Vassbotn, and A. Hartmann
Better microvascular function on long-term treatment with lisinopril than with nifedipine in renal transplant recipients
Nephrol. Dial. Transplant.,
July 1, 2001;
16(7):
1465 - 1470.
[Abstract]
[Full Text]
[PDF]
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J. Calles-Escandon and M. Cipolla
Diabetes and Endothelial Dysfunction: A Clinical Perspective
Endocr. Rev.,
February 1, 2001;
22(1):
36 - 52.
[Abstract]
[Full Text]
[PDF]
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J. M. A. van Ampting, M. L. Hijmering, J. J. Beutler, R. E. van Etten, H. A. Koomans, T. J. Rabelink, and E. S. G. Stroes
Vascular Effects of ACE Inhibition Independent of the Renin-Angiotensin System in Hypertensive Renovascular Disease : A Randomized, Double-Blind, Crossover Trial
Hypertension,
January 1, 2001;
37(1):
40 - 45.
[Abstract]
[Full Text]
[PDF]
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C. Cheetham, J. Collis, G. O'Driscoll, K. Stanton, R. Taylor, and D. Green
Losartan, an angiotensin type 1 receptor antagonist, improves endothelial function in non-insulin-dependent diabetes
J. Am. Coll. Cardiol.,
November 1, 2000;
36(5):
1461 - 1466.
[Abstract]
[Full Text]
[PDF]
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A. Maiorana, G. O'Driscoll, L. Dembo, C. Cheetham, C. Goodman, R. Taylor, and D. Green
Effect of aerobic and resistance exercise training on vascular function in heart failure
Am J Physiol Heart Circ Physiol,
October 1, 2000;
279(4):
H1999 - H2005.
[Abstract]
[Full Text]
[PDF]
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D.W. Laight, M.J. Carrier, and E.E. Anggard
Antioxidants, diabetes and endothelial dysfunction
Cardiovasc Res,
August 18, 2000;
47(3):
457 - 464.
[Abstract]
[Full Text]
[PDF]
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Abstract
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