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Reza Aghamohammadzadeh,
Adam S Greenstein,
Rahul Yadav,
Maria Jeziorska,
Salam Hama,
Fardad Soltani,
Phil W Pemberton,
Basil Ammori,
Rayaz A Malik,
Handrean Soran, Anthony M Heagerty
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ABSTRACT: OBJECTIVES: The aim of this study was to investigate the effects of bariatric surgery on small artery function and the mechanisms underlying this. BACKGROUND: In lean healthy humans, perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arteries, but this is lost in obesity-associated conditions such as the Metabolic Syndrome and Type II Diabetes where there is evidence of adipocyte inflammation and increased oxidative stress. METHODS: Segments of small subcutaneous artery and perivascular fat were harvested from severely obese individuals before (n = 20) and 6 months after bariatric surgery (n = 15). Small artery contractile function was examined in-vitro using wire myography and perivascular adipose tissue (PVAT) morphology was assessed using immunohistochemistry. RESULTS: The anticontractile activity of PVAT was lost in obese patients before surgery when compared with healthy volunteers, and was restored 6 months after bariatric surgery. In-vitro protocols using superoxide dismutase and catalase rescued PVAT anticontractile function in tissue from obese individuals prior to surgery. The improvement in anticontractile function following surgery was accompanied by improvements in insulin sensitivity, serum glycaemic indices, inflammatory cytokines, adipokine profile, and systolic blood pressure together with increased PVAT adiponectin and nitric oxide bioavailability and reduced macrophage infiltration and inflammation. These changes were observed despite the patients remaining severely obese. CONCLUSIONS: Bariatric surgery and its attendant improvements in weight, blood pressure, inflammation and metabolism collectively reverse the obesity-induced alteration to PVAT anticontractile function. This reversal is attributable to reductions in local adipose inflammation and oxidative stress with improved adiponectin and nitric oxide bioavailability.
Journal of the American College of Cardiology 05/2013; · 14.16 Impact Factor
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ABSTRACT: Prevention of target organ damage represents the El Dorado for clinicians who treat hypertension. Although many of the cardiovascular sequelae of chronic hypertension are due to large artery atherosclerosis, an equal number are due to small artery dysfunction. These microvascular complications include eye disease (retinopathy), kidney failure, diastolic dysfunction of the heart and small vessel brain disease leading to stroke syndromes, dementia and even depression. Examination of the retinal vasculature represents the only way to reliably derive information regarding small arteries responsible for these diverse pathologies. This review aims to summarise the rapidly accruing evidence indicating that easily observable abnormalities of retinal arteries reflect target organ damage elsewhere in the body of hypertensive patients. In tandem, we also present putative mechanisms by which hypertension and diabetes fundamentally change small artery structure and function and how these processes may lead to target organ damage.
Current Hypertension Reports 04/2013; · 2.50 Impact Factor
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ABSTRACT: OBJECTIVE This study aims to identify the potential mechanisms by which perivascular adipose tissue (PVAT) reduces tone in small arteries. METHODS AND RESULTS Small mesenteric arteries from wild type and BK(Ca) knockout mice were mounted on a wire myograph in the presence and absence of PVAT and contractile responses to norepinephrine were assessed. Electrophysiology studies were performed in isolated vessels to measure changes in membrane potential produced by adiponectin. Contractile responses from wild type mouse small arteries were significantly reduced in the presence of PVAT. This was not observed in the presence of a BK(Ca) channel inhibitor or with NOS inhibition or in BKCa or adiponectin knockout mice. Solution transfer experiments demonstrated the presence of an anticontractile factor released from PVAT. Adiponectin induced vasorelaxation and hyperpolarisation in wild type arteries was not evident in the absence or after inhibition of BK(Ca) channels. PVAT from BK(Ca) or adiponectin knockout mice failed to elicit an anticontractile response in wild type arteries. CONCLUSIONS PVAT releases adiponectin which is an anticontractile factor. Its effect on vascular tone is mediated by activation of BK(Ca) channels on vascular smooth muscle cells and adipocytes and by endothelial mechanisms.
AJP Heart and Circulatory Physiology 01/2013; · 3.71 Impact Factor
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ABSTRACT: The advent of the obesity epidemic has highlighted the need to re-assess more closely the pathophysiology of obesity-related hypertension with the aim of identifying new therapies. In this article, we review the role of the renin-angiotensin-aldosterone system, sympathetic nervous system, and inflammation in relation to the pathophysiology of this condition. We also discuss the potential role of the perivascular adipose tissue in the context of obesity-related hypertension.
Annals of medicine 06/2012; 44 Suppl 1:S74-84. · 3.52 Impact Factor
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ABSTRACT: The Brown Norway rat is highly susceptible to cerebral haemorrhage when hypertension is induced experimentally, compared with the Long Evans. The aims of the study were to compare the myogenic properties and also the collagen-staining profile of the middle cerebral artery (MCA) and a small systemic artery (cremaster) from Brown Norway and Long Evans rats.
In-vitro pressure myography was used to compare the myogenic properties and the distensibility of MCA and cremaster arteries from Brown Norway rat, with those of the Long Evans rat. Histologically prepared arterial sections were stained with picrosirius red to compare the collagen-staining profile of MCA and cremaster from these strains of rat.
In the presence of myogenic tone, the active pressure-diameter relationship (20-200 mmHg) was significantly different in MCA from the Brown Norway, but not cremaster arteries, compared with the Long Evans, characterized by in the lack of a myogenic range in the Brown Norway. Midwall collagen staining was significantly increased in MCA from the Brown Norway rat, compared with the Long Evans rat; this difference between rat strains was not observed in the cremaster arteries. However, the stress-strain relationship of MCA and cremaster arteries from the Brown Norway rat was shifted to the right, indicating an increased distensibilty of arteries from both vascular beds, compared with the Long Evans.
These data demonstrate impaired myogenic properties and differences in the collagen-staining profile of MCA but not cremaster arteries from the Brown Norway rat, compared with the Long Evans. The impaired myogenic properties of MCA from the Brown Norway rat compared with the Long Evans may explain their increased susceptibility to cerebral haemorrhage when hypertension is induced experimentally.
Journal of hypertension 03/2012; 30(5):926-31. · 4.02 Impact Factor
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ABSTRACT: Previous studies have demonstrated that hypertension and diabetes induce significant structural remodelling of resistance arteries from various vascular beds. The hypothesis of this study is that structural alterations of small coronary arteries may occur during hypertension and diabetes. This study is the first to compare human coronary small resistance artery structure from normotensive and hypertensive patients, with and without diabetes undergoing coronary arterial bypass graft surgery.
Small arteries were dissected from the atrial appendage removed from nondiabetic normotensive patients, nondiabetic hypertension and diabetic normotensive patients and hypertensive diabetic patients. Arteries were mounted in a pressure myograph and lumen diameter and wall thickness were measured across the pressure range of 3-100 mmHg to assess vessel structure and distensibility.
There were no significant differences in the lumen diameter, wall thickness, wall-to-lumen ratio and cross-sectional area of arteries in all groups. Arteries from nondiabetic patients with hypertension demonstrated decreased distensibility compared with nondiabetic normotensive patients. There is no difference in distensibility between vessels from diabetic hypertensive patients and either diabetic or nondiabetic normotensive patients.
Neither diabetes nor hypertension appears to have influenced arterial structure which may indicate that successful treatment of hypertension is associated with normal vascular structure in coronary small arteries.
Journal of hypertension 11/2011; 30(2):384-9. · 4.02 Impact Factor
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Anthony M Heagerty
American Journal of Hypertension 11/2011; 25(1):22. · 3.18 Impact Factor
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Anthony M Heagerty
The Lancet 08/2011; 378(9798):1200-2. · 38.28 Impact Factor
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ABSTRACT: Damage to renal artery myogenic tone is universally associated with progressive kidney damage. Recently, we have observed that mutations in the beta adducin subunit are associated with proteinuria in the Milan rat. Because of the role of adducin as a component of the cytoskeleton we hypothesized that this mutation may be associated with changes in myogenic tone.
Congenic rats were generated with beta adducin subunit mutation (NB rats) and compared with a previously studied rat model with alpha adducin subunit mutation (NAs rats). Blood pressure and urinary protein excretion were studied at two time points: 6 weeks and 4 months of age, and at these time points, small renal, middle cerebral and skeletal (cremaster) arteries were isolated and studied using pressure myography. Agonist-induced vasoconstriction was not different between the two groups at any age. However, myogenic tone in renal arteries was significantly damaged in the NB rat compared to its NAs counterpart and this was associated with a decrease in vascular distensibility. There was a smaller reduction in myogenic tone in the middle cerebral arteries from the NB rat, whereas in the skeletal arteries there was no difference between the two strains. In the NB rat, this tissue-specific damage to myogenic tone was associated with progressive proteinuria despite lower blood pressure than the NAs rat.
Mutations in the beta subunit of the adducin protein result in damage to renal artery myogenic tone and this is associated with renal damage as manifest by proteinuria.
Journal of hypertension 03/2011; 29(3):466-74. · 4.02 Impact Factor
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ABSTRACT: The aim of this study was to determine whether macrophages dispersed throughout perivascular fat are crucial to the loss of anticontractile function when healthy adipose tissue becomes inflamed and to gain an understanding of the mechanisms involved.
Pharmacological studies on in vitro small arterial segments from a mouse model of inducible macrophage ablation and on wild-type animals were carried out with and without perivascular fat using 2 physiological stimuli of inflammation: aldosterone and hypoxia. Both inflammatory insults caused a similar loss of anticontractile capacity of perivascular fat and increased macrophage activation. Aldosterone receptor antagonism and free radical scavengers were able to restore this capacity and reduce macrophage activation. However, in a mouse deficient of macrophages CD11b-diptheria toxin receptor (CD11b-DTR), there was no increase in contractility of arteries following aldosterone incubation or hypoxia.
The presence and activation of macrophages in adipose tissue is the key modulator of the increase in contractility in arteries with perivascular fat following induction of inflammation. Despite multiple factors that may be involved in bringing about the vascular consequences of obesity, the ability of eplerenone to ameliorate the inflammatory effects of both aldosterone and hypoxia may be of potential therapeutic interest.
Arteriosclerosis Thrombosis and Vascular Biology 01/2011; 31(4):908-13. · 6.37 Impact Factor
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ABSTRACT: Late-life depression is increasingly viewed as a vascular illness because of patients exhibiting characteristic white matter brain lesions and in vivo large artery endothelial dysfunction. However, the "vascular depression" hypothesis pertains to the microvasculature, and this circulation has not been studied in this context. Our objective was to examine structure and function of small subcutaneous arteries in patients with late-life depression. Thus, 16 patients aged 71.8±4.0 years with late-life depression were compared with 15 control participants aged 72.1±5.9 years. There were similar cardiovascular profiles between the 2 groups. All of the participants underwent MRI brain scans and subcutaneous gluteal fat biopsy from which small arteries were isolated and studied using pressure myography. Cerebral microvascular damage in depressed patients was confirmed by assessment of basal ganglia Virchow-Robin space scores (depressed patients 3.9±1.7 versus controls: 2.5±1.6; P=0.01). Contractility to norepinephrine was equivalent in both groups, but relaxation of the small arteries to acetylcholine was significantly reduced in depressed patients (84.0±4.0%) compared with control participants (96.0±1.4%; P=0.012). This difference in arterial relaxation was reduced but not entirely eliminated when NO synthase was inhibited. Depressed patients also exhibited hypertrophic wall growth with an increase in medial cross-sectional area (P=0.035, multiple ANOVA and wall thickness; P=0.04, multiple ANOVA). In conclusion, despite similar cardiovascular profiles, depressed patients with cerebral microvascular damage show abnormalities of subcutaneous small artery structure and function.
Hypertension 10/2010; 56(4):734-40. · 6.21 Impact Factor
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ABSTRACT: The mechanisms by which perivascular adipose tissue (PVAT) can reduce vascular contractility remain to be elucidated and may underlie the associations of obesity with hypertension, insulin resistance and cardiovascular disease. This study investigates the effects of aldosterone and obesity in isolated rat aorta. Healthy and obese male rats were killed by stunning and cervical dislocation. The mesenteric bed was removed and arteries dissected with and without PVAT. Arteries were mounted on a wire myograph and were constricted with 60 mM KPSS. Cumulative concentration responses (10(-9)-10(-5) M) to norepinephrine (NE) were performed before and after 10 min incubation with aldosterone (5 nM). Endothelial integrity was confirmed by relaxation to 10(-5) M acetylcholine. Responses are expressed as mean (+/-SEM) percentage of KPSS constriction and analysed using two-way ANOVA. PVAT (n=10) significantly (p<0.05) reduced constriction in healthy vessels (PVAT: 81 (20)% vs no PVAT: 140 (27)% at 10(-5) M NE). The anticontractile properties of PVAT are abolished (n=6) in the presence of aldosterone (PVAT: 53 (24)% vs no PVAT: 62 (35)% at 10(-5) M NE). Aldosterone significantly reduced tension (p<0.05) compared with no PVAT controls. The anticontractile properties of PVAT (n=6) are absent in arteries from obese animals (PVAT: 105 (33)% vs no PVAT: 91 (15)% at 10(-5) M NE); however, in the presence of aldosterone (n=6) constrictions are significantly increased (p<0.05) in arteries with (PVAT: 133 (49)% vs no PVAT: 89 (18)% at 10(-5) M NE).These results demonstrate that obesity and aldosterone impair the anticontractile effects of PVAT. Aldosterone reduces contractility in healthy arteries but increases contractility in obese arteries.
Heart (British Cardiac Society) 09/2010; 96(17):e22-3. · 4.22 Impact Factor
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ABSTRACT: Cerebrovascular disease plays an important role in depressive disorder, especially in older adults. An understanding of vascular function in depression is important etiologically and to develop innovative treatments that may improve prognosis by ameliorating vascular damage.
This study assessed endothelial function, arterial stiffness, and atherosclerosis in a variety of vessel beds in 25 elderly subjects with depressive disorder compared with 21 nondepressed control subjects. Subjects underwent pulse wave velocity, pulse wave analysis, carotid intima media thickness analysis, and magnetic resonance imaging. A subset (16 patients and 15 control subjects) had assessment of biopsied small artery dilatation to acetylcholine to further assess endothelial function.
The mean sample age was 72.4 years with an average age at onset for depression of 60 years. Mean carotid intima media thickness was significantly higher in depressed subjects (p < .01). Pulse wave velocity was 1.6 m/sec higher in depressed subjects (borderline significance). There was a significant reduction in the dilatation response to acetylcholine in preconstricted small arteries (p = .01). On magnetic resonance imaging, depressed subjects had significantly more dilated Virchow-Robin spaces in the basal ganglia (p = .01). Depressed subjects had greater volume of white matter lesions in all regions, but this did not reach statistical significance. There were no baseline differences in vascular risk.
Depression in the elderly is associated with poorer endothelial function and more atherosclerosis. This is associated with a greater white matter hyperintensities lesion load and basal ganglia microangiopathy. The use of vasoprotective drugs to improve endothelial function or retard atherosclerosis as depression-modifying agents should be explored.
Biological psychiatry 07/2010; 68(2):133-9. · 8.93 Impact Factor
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ABSTRACT: It has been known for some considerable time that sustained hypertension changes the circulatory architecture both in the heart and blood vessels. The histopathological alterations are of considerable interest because once they have developed they appear to carry an adverse prognostic risk. In the heart it is apparent that there is hypertrophy. This extends also to the large- and medium-sized blood vessels but at the level of the smaller arteries that contribute to vascular resistance, this is not the case: it is clear that the physiological response to higher pressures is a change in the positional conformation of the pre-existing tissue constituents and as a result of this the lumen is narrowed. This brief review looks at our knowledge in this area and attempts to clarify our understanding of how hypertension brings these about and what happens when these homeostatic mechanisms break down. From a therapeutic perspective it appears imperative to control blood pressure in an attempt to reverse or prevent such alterations to cardiovascular structure. Our knowledge is fast expanding in this field and it is only to be anticipated that as detection methodology improves everyday practice will alter as we profile our patients in terms of structural alterations in the ventricle and blood vessels.
Journal of Cellular and Molecular Medicine 05/2010; 14(5):1037-43. · 4.13 Impact Factor
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ABSTRACT: Type 2 diabetes mellitus profoundly changes small artery remodeling in response to hypertension. Abnormal increases of both wall thickness and lumen diameter are associated with an increased mortality. Changes to small artery structure in response to blood pressure (BP) in patients with type 1 diabetes mellitus have never been examined. In 1997, 17 patients with type 1 diabetes mellitus and 9 control subjects underwent in vitro assessment of gluteal-fat small arteries using pressure myography. Patients with BP <140/90 mm Hg (systolic BP: 119+/-3 mm Hg; n=12) had normal-resistance artery structure. However, patients with BP >140/90 mm Hg (systolic BP: 152+/-5 mm Hg; n=5) demonstrated vascular hypertrophic remodeling with a significant increase in the medial cross-sectional area and wall thickness. In 2008, 8 of the original 17 diabetic patients returned for a repeat assessment. All 8 of the patients had significantly improved cholesterol (2008: 154+/-9 mg/dL versus 1997: 191+/-9 mg/dL; P=0.01) and low-density lipoprotein cholesterol (2008: 79+/-8 mg/dL versus 1997: 122+/-9 mg/dL; P=0.003) but higher BPs (systolic BP: 2008: 136+/-3 mm Hg versus 1997: 119+/-6 mm Hg; P=0.03). Glycemia was improved (2008: 7.9+/-0.3% versus 1997: 8.9+/-0.6%; P=0.17), but not significantly so. In the small arteries studied, there were significant increases in medial wall thickness and wall:lumen ratio, but cross-sectional area was unchanged, indicating eutrophic remodeling. Collectively, these findings suggest that, with poor metabolic control, small arteries from patients with type 1 diabetes mellitus show hypertrophic growth in response to elevated BP, similar to that seen in type 2 diabetes mellitus. However, metabolic improvements enable eutrophic remodeling to occur in response to an increase in BP. This has only been observed previously in patients without diabetes mellitus.
Hypertension 08/2009; 54(1):134-41. · 6.21 Impact Factor
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ABSTRACT: Diabetic individuals have a significantly increased likelihood of developing cardiovascular disease. Whilst part of this association is explained by the presence of concomitant risk factors, large epidemiological studies have consistently reported diabetes as a strong risk factor for the development of heart failure after adjusting for such covariates. This has resulted in the notion that there is a distinct cardiomyopathy specific to diabetes, termed 'diabetic cardiomyopathy'. The natural history is characterized by a latent subclinical period, during which there is evidence of diastolic dysfunction and left ventricular hypertrophy, before overt clinical deterioration and systolic failure ensue. These clinical findings have been supported by a growing body of experimental data which support the notion that diabetes inflicts a direct insult to the myocardium, with cellular, structural and functional changes manifest as the diabetic myocardial phenotype. Several of these mechanisms appear to work in unison, forming complicated reciprocal pathways of disease. Reactive oxygen species and alterations in intracellular calcium homeostasis appear to play significant roles in many of these mechanisms. Determining the hierarchy of this cascade of disease will allow identification of the pathological trigger most responsible for disease. Translational research in this field is currently hindered by a lack of clinical studies and intervention trials specifically in patients with diabetic cardiomyopathy. Future clinical and experimental studies of accurate models of diabetic cardiomyopathy should help to define the true aetiology and lead to the development of specific pharmacotherapies for this condition, ultimately reducing the increased cardiovascular morbidity and mortality in diabetic patients.
Best practice & research. Clinical endocrinology & metabolism 07/2009; 23(3):347-60. · 3.89 Impact Factor
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ABSTRACT: Diabetic cardiomyopathy is a distinct primary disease process, independent of coronary artery disease, which leads to heart failure in diabetic patients. Epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Novel echocardiographic and MR (magnetic resonance) techniques have enabled a more accurate means of phenotyping diabetic cardiomyopathy. Experimental models of diabetes have provided a range of novel molecular targets for this condition, but none have been substantiated in humans. Similarly, although ultrastructural pathology of the microvessels and cardiomyocytes is well described in animal models, studies in humans are small and limited to light microscopy. With regard to treatment, recent data with thiazolidinediones has generated much controversy in terms of the cardiac safety of both these and other drugs currently in use and under development. Clinical trials are urgently required to establish the efficacy of currently available agents for heart failure, as well as novel therapies in patients specifically with diabetic cardiomyopathy.
Clinical Science 06/2009; 116(10):741-60. · 4.61 Impact Factor
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Adam S Greenstein,
Kaivan Khavandi,
Sarah B Withers,
Kazuhiko Sonoyama,
Olivia Clancy,
Maria Jeziorska,
Ian Laing,
Allen P Yates,
Philip W Pemberton,
Rayaz A Malik, Anthony M Heagerty
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ABSTRACT: Inflammation in adipose tissue has been implicated in vascular dysfunction, but the local mechanisms by which this occurs are unknown.
Small arteries with and without perivascular adipose tissue were taken from subcutaneous gluteal fat biopsy samples and studied with wire myography and immunohistochemistry. We established that healthy adipose tissue around human small arteries secretes factors that influence vasodilation by increasing nitric oxide bioavailability. However, in perivascular fat from obese subjects with metabolic syndrome (waist circumference 111+/-2.8 versus 91.1+/-3.5 cm in control subjects, P<0.001; insulin sensitivity 41+/-5.9% versus 121+/-18.6% in control subjects, P<0.001), the loss of this dilator effect was accompanied by an increase in adipocyte area (1786+/-346 versus 673+/-60 mum(2), P<0.01) and immunohistochemical evidence of inflammation (tumor necrosis factor receptor 1 12.4+/-1.1% versus 6.7+/-1%, P<0.001). Application of the cytokines tumor necrosis factor receptor-alpha and interleukin-6 to perivascular fat around healthy blood vessels reduced dilator activity, resulting in the obese phenotype. These effects could be reversed with free radical scavengers or cytokine antagonists. Similarly, induction of hypoxia stimulated inflammation and resulted in loss of anticontractile capacity, which could be rescued by catalase and superoxide dismutase or cytokine antagonists. Incubation with a soluble fragment of adiponectin type 1 receptor or inhibition of nitric oxide synthase blocked the vasodilator effect of healthy perivascular adipose tissue.
We conclude that adipocytes secrete adiponectin and provide the first functional evidence that it is a physiological modulator of local vascular tone by increasing nitric oxide bioavailability. This capacity is lost in obesity by the development of adipocyte hypertrophy, leading to hypoxia, inflammation, and oxidative stress.
Circulation 04/2009; 119(12):1661-70. · 14.74 Impact Factor
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ABSTRACT: Although, it is accepted that there is an excess of cardiovascular mortality in acromegaly, it is uncertain whether this is due to the direct effects of growth hormone-induced-cardiomyopathy or is a consequence of atherosclerosis secondary to the metabolic syndrome often observed in this condition. Direct comparison of a mouse model of acromegaly to a mouse model of Laron's syndrome allowed us to carry out detailed phenotyping and better understand the role GH plays in the circulatory system.
Transgenic mice that overexpress the growth hormone gene (GH) developed gigantism, including insulin resistance and higher blood pressures commensurate with increased body mass. In these giant mice, the hearts were hypertrophied but haemodynamic studies suggested contractile function was normal. Segments of small arteries mounted in a pressure myograph showed vascular wall hypertrophy but a preserved lumen diameter. Vascular contractile function was normal. Mice in which the GH receptor gene was disrupted or 'knocked out' were dwarf and had low blood pressure, small hearts and blood vessels but a normally functioning circulation. Correlations of body mass with cardiovascular parameters suggested that blood pressure and structural characteristics develop in line with body size.
In this transgenic mouse model of acromegaly, there is cardiac and vascular hypertrophy commensurate with GH excess but normal function. Our findings support the contention that the excess mortality in this condition may be due to the development of hypertrophic cardiomyopathy rather than increased rates of atherosclerotic coronary artery disease.
Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 04/2009; 19(5):413-9. · 2.35 Impact Factor
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British Journal of Pharmacology 02/2009; 120(4):653 - 661. · 4.41 Impact Factor
