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Biomedical subjects

William G Haynes

Publications and source records attributed to William G Haynes.

At least 19 recordsLinked to original sources
PubMed2006

Neuropsychological performance is associated with vascular function in patients with atherosclerotic vascular disease.

OBJECTIVE: We previously reported preliminary data (N=14) demonstrating a significant and positive relationship between forearm vascular function and neuropsychological performance in individuals with atherosclerotic vascular disease (AVD). The current study was conducted to confirm and extend those findings in a much larger, nonoverlapping sample. METHODS AND RESULTS: Participants were 82 individuals with AVD, with no history of stroke, cardiac surgery, or dementia. Forearm vascular function was measured before and after brachial artery infusion of vasoactive agents (acetylcholine, nitroprusside, verapamil). Neuropsychological functioning was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status. Statistical analysis included multiple regression and partial correlations, controlling for education. Vascular function was significantly and positively associated with neuropsychological performance [R2 change = 0.116, F change (3,74) = 3.72, P = 0.015]. Follow-up analyses indicated that smooth muscle function was the aspect of vascular function most strongly associated with neuropsychological performance. Individual vascular risk factors were not significantly associated with neuropsychological performance when controlling for vascular function. CONCLUSIONS: Better vascular function is significantly associated with better neuropsychological performance in individuals with AVD. It is possible that this relationship exists in healthy elderly individuals as well, although this cannot be determined based on the existing data, because a healthy comparison group was not studied. With additional research, measures of vascular function might be useful in the early identification of individuals who are at greatest risk for developing vascular cognitive impairment.

Aged↗
PubMed2006

Obesity and insulin resistance but not hyperandrogenism mediates vascular dysfunction in women with polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with biochemical evidence of early atherosclerosis; however, data regarding vascular function are controversial. We hypothesized that resistance vessel function (mediated by the endothelium or smooth muscle) would be impaired in women with PCOS and aimed to determine the contribution of hyperandrogenism, obesity, or insulin resistance to vascular dysfunction. DESIGN: Prospective study. SETTING: University practice. PATIENT(S): Women with PCOS (n = 24) and age/weight-matched controls (n = 22). INTERVENTION(S): Vascular function was assessed by measuring forearm vasodilatation in response to both endothelium-dependent (acetylcholine/bradykinin) and endothelium-independent dilators (nitroprusside/verapamil). MAIN OUTCOME MEASURE(S): Resistance vessel function. RESULT(S): Forearm vasodilatation to all four drugs was reduced (>50%) in obese PCOS compared to lean PCOS subjects. There was no significant difference in vascular function between obese or lean women with PCOS compared to corresponding controls. Androgen levels did not correlate with vascular function. Stepwise regression analysis showed that body mass index (BMI) contributed maximally to vascular dysfunction (R(2) = 0.47). CONCLUSION(S): This comprehensive study demonstrates for the first time that obese women with PCOS have markedly reduced vascular smooth muscle function compared to lean subjects with PCOS. In our study obesity and insulin resistance, but not hyperandrogenism, appeared to be significant modulators of vascular function.

Adolescent↗
PubMed2006

Antecedent hypoglycemia, catecholamine depletion, and subsequent sympathetic neural responses.

Antecedent hypoglycemia is well known to impair sympathetic responses to subsequent hypoglycemia. However, it is less clear whether this occurs through altered sympathetic neural traffic or through decreased adrenal catecholamine release per se. It is also not clear whether antecedent hypoglycemia impairs sympathetic responsiveness to subsequent nonhypoglycemic sympathetic stimuli. We exposed rats to two episodes of insulin-induced hypoglycemia or sham hypoglycemia (n = 15 per group) on d -2 and -1 before exposure to transient (10 min) hypotension on d 0. Adrenal sympathetic nerve activity (SNA) was directly recorded in the conscious state and plasma catecholamine concentrations were assessed. We also examined the effect of antecedent hypoglycemia on phosphorylated and nonphosphorylated tyrosine hydroxylase (TH) protein expression as well as the expression of phenylethanolamine N-methyltransferase. Adrenal SNA was not significantly altered by antecedent hypoglycemia either at baseline of d 0 (before hypotension) or in response to hypotension. In contrast, plasma epinephrine (EPI) responsiveness was impaired by more than 50% (P = 0.025) in rats exposed to antecedent vs. sham hypoglycemia. Antecedent hypoglycemia had no effect on norepinephrine responsiveness to hypotension. In studies of adrenal tissue from separate rats, antecedent hypoglycemia decreased adrenal EPI content but did not significantly alter the expression of TH, phosphorylated TH, or phenylethanolamine N-methyltransferase. In summary, antecedent hypoglycemia impaired EPI responsiveness to subsequent hypotension despite no reduction in adrenal SNA and in association with reduced adrenal EPI content. Thus, antecedent hypoglycemia impaired responsiveness to a subsequent nonhypoglycemic sympathetic stimulus, an effect mediated at the level of the adrenal medullae.

Adrenal Glands↗
PubMed2006

Homocysteine: role and implications in atherosclerosis.

Hyperhomocysteinemia promotes atherosclerosis and is most commonly caused by B-vitamin deficiencies, especially folic acid, B(6), and B(12); genetic disorders; certain drugs; and renal impairment. Elevated homocysteine promotes atherosclerosis through increased oxidant stress, impaired endothelial function, and induction of thrombosis. Prospective studies have shown that elevated plasma homocysteine concentrations increase risk of cardiovascular disease by twofold and risk of cerebrovascular disease to a lesser degree. Hyperhomocysteinemia should be identified in patients with progressive or unexplained atherosclerosis and treated appropriately. Treatment of hyperhomocysteinemia is primarily through vitamin supplementation; folic acid and vitamins B(6) and B(12) are the mainstay of therapy. Betaine and 5-methyl tetrahydro-folate are also effective in lowering homocysteine levels. Treatment of moderately elevated plasma homocysteine in patients without atherosclerosis should be deferred until the completion of randomized outcome trials.

Atherosclerosis↗
PubMed2005

Lack of dilator effect of leptin in the hindlimb vascular bed of conscious rats.

Leptin acts in the hypothalamus to decrease appetite and increase sympathetic nerve activity. Some in vitro studies have suggested that leptin may possess vasodilator actions that oppose sympathetically mediated vasoconstriction. We tested whether leptin is a vasodilator of the hindlimb vascular bed in vivo, and also whether it alters vasodilation to acetylcholine or sodium nitroprusside. In conscious instrumented Sprague-Dawley rats we measured iliac blood flow responses to local arterial infusion of acetylcholine (0.1 and 1 microg/min) and sodium nitroprusside (1 and 10 microg/min) before and after 2 h of intra-arterial leptin (at doses of 0.1 or 1 mg/kg, n=10 each) or vehicle (n=10). Leptin infusion over 2 h did not change mean arterial pressure, heart rate or iliac flow and conductance. In addition, leptin did not significantly alter the vasodilation (increase in the conductance ratio between infused and non-infused arteries) induced by acetylcholine, whereas pre-treatment with a nitric oxide synthesis inhibitor, N(G)-nitro-L-arginine methyl ester, significantly attenuated the vasodilation to acetylcholine. Leptin also did not affect the vasodilation to sodium nitroprusside. Lack of effect of leptin on vasodilator function could not be due to the activation of the sympathetic nervous system because lumbar sympathoactivation was obtained only 4 h after the iliac infusion of 1 mg/kg/h of leptin. These findings are in accordance with our previous results and argue against a meaningful direct dilator action of leptin on resistance vessels in vivo.

Acetylcholine↗
PubMed2005

Role of leptin in obesity-related hypertension.

Obesity in humans causes hypertension, myocardial hypertrophy and coronary atherosclerosis, and increased cardiovascular morbidity and mortality that is thought to be related to sympathetic overactivity. Leptin is an adipocyte-derived hormone that acts in the hypothalamus to regulate appetite, energy expenditure and sympathetic nervous system outflow. One of the major mechanisms leading to the development of obesity-induced hypertension appears to be leptin-mediated sympatho-activation. Leptin adversely shifts the renal pressure-natriuresis curve, leading to relative sodium retention. Although obesity is generally associated with resistance to the anorexic and weight-reducing actions of leptin, our work has shown preservation of its sympatho-excitatory and pressor actions. This selective leptin resistance of obesity, coupled with hyperleptinaemia, may play a critical role in the cardiovascular complications of obesity. Increased information about leptin and its mechanisms of actions should help the development of safe and effective pharmacological treatments of obesity and obesity-related hypertension.

Animals↗
PubMed2005

Effects of aging and atherosclerosis on endothelial and vascular smooth muscle function in humans.

BACKGROUND: Nitric oxide is an endothelium dependent dilator, which may protect against atherosclerosis. Several studies have shown a decrease in nitric oxide activity with aging, however none have assessed aging and atherosclerosis separately. We tested the hypothesis that aging blunts both basal and receptor-mediated endothelial nitric oxide release in humans. METHODS: We examined whether forearm blood flow responses to intra-arterial acetylcholine, and nitroprusside, were altered with aging, with and without co-infusion of an inhibitor of nitric oxide synthase (N(G)-mono-methyl-L-arginine) in three groups of human subjects; a group with clinical atherosclerotic vascular disease (n = 31, 21 M), otherwise healthy elderly (n = 17, 13 M), and healthy young controls (n = 15, 8 M). RESULTS: There was no difference in basal flows between the three groups. There was also no difference in the dilatation to either acetylcholine or nitroprusside responses between the AVD and the healthy elderly group; however, aging significantly decreased acetylcholine or nitroprusside responses when compared to the young controls (p < 0.02). Furthermore, the ratio between acetylcholine and nitroprusside, a marker of endothelial NO synthase activity, was significantly greater in the young volunteers (0.816 +/- 0.094% vs. 0.892 +/- 0.146 % vs. 1.389 +/- 0.2%, in atherosclerotic vascular disease, healthy elderly group, and young controls respectively). CONCLUSIONS: Forearm blood flow responses to endothelium dependent and independent stimuli are blunted with aging, independent of the presence of atherosclerotic disease. Moreover, the normal aging process may induce significant global vascular dysfunction (involving the endothelium and the vascular smooth muscle); to as great a degree as clinically manifest atherosclerosis.

Acetylcholine↗
PubMed2005

Effect of hyperhomocysteinemia induced by methionine administration on flow-mediated dilatation of the brachial artery in healthy subjects.

Homocysteine may contribute to systolic hypertension and cardiac events by decreasing conduit artery compliance and inducing endothelial dysfunction. The effects of the experimental induction of hyperhomocysteinemia on systemic arterial compliance and pulsewave velocity are unclear, with contradictory results from previous studies. The investigators tested whether oral methionine impairs brachial artery compliance in addition to endothelial function.

Administration, Oral↗
PubMed2005

Endothelial effects of leptin: implications in health and diseases.

Leptin is an adipocyte-derived hormone that plays a major role in the regulation of energy homeostasis through its action in the central nervous system. Leptin also acts on several peripheral tissues, including the vascular endothelium. The leptin receptor has been identified in endothelial cells. Leptin action on the endothelium modulates several physiologic processes, with potential implications in pathophysiologic diseases associated with obesity. Leptin stimulation of angiogenesis has attracted attention because of its potential involvement in retinopathy and atherosclerosis. Leptin activation of endothelial oxidative stress also has implications in atherosclerosis and inflammation. However, data on the impact of the endothelial effect of leptin on arterial pressure are contrasting. Although some investigators have shown that leptin action on the endothelial nitric oxide system tends to decrease arterial pressure, others have shown no contribution from the endothelial effect of leptin to the control of arterial pressure. Further characterization of the endothelial effects of leptin will, it is hoped, help in the understanding of the different pathophysiologic diseases associated with obesity.

Animals↗
PubMed2005

Dietary and medical therapy of obesity.

Surgery is not a cure for obesity but is an effective tool for limiting food consumption. If severely obese patients do not respond to a treatment plan that includes nutritional, exercise, and behavioral interventions plus antiobesity drugs, bariatric surgery may be appropriate. Proper diet selection after bariatric surgery involves more than the energy value and macronutrient composition. Adequate vitamin and mineral composition of the diet is essential to ensure that surgery improves nutritional status. Malabsorption is present to some extent with most surgeries. Therefore, diet after surgery should be monitored closely for adequacy by a nutritionist.

Anti-Obesity Agents↗
PubMed2005

Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines.

Obesity is associated with hypertension, diabetes, dyslipidaemias and metabolic syndrome, and causes substantial morbidity and mortality from cardiovascular and other diseases. The cost to treat obesity and its complications in the US has increased steeply and is currently estimated to be USD 100 billion. Current therapy for obesity is mainly based on changes in lifestyle that often fail. Existing pharmacological treatment is marginally efficient and poorly tolerated. The discovery of leptin and related neural mechanisms of energy metabolism regulation has opened the doors to potential targets for new antiobesity drugs. In this review, new pharmacological targets are discussed and an update on the development of emerging antiobesity drugs is provided. Despite intense investigation, the pipelines for antiobesity drugs in late stages of development are relatively empty. Breakthrough treatments for obesity may take some years to emerge. Clinical trials will be necessary to clarify the impact of new antiobesity drugs on hard cardiovascular and metabolic end points.

Anti-Obesity Agents↗
PubMed2005

Role of selective leptin resistance in diet-induced obesity hypertension.

Leptin is an adipocyte-derived hormone that plays a key role in the regulation of body weight through its actions on appetite and metabolism. Leptin also increases sympathetic nerve activity (SNA) and blood pressure. We tested the hypothesis that diet-induced obesity is associated with resistance to the metabolic actions of leptin but preservation of its renal SNA and arterial pressure effects, leading to hypertension. Mice were fed a high-fat diet for 10 weeks to induce moderate obesity. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular leptin was significantly attenuated in the obese mice. Regional SNA responses to leptin were differentially altered in diet-induced obese mice. Renal SNA response to leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated in obese mice. Radiotelemetric arterial pressure was approximately 10 mmHg higher in obese mice. Furthermore, the increase in arterial pressure in response to long-term (12 days) leptin treatment was preserved in obese mice. Thus, mice with diet-induced obesity exhibit circulating hyperleptinemia and resistance to the metabolic actions of leptin. However, there is preservation of the renal sympathetic and arterial pressure responses to leptin, which represent a potential mechanism for the adverse cardiovascular consequences of obesity.

Adipose Tissue, Brown↗
PubMed2004

Obesity-associated hypertension: new insights into mechanisms.

Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension.

Adiponectin↗
PubMed2004

Blood vessel function and cognition in elderly patients with atherosclerosis.

BACKGROUND AND PURPOSE: Although a strong relationship has been established between vascular disease and cognitive decline, the current challenge is to identify vascular risk factors and mechanisms that are associated with cognitive function before the development of severe dysfunction (eg, vascular dementia). This study was conducted to determine the relationship between blood vessel function and cognition in elderly patients with atherosclerosis. METHODS: Participants were 14 elderly individuals with atherosclerotic vascular disease, who had no history of stroke, cardiac surgery, or dementia diagnosis. Forearm blood flow was measured before and after brachial artery infusion of 3 vasoactive agents (verapamil, acetylcholine, nitroprusside), and these measures of vessel function were then correlated with neuropsychological performance (total scale score on the Repeatable Battery for the Assessment of Neuropsychological Status). RESULTS: Positive correlations were found between neuropsychological performance and vasodilation in response to all 3 agents, with 2 reaching statistical significance (verapamil: rho=0.78, P=0.001; nitroprusside: rho=0.56, P=0.038) and the third showing a strong trend toward significance (acetylcholine: rho=0.49, P=0.076). Correlations between neuropsychological performance and more conventional vascular-related variables were much weaker. CONCLUSIONS: These data provide preliminary evidence of a relationship between resistance vessel function and neuropsychological performance. With further research, measures of vessel dysfunction may be useful in identifying individuals at risk for cognitive decline and vascular dementia.

Aged↗
PubMed2004

Role of xanthine oxidase in conduit artery endothelial dysfunction in cigarette smokers.

Xanthine oxidase contributes to oxidant stress and has been proposed as a risk factor for endothelial dysfunction. We studied the role of xanthine oxidase in conduit artery endothelial dysfunction in 12 smokers and 12 controls. Conduit artery vasodilation was impaired in smokers (4.3%) compared with controls (7.9%) (p = 0.006) and improved with xanthine oxidase inhibition in smokers (9.2%, p <0.001).

Adult↗
PubMed2004

Adipose depot-specific modulation of angiotensinogen gene expression in diet-induced obesity.

Adipose tissue represents an important source of angiotensinogen (AGT). We investigated the effect of obesity induced by a high-fat diet on the expression of mouse (mAGT) and human AGT (hAGT) genes in liver, kidney, and heart and different adipose depots in normal mice (C57BL/6J), and in transgenic mice expressing the hAGT gene under the control of its own promoter. Mice were fed a high-fat diet (45% kcal) or normal chow (10% kcal) for 10 and 20 wk. The expression of mAGT and hAGT mRNA was quantified using an RNAse protection assay. Mice on the high-fat diet exhibited increased weight, fat mass, and plasma leptin. Expression of mAGT or hAGT genes was not affected by high-fat diet in nonadipose tissues, brown adipose tissue, or subcutaneous white fat. In contrast, high-fat diet increased both mAGT and hAGT gene expression in visceral adipose depots (omental, reproductive, and perirenal fat). Thus obesity-induced by a high-fat diet is associated with a tissue-specific increased expression of both mouse and human AGT genes in intra-abdominal adipose tissue. Our findings also suggest that 1.2 kb of regulatory sequences present in the hAGT transgene are sufficient to transcriptionally respond to a high-fat diet in an adipose-specific and depot-specific manner.

Adipose Tissue↗