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Masuo K.,Baker IDI Heart and Diabetes Institute | Masuo K.,Nucleus Network Ltd | Lambert G.W.,Baker IDI Heart and Diabetes Institute | Lambert G.W.,Monash University
Current Hypertension Reviews | Year: 2011

Epinephrine accounts for 80%, while norepinephrine accounts for 20% of the total hormone secreted from the adrenal medulla. Further, in certain situations epinephrine may be released as a co-transmitter with norepinephrine from postganglionic sympathetic nerves. Epinephrine is known as a prime mover in the "fight or flight" response with epinephrine elevating heart rate, augmenting neurogenic vasoconstriction, reducing blood flow to the skin and the kidneys, increasing the production of sweat, and widening the smaller bronchioles in the lungs. Its action raises bloodsugar levels by stimulating glucose production in the liver, and blood fatty-acid levels in adipose tissue. These effects on the cardiovascular system could perhaps play an important role in the onset and maintenance of hypertension, obesity and the metabolic syndrome (type 2 diabetes). The "epinephrine hypothesis" proposes that circulating epinephrine is taken up by sympathetic nerves, thereby promoting norepinephrine release during sympathetic nervous system stimulation. It is suggested that binding of co-released epinephrine to pre-synaptic β-adrenoceptors augments exocytotic release of norepinephrine and contribute to high blood pressure (hypertension). Thus, the "epinephrine hypothesis" might explain how the adreno-medullary hormonal system could contribute to the development of essential hypertension by augmenting sympathoneuroral norepinephrine release. There is evidence that the sympathetic nerves of hypertensive patients do release epinephrine as a co-transmitter. In this review, results will be presented which suggest that epinephrine is synthesized in situ in sympathetic nerve endings via the action of phenylethanolamine-N-methyltransferase (PNMT), which is induced by chronic mental stress exposure. Accordingly, this represents a biomarker of chronic mental stress, rather than a specific mechanism of hypertension, as proposed in the "epinephrine hypothesis". © 2011 Bentham Science Publishers.


Masuo O.,Nucleus Network Ltd. | Masuo O.,Baker IDI Heart and Diabetes Institute | Esler M.D.,Baker IDI Heart and Diabetes Institute
Current Hypertension Reviews | Year: 2010

Obesity, hypertension, obesity-related hypertension and the metabolic syndrome are growing health problems. Importantly, while frequently associated, not all obese subjects have hypertension. It is widely recognized that heightened sympathetic nerve activity and insulin resistance (or hyperinsulinemia) relate to obesity, hypertension and the metabolic syndrome. However, the precise relationships between heightened sympathetic nerve activity and insulin resistance in obesity and hypertension remain uncertain. Many investigators have indicated that insulin resistance may play a major role in obesity, hypertension, and obesity-related hypertension, and heightened sympathetic nerve activity accompanies insulin resistance. On the other hand, some investigators have reported in a series of longitudinal studies that heightened sympathetic nerve activity may be a prime mover for obesity, hypertension, and obesity-related hypertension, and insulin resistance may play an ancillary role. Blunted sympathetic nerve responses to insulin stimulation was observed during oral glucose loading only in insulin resistant subjects, obese subjects or hypertensive subjects, suggesting that the relationships between insulin resistance and sympathetic nerve activity might be different due to the stage of obesity, hypertension, or severity of insulin resistance. Both hypotheses emphasize the close linkage between insulin resistance and heightened sympathetic nerve activity; however, which is the prime mover for obesity or hypertension remains unknown. The purpose of this review is to provide the current findings on the relationships between sympathetic nerve activity and insulin resistance in obesity, hypertension, and the metabolic syndrome. © 2010 Bentham Science Publishers Ltd.


Masuo K.,Nucleus Network Ltd. | Masuo K.,Baker IDI Heart and Diabetes Institute | Lambert G.W.,Baker IDI Heart and Diabetes Institute | Esler M.D.,Baker IDI Heart and Diabetes Institute | And 3 more authors.
Hypertension Research | Year: 2010

Sympathetic nervous system hyperactivity is observed in patients with renal injury, renovascular hypertension, chronic kidney disease (CKD) and end-stage renal disease (ESRD). Elevated sympathetic activity is of prognostic relevance in that plasma norepinephrine concentrations predict survival and the incidence of cardiovascular events in patients with ESRD, as well as future renal injury in normotensive healthy subjects with renal function in the normal range. Renal injury, CKD and ESRD are often associated with obesity, and its common sequelae hypertension and diabetes. In fact, hypertension and diabetes mellitus are the main causes of ESRD in western societies and together account for approximately more than 50% of ESRD incidence in the United States and Japan. Obesity also leads to increases in the incidence of cardiovascular diseases. Several clinical and epidemiological studies have clearly documented that heightened sympathetic nervous activity has an important role in the onset and maintenance of obesity and hypertension. Elevated sympathetic nervous activity may actually represent an important mechanism contributing to the onset and maintenance of renal injury at least in part through its concomitant adverse effects on obesity and hypertension. Understanding the contribution of sympathetic nervous hyperactivity to the onset and maintenance of renal injury might aid in the prevention and treatment of renal injury, CKD and ESRD. Very recently, renal sympathetic denervation was shown to be a potentially novel therapeutic strategy in resistant hypertension. In addition, renin-angiotensin system inhibitors are recommended as the initial therapy because of their renal protective effect, especially in hypertensive patients with type 2 diabetes or with proteinuria. The purpose of this review is to provide an overview of our current knowledge on the relationships between sympathetic nerve activity and renal function to further our understanding of the precise roles of sympathetic nerve activity in renal injury, particularly in the context of obesity and hypertension. These insights may be useful to improve prevention and treatment of renal injury in these patients. © 2010 The Japanese Society of Hypertension All rights reserved.


Masuo K.,Baker IDI Heart and Diabetes Institute | Masuo K.,Nucleus Network Ltd.
Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry | Year: 2010

Obesity is an escalating global health problem and established cardiovascular risk factor for the development of cardiovascular and metabolic diseases. Leptin derived from the adipose tissue acts centrally to suppress appetite and increase energy expenditure, therefore leptin resistance is considered as an important mechanism for the onset and maintenance of obesity; Leptin analogues as well as leptin receptor blockers have been candidates for the treatment of obesity, however clinical trials in obese populations have yielded variable results. Given specific circumstances in obese subjects could optimize the beneficial actions of the hormone and minimize its deleterious effects. In this review, human recombinant leptin (pegylated polyethylene glycol recombinant human leptin (PEG-OB) and recombinant methionyl human leptin (r-metHuLeptin) is developed to control resistant and morbid obesity will be discussed. © 2010 Bentham Science Publishers Ltd.


Masuo K.,Nucleus Network Ltd | Masuo K.,Baker IDI Heart and Diabetes Institute
Current Hypertension Reviews | Year: 2011

Obesity, hypertension and obesity-related hypertension are growing health problems. Several epidemiological studies have shown a high prevalence of cardiovascular complications and all cause of mortality in obesity and hypertension. Obesity and hypertension are important and independent risk factors for cardiovascular disease development. An integrated cardiovascular risk management approach involving aggressive blood pressure (BP) control should be adopted in patients at high cardiovascular risk (i.e. those with ischemic heart disease, end-organ damage, type 2 diabetes) and the use of well-tolerated antihypertensive agents with protective benefits beyond BP lowering. The identification and management of risk factors is an important part of the overall management of hypertensive patients. Given that obese patients are more predisposed to target organ damage development, stringent targets for blood pressure control have been set in clinical guidelines, including those of the Joint National Committee (JNC-7) [1], the World Health Organisation and the International Society of Hypertension (WHO/ISH) [2], the European Society of Hypertension (ESH) [3] and the Japanese Society of Hypertension (JSH-2009) [4]. Pertinently, clinical trials and real-life evidence suggest that these targets are difficult to achieve. Hypertension in obesity is characterized by stimulation of the renin-angiotensin-aldosterone system (RAAS), elevated sympathetic activity, insulin resistance and selective leptin resistance. Importantly, these characteristics, even in isolation constitute risk factors for cardiovascular disease development and progression. It is therefore imperative that pharmacological treatments should be selected based on favourable effects on these factors. Furthermore, in choosing an antihypertensive agent, effectiveness needs to be accompanied by favourable metabolic, cardioprotective, and renal protective properties. Recent pharmacogenetic studies have shown that several polymorphisms may contribute to antihypertensive effectiveness. Weight loss is recommended as the first line of treatment for hypertension associated with obesity. Indeed, lifestyle modification including a low caloric diet, reducing sedentary behaviour and exercise form the foundation of all therapy. For the subjects who are more severe obesity or inability to undertake an exercise program, bariatric surgery are recommended. Anti-obesity drugs have been developed but unfortunately some were associated with significant side effects and were recently withdrawn from the markets in the United States, Europe and Australia. Leptin administration has a theoretical basis in obesity therapy and, while it has been examined in overweight and obese human subjects and in animal models, the anti-obesity effects of leptin administration are controversial. The combination of high blood pressure with obesity, for a variety of reasons, renders the hypertension difficult to control, with patients frequently requiring two or more types of medications to achieve blood pressure goals. Many large cohort studies have compared the efficacies of antihypertensive drug classes in hypertensive patients with the metabolic syndrome, however, there are few systemic reviews of antihypertensive drug treatments for patients with obesity. Moreover the mechanisms underlying both obesity and hypertension remain to be elucidated therby making it difficult to achieve blood pressure goals. In this review I aim to provide a synthesis of the current data examining both pharmacological and nonpharmacological antihypertensive treatments in those patients with obesity-related hypertension. © 2011 Bentham Science Publishers.


Masuo K.,Nucleus Network Ltd. | Masuo K.,Osaka University | Rakugi H.,Nucleus Network Ltd. | Ogihara T.,Nucleus Network Ltd. | And 2 more authors.
Current Diabetes Reviews | Year: 2010

Overweight and obesity is a growing "world-wide epidemic problem". Because as many as, two-third of the adult population and a growing number of children are overweight. The prevalence of diabetes, especially type 2 diabetes and hypertension have significantly increased with the prevalence of obesity. Obesity accompanying type 2 diabetes and hypertension are known to be closely linked with insulin resistance and elevated sympathetic nervous activity. It has been well documented that obesity, hypertension, and diabetes are high risk factors for subsequent cardiovascular and renal complications. Many patients are both diabetic and hypertensive; while they are obese, but not all diabetic patients have hypertension, indicating that insulin resistance is not only a mechanism for blood pressure elevation in diabetic-hypertensive patients. Several investigators have reported that sympathetic nervous activation relates to cardiovascular complications in patients with hypertension, diabetes, and obesity, and that sympathetic nerve activity accompanying insulin resistance is closely linked with left ventricular hypertrophy in healthy subjects. In addition, sympathetic nerve activation may predict future renal injury in healthy normotensive subjects. These findings suggest that elevated sympathetic nerve activity associated with insulin resistance may contribute to the onset and maintenance of cardiovascular and renal complications in diabetes, and hypertension in obesity. Further, genetic polymorphisms of the β2- and β3-adrenoceptor gene have been associated with type-2 diabetes and insulin resistance in many epidemiological studies and might be another factor responsible for the close relationship between insulin resistance and heightened sympathetic nerve activity. Thus, focusing on the interactions between insulin resistance, sympathetic nervous activity and β-adrenoceptor polymorphisms might help in understanding the precise relationships between insulin resistance and sympathetic nerve activity in type 2 diabetes and obesity-related hypertension. The purpose of this article is to provide a synthesis of the current findings on the mechanisms of the onset and maintenance of cardiovascular and renal complications in obesity, diabetes and hypertension. A better understanding of the relationships of sympathetic nervous system activity and insulin resistance might help with the clinical treatment of diabetes and hypertension in obesity. Further, to clarify the pathogenesis and mechanisms of the association between obesity, diabetes, and hypertension may lead to reductions in cardiovascular and renal risk. © 2010 Bentham Science Publishers Ltd.


Masuo K.,Nucleus Network Ltd | Masuo K.,Baker IDI Heart and Diabetes Research Institute | Rakugi H.,Osaka University | Ogihara T.,Osaka University
Current Hypertension Reviews | Year: 2010

Obesity, hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome are rapidly growing public health problems. Heightened sympathetic nerve activity is a well-established observation in obesity, hypertension and diabetes mellitus. Human obesity, hypertension and diabetes have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the β-adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to obesity. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. However, the precise relationships of the polymorphisms of β2-and β3-adrenoceptor genes with sympathetic nervous system activity, obesity, hypertension and metabolic syndrome have not been fully clarified. A few studies regarding the relationships between sympathetic nervous activity and adrenoceptor polymorphisms in the same studies have been reported. Masuo et al. have observed in a series of studies in a Japanese male cohort that: 1) β2-adrenoceptor polymorphisms are associated with heightened sympathetic nerve activity, and predict the future onset of obesity and hypertension in nonobese individuals, 2) β2-adrenoceptor polymorphisms accompanied by heightened sympathetic nerve activity and abdominal obesity, predict weight loss resistance during a weight loss program, and also predict rebound weight gain, 3) β2-adrenoceptor polymorphisms are linked to blunted leptin-mediated sympathetic nerve activation, leptin-resistance and resultant obesity, 4) β2-adrenoceptor polymorphisms are related to insulin-resistance, in both nonobese and obese normotensive individuals, and 5) β3-adrenoceptor polymorphism is directly linked to obesity and hypertension, but only in obese individuals. These suggest that β2-and β3-adrenoceptor polymorphisms accompanying heightened sympathetic nerve activity play a major role in the onset and the maintenance of obesity, hypertension and insulin resistance. This article provides the current topics involving the influence of the sympathetic nervous system and β2-and β3-adrenoceptor polymorphisms in obesity, hypertension and metabolic syndrome (type 2 diabetes). © 2010 Bentham Science Publishers Ltd.


Masuo K.,Nucleus Network Ltd | Masuo K.,Baker IDI Heart and Diabetes Research Institute
Current Hypertension Reviews | Year: 2013

Hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome associated with obesity are rapidly growing public health problems. Sympathetic nerve activation is well documented in hypertension, diabetes mellitus, and obesity, hypertension and diabetes are determined by genetic background and environmental factors. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of sympathetic nervous system in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2- adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the β-adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to hypertension. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. This review is an update of several versions published of the relationships between adrenoceptor polymorphisms and hypertension, diabetes and obesiy based on the my own review on the relationship with obesity in 2011 in "Journal of Obesity" [1], and another of my own reviews on the relationships with hypertension in 2010 in "International journal of Hypertension" [2], with 37 articles provided by the "PubMed" with the keywords of "adrenoceptor polymorphisms, obesity, hypertension and diabetes" searched on December 2013. However, the relationships of the polymorphisms of β2- and β3-adrenoceptor genes with sympathetic nervous system activity, hypertension and metabolic syndrome have been still discordant, it might be related to the ethnicity, gender, severeity of obesity, duration of hypertension or obesity, etc (refer the "Possible confounding variable affecting the relationships" section and Table 4). Therefore, this review may not be so much different from the previous ones, but, of importance, currently most investigations have shown that the β-adrenoceptor polymorphisms accompanying sympathetic nervous activity contribute to the onset and maintenance of hypertension, diabetes and obesity. © 2013 Bentham Science Publishers.


Masuo K.,Nucleus Network Ltd | Masuo K.,Baker IDI Heart and Diabetes Research Institute | Lambert G.W.,Baker IDI Heart and Diabetes Research Institute
Journal of Obesity | Year: 2011

Obesity, hypertension, and type 2 diabetes are rapidly growing public health problems. Heightened sympathetic nerve activity is a well-established observation in obesity, hypertension, and type 2 diabetes. Human obesity, hypertension, and diabetes have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity are mainly mediated via the β2, and β3-adrenergic receptors in humans. Further, β2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. β-adrenoceptor polymorphisms have also been associated with adrenoceptor desensitization, increased adiposity, insulin resistance, and enhanced sympathetic nervous activity. Many epidemiological studies have shown strong relationships between adrenoceptor polymorphisms and obesity, but the observations have been discordant. This paper will discuss the current topics involving the influence of the sympathetic nervous system and β2- and β3-adrenoceptor polymorphisms in obesity. © 2011 Kazuko Masuo and Gavin W. Lambert.


PubMed | Nucleus Network Ltd
Type: | Journal: Current hypertension reviews | Year: 2014

Many reviews focused on the role of sympathetic nervous activity in hypertension have been published. Recently a new treatment, radiofrequency renal denervation for the treatment of resistant hypertension has been developed and examined in several clinical trials such as the Symplicity HTN and EnligHTN studies. In the Symplicity HTN-1 study the efficacy for lowering blood pressure remained satisfactory at 3 years follow up and many ancillary ameliorative effects have been reported including cardiovascular, psychosocial, and metabolic effects. The purpose of this review is to provide the current findings on the relationships between sympathetic nerve activity and hypertension, especially focus on the importance of renal sympathetic nervous activity for the onset and development of hypertension. In addition, the methods to assess sympathetic nervous activity are reviewed.

The renal denervastion was developed for the treatment-resistant hypertensive patients, and excessive confidence of the efficacy and safety existed by the end of 2013, although several issues on the efficacy and safety were reported in 2014. Furthermore, long-term efficacy and impact on renal function have been unclear. Those issues have to be clear for clinical usage. This review will also address the recent data from the renal denervation.

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