Hyporeinemic hypoaldosteronism, also referred to as type IV or hyperkalemic renal tubular acidosis, is characterized by low levels of plasma renin and aldosterone resulting in mild hyperkalemia and metabolic acidosis. It is most commonly found in patients with diabetic renal dysfunction however can arise from a myriad of disorders affecting the interstitum of the kidney. The subtle presentation of hyporeinemic hypoaldosteronism makes it an underrecognized cause of metabolic disturbances in the individual with chronic kidney disease. The underlying pathophysiology is complex and affected by multiple regulatory mechanisms. Evaluation and treatment are essential to the accurate diagnosis of the condition and its management, particularly in the setting of medications that affect levels of serum potassium.

Sympathetic hyperactivity has an important role in cardiovascular mortality in patients with type 2 diabetes (T2D). Thyrotropin-releasing hormone (TRH)-containing fibers innervate autonomic motor and premotor nuclei of the brainstem and spinal cord that regulate cardiovascular functions. We compared cardiovascular responses to application of TRH-analog in the brainstem of Wistar and T2D Goto–Kakizaki (GK) rats. GK rats exhibited basal systolic hypertension (152±2 mm Hg) and had a significantly potentiated, dose-related hypertensive response to intracisternal (i.c.) injection of the TRH-analog RX77368 (10–60 ng). In GK rats only, i.c. RX77368 (30–60 ng) markedly increased heart rate (HR; +88 b.p.m.) and induced acute cardiac mortality (100%), concurrent with extreme hyperglycemia (>26 mmol l−1), increased plasma H2O2 and 8-isoprostane, and enhanced heart expression of NADPH oxidase 4 and vascular cell adhesion molecule-1 mRNAs. GK rats also had elevated basal plasma epinephrine, higher adrenal gene expression of tyrosine hydroxylase and dopamine β-hydroxylase (DβH), and greater plasma catecholamine and adrenal DβH responses to i.c. TRH-analog, compared with Wistar rats. In GK rats, hexamethonium blocked i.c. RX77368-induced hypertensive and tachycardic responses, and reduced mortality by 86%, whereas phentolamine abolished the hypertensive response but enhanced tachycardia (+160 b.p.m.), and reduced mortality by 50%. The angiotensin II type 1 receptor antagonist irbesartan prevented i.c. RX77368-induced increases in blood pressure, HR and mortality. In conclusion, sympathetic overactivation triggered by brainstem TRH contributes to the mechanism of cardiovascular morbidity and mortality in T2D, which involves heightened cardiac inflammation and peripheral oxidative stress responses to sympathetic drive, and a mediating role of the renin–angiotensin system.

The epidemic-like rise in the prevalence of obesity constitutes an undoubted and serious global health problem. Importantly, hypertension and diabetes are frequently associated with obesity and, together, constitute a significant burden in terms of patients' morbidity and escalating health care costs. When considered in isolation, obesity, hypertension, and diabetes are all associated with increased risk of the development of cardiovascular and renal complications; however, the coexistence of this triumvirate generates a substantial elevation in disease risk. The driving forces linking obesity, hypertension, and diabetes remain to be clarified due, in part, to the complex and multifactorial nature of the conditions that involve combinations of environmental, genetic, life style, and behavioural confounders. Additionally, it is recognized that neuroendocrine mechanisms, including insulin resistance, sympathetic nervous activation, and stimulation of the renin-angiotensin-aldosterone system (RAAS), are also involved [1–4]. This special issue on hypertension and type 2 diabetes related to obesity includes several epidemiological studies focusing on the prevalence of metabolic syndrome, type 2 diabetes, and hypertension. New data emanating from Peru, Ethiopia, Sudan, Egypt, and Nepal documents the prevalence of cardiometabolic disease in these countries as being similar to that reported in westernized countries such as the USA, Canada, Australia, and European countries as well as Japan [5, 6]. Importantly, an emerging body of data, such as that presented by Professor C. Brufani et al., highlights the importance of obesity in children. They reported the contribution of birth weight to central fat depot and insulin sensitivity in metabolic syndrome in obese Italian children. The challenge will be in designing and implementing effective strategies to arrest and reverse this pattern. The strong linkage between hypertension and type 2 diabetes was reviewed by Professor E. Dean which provides insight into the mechanisms involved. Dr. S. Horita et al. reviewed the contribution of the kidneys, especially renal sodium transport, to the development of insulin resistance and hypertension in obesity. Diabetic patients and obese individuals frequently present with different circadian patterns of blood pressure compared to nondiabetic or nonobese subjects. A nondipping pattern is very common in obese hypertensive patients. In diabetic patients, ambulatory blood pressure monitoring provides a more robust measure in predicting future cardiovascular events than clinic blood pressure. Dr. C. Anigbogu et al. provided evidence that in rats the circadian rhythm of blood pressure and heart rate changes with progression of diabetes. Professor K. Eguchi reviewed recent epidemiological studies in diabetes and obesity using ambulatory blood pressure monitoring. Taken together, these observations demonstrate the importance of ambulatory blood pressure monitoring. The first line of therapy for the treatment of type 2 diabetes and obesity-related hypertension is weight loss with lifestyle modifications such as diet and exercise. Nonpharmacological treatments were outlined by Dr. J. Pappachan et al. Another article by S. Guy et al. indicated that video gaming provided some benefit in initiating lifestyle modifications that aided in weight loss. Patients with diabetes and hypertension frequently present with atherogenic diseases and dyslipidemia. Dr. E. Morales-Villegas and colleagues provided a review indicating that statins are very effective in treating dyslipidemia and reducing overall cardiovascular risk. This special issue covered a wide range of materials with a focus on type 2 diabetes and hypertension. Articles included epidemiology, physiology, and treatments. In summary, this issue demonstrated that (i) abdominal obesity is related to the high prevalence of hypertension and type 2 diabetes regardless of ethnicity, (ii) insulin resistance is a major mechanism linking the onset and development of hypertension and type 2 diabetes, and (iii) weight loss with diet and exercise is an important aspect in treating hypertension in type 2 diabetes and aids in increasing the efficacy of antihypertensive medications. Further investigations on mechanisms and genetics are needed in order to develop appropriate and effective therapeutic regimens in order to prevent and limit obesity-related illnesses such as hypertension and type 2 diabetes. Early intervention is vital, given emerging evidence of end-organ dysfunction in young overweight or obese individuals [7, 8].

Overweight and obesity is a growing "world-wide epidemic problem" as many as, because two-thirds of the adult population and a growing number of children are overweight. The prevalence of diabetes mellitus, especially type 2 diabetes mellitus, metabolic syndrome and hypertension are significantly increased with the prevalence of obesity. Many patients are both diabetic and hypertensive as well as being obese.Obesity, hypertension and diabetes are involved in the six leading causes of death in the United States. Obesity, hypertension, and diabetes (metabolic syndrome) are high risk factors for subsequent cardiovascular and renal complications. Sympathetic nervous activation and insulin resistance frequently observed in obesity may play major roles in cardiovascular and renal complications in patients with hypertension, diabetes, and obesity.The purpose of this article is to provide a synthesis of the current findings from epidemiological surveys on the relationships of obesity, hypertension and diabetes mellitus and the mechanisms of the onset and maintenance of cardiovascular and renal complications in obesity, hypertension, diabetes mellitus and metabolic syndrome. A better understanding of the close linkage of obesity with hypertension and diabetes may help with the clinical treatment of obesity, and may lead to reductions in cardiovascular and renal risk.

Objective: β2-adrenoceptor (ADRB2) polymorphisms are closely linked to hypertension and obesity, and both of them are major cardiac risk. Left ventricular hypertrophy (LVH) is more common in people who have hypertension or obesity. We examined the relationships between ADRB1 and ADRB2 polymorphisms and LVH in nonobese, normotensive subjects. Methods: In 447 middle-aged, normotensive, nonobese men, ADRB1 (Arg389Gly, Ser49Gly) and ADRB2 (Arg16Gly, Gln27Glu) polymorphisms, BMI, BP, heart rates (HR), total body fat-mass, waist-to-hip ratio (W/H), plasma norepinephrine (NE) and ECG were measured after overnight fasting in the supine position. LVH was determined by ECG. Results: Thirty-nine subjects (8.7%) showed LVH on ECG. Subjects with LVH had higher plasma NE and HR compared to those without LVH (both P<.05). Distributions of Gly389 and Gly49 alleles of ADRB1 polymorphisms were 23.5% (Arg/Arg:Arg/Gly:Gly/Gly=270:144:33) and 14.1% (Ser/Ser:Ser/ Gly:Gly/Gly=327:114:6). Thirty-seven subjects with LVH (94.9%) carried Gly389 and Gly49 alleles, especially homozygous for Gly389 or Gly49. Subjects with Gly389 or Gly49 alleles had higher frequencies of LVH (20.9% vs. 0.7%, 30.8% vs. 0.6%). Subjects carrying Gly389 or Gly49 alleles had higher plasma NE and HR (both P<.05), whereas BMI, fat mass, W/H and BP were similar. The Gly16 and Glu27 alleles of ADRB2 polymorphisms were noted in 42.8% (Arg/Arg :Arg/Gly:Gly/Gly=69:245:133) and 36.6% of the subjects (Gln/Gln:Gln/Glu:Glu/ Glu=176:215:56). Twenty-nine subjects with LVH (74.4%) carried Gly16 allele, especially Gly16 homozygous. Subjects with Gly16 allele had higher frequencies of LVH (P<.05), and they had greater BMI, fat mass, W/H, BP, HR and NE compared to those without Gly16 allele (all P<.05). Conclusions: Subjects carrying Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 allele of ADRB2 polymorphism had higher frequency of LVH accompanying high plasma NE. ADRB1 and ADRB2 polymorphisms play important roles in LVH even in nonobese, normotensive subjects. ADRB1 polymorphisms might relate to LVH through heightened sympathetic nerve activity, but ADRB2 polymorphisms might relate to LVH through obesity, hypertension and heightened sympathetic nerve activity.

Background Plasma uric acid has been associated with hypertension in a variety of disorders, and has been shown to be predictive of hypertension. The mechanistic role of uric acid in the development of hypertension is not known however. Method We tested the hypothesis that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation and oxidative stress by stimulating the vascular renin–angiotensin system (RAS). Rat VSMC were exposed to 0–300 μmol uric acid for 48 h. Results Uric acid (200 and 300 μmol) stimulated the proliferation of VSMC as measured by thymidine uptake. This effect was prevented by 10−6 mol losartan or by 10−6 mol captopril. Incubation of VSMC with uric acid for 48 h also increased angiotensinogen messenger RNA expression and intracellular concentrations of angiotensin II. These responses were also inhibited by losartan and captopril. Increased expression of angiotensinogen mRNA was also inhibited by co-incubation with PD 98059, a mitogen-activated protein (MAP) kinase inhibitor. Uric acid stimulated the production of hydrogen peroxide and 8-isoprostane in VSMC. These increases in oxidative stress indicators were significantly reduced by co-incubating the cells with captopril or losartan. Uric acid also decreased nitrite and nitrate concentrations in the culture medium, an effect that was prevented by losartan and captopril. Conclusion These results demonstrate that uric acid stimulates proliferation, angiotensin II production, and oxidative stress in VSMC through tissue RAS. This suggests that uric acid causes cardiovascular disorders by stimulating the vascular RAS, and this stimulation may be mediated by the MAP kinase pathway.

When it comes to synaptic vesicles, synapses seem to know a thing or two about supply and demand. High-frequency stimulation increases exocytosis and results in an accelerated recruitment of additional vesicles within the nerve terminal, a process thought to rely on intracellular calcium. This week, Hosoi et al. took advantage of the accessibility of the presynaptic terminal at the calyx of Held to examine the relationship between intracellular calcium and vesicle recruitment. The authors used paired presynaptic and postsynaptic recordings to measure simultaneously presynaptic calcium levels and postsynaptic responses. Replenishment of the fast-releasing vesicle pool increased with presynaptic calcium levels, thus helping to sustain release during high-frequency firing. This relationship was quasilinear, similar to the calcium dependence of facilitation and posttetanic potentiation. These processes have much slower kinetics than the highly nonlinear calcium dependence of transmitter release and thus appear to be tuned to slowly changing global calcium levels in nerve terminals.

Renal injury is common in obesity and hypertension. In the present study, we examined relationships between renal function alterations, plasma norepinephrine (NE), and β2-adrenoceptor polymorphisms in a longitudinal design over 5 years. In 219 nonobese, normotensive men with entry-normal renal function, we measured serum blood urea nitrogen (BUN), creatinine, creatinine clearance, plasma NE, homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), total body fat mass, and blood pressure (BP) annually for 5 years. β2 (Arg16Gly, Gln27Glu)-adrenoceptor polymorphisms were determined. The subjects were stable in body weight and BP (<10%) for 5 years. High plasma NE was defined as ≥mean+1 SD at entry. Thirty-seven subjects had entry-high plasma NE and 182 were entry-normal. Entry-high plasma NE subjects had significantly greater total body fat mass and plasma NE and significantly lower creatinine clearance at entry and throughout the study. Increases in BMI, fat mass, BP, plasma NE, BUN, and creatinine, as well as the reduction in creatinine clearance in the 5 years, were significantly greater in entry-high NE subjects. These subjects had significantly higher frequencies of the Gly16 allele of β2-adrenoceptor polymorphisms. Throughout the study, subjects carrying the Gly16 allele had higher plasma NE, HOMA-IR, and fat mass, and significantly greater reductions in creatinine clearance. Plasma NE at entry was a determinant variable for changes in BUN, creatinine, and creatinine clearance over the 5-year period in multiple regression analysis. In conclusion, high plasma NE at entry, associated with the Gly16 allele of the β2-adrenoceptor polymorphisms, predict renal function deterioration (seen in elevations of BUN and creatinine and reduction of creatinine clearance) over a 5-year period accompanying further heightened sympathetic nerve activity and deterioration of insulin resistance.

Environmental and genetic factors, notably ApoE4, contribute to the etiology of late-onset Alzheimer's disease (LOAD). Reduced mRNA and protein for an apolipoprotein E (ApoE) receptor family member, SorLA (LR11) has been found in LOAD but not early-onset AD, suggesting that LR11 loss is not secondary to pathology. LR11 is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to secretases that generate β-amyloid (Aβ). Genetic polymorphisms that reduce LR11 expression are associated with increased AD risk. However these polymorphisms account for only a fraction of cases with LR11 deficits, suggesting involvement of environmental factors. Because lipoprotein receptors are typically lipid-regulated, we postulated that LR11 is regulated by docosahexaenoic acid (DHA), an essential ω-3 fatty acid related to reduced AD risk and reduced Aβ accumulation. In this study, we report that DHA significantly increases LR11 in multiple systems, including primary rat neurons, aged non-Tg mice and an aged DHA-depleted APPsw AD mouse model. DHA also increased LR11 in a human neuronal line. In vivo elevation of LR11 was also observed with dietary fish oil in young rats with insulin resistance, a model for type II diabetes, another AD risk factor. These data argue that DHA induction of LR11 does not require DHA-depleting diets and is not age dependent. Because reduced LR11 is known to increase Aβ production and may be a significant genetic cause of LOAD, our results indicate that DHA increases in SorLA/LR11 levels may play an important role in preventing LOAD.