Conscious normotensive and two-kidney, one-clip Goldblatt hypertensive rabbits were studied to determine the sensitivity of the arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate. The relations of the mean arterial pressure-RSNA and mean arterial pressure-heart rate were examined over a wide range of blood pressures produced by infusions of phenylephrine and nitroglycerin. The maximum slope obtained by logistic function analysis was considered to represent the baroreflex sensitivity. In the early hypertensive group (n=8; mean arterial pressure+SEM, 88±2 mm Hg) on day 5 after renal clip application, the maximum slope of the mean arterial pressure-RSNA relation was -11.3+± 1.2, which was significantly greater than that of the sham normotensive group (-6.9+±0.3, p<0.05). The maximum slope (-4.3+±0.2) of the mean arterial pressure-RSNA relation in the late hypertensive group (n=8; mean arterial pressure, 96±3 mm Hg) on day 21 after renal clipping was significantly smaller than that of another sham group (-7.2 +0.2, p <0.05). In contrast to these changes in the baroreflex control of RSNA, the control of heart rate was attenuated according to the magnitude of mean arterial pressure. To elucidate the mechanisms underlying the potentiated baroreflex, the effects of endogenous neuropeptides were investigated. First, plasma concentrations of angiotensin II and arginine vasopressin that are known to affect the baroreflex were determined. Plasma concentrations of vasopressin (3.1±0.6 pg/ml) as well as of angiotensin II (34±+7 pg/ml) were increased in the early hypertensive group, and the plasma vasopressin returned to a similar level to the sham group in the late hypertensive group (1.3+±0.4 pg/ml). Second, to study endogenous effects of these neuropeptides on the baroreflex, the maximum slopes of the baroreflex curves during infusions of antagonists for the peptides were determined in the early hypertensive group. The maximum slope of mean arterial pressure-RSNA during intravertebral arterial [Sar', Ala8]-angiotensin II (-16.4±1.5) was significantly greater (p<0.05), whereas the maximum slope during intravertebral arterial infusion of d(CH2)5Tyr(Me)arginine vasopressin (-4.7±0.5) was significantly smaller (p<0.05) than that during vehicle infusion (-11.3+±1.2). These results suggest that the baroreflex control of RSNA was potentiated in the early phase of two-kidney, one-clip hypertension in conscious rabbits and that endogenous arginine vasopressin and angiotensin II, which counteract each other, were apparently involved in the potentiated baroreflex mechanism. (Circulation Research 1990;67:1309-1322 H _~umoral factors such as angiotensin II (Ang hypertension.1-4 In addition to their actions on the II), arginine vasopressin (AVP), and norheart, the kidneys, and the blood vessels, these epinephrine (NE) are known to be involved peptides (Ang II and AVP) have been shown to in the development and maintenance of renovascular modulate the arterial baroreceptor reflex through various mechanis...

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Recently, sarcopenia has attracted attention as therapeutic target because it constitutes a risk factor for metabolic and cardiovascular diseases. We focused 5-aminolevulinic acid (ALA) which act as electron carriers in the mitochondrial electron transport system. The mice that received ALA for 8 weeks gained muscle strength and endurance, and exhibited increased muscle mass and mitochondrial amount. Administration of ALA to sarcopenia mice aged 100 weeks and chronic kidney disease (CKD) model mice also increased muscle mass and improved physical performance. Metabolome analysis revealed increased branched-chain amino acids (BCAAs) levels in the skeletal muscle of ALA-treated mice. Quantitative PCR analysis revealed decreased expression levels in branched-chain amino acid transaminases (BCATs) that degrade BCAAs and other muscle-degrading factors, and increased levels of mitochondria-activating factors. We also studied in cultured myocytes and obtained compatible results. ALA-treated mice tended to increase body weight, but reduced blood glucose level. These suggested that ALA treatment not only activated muscle mitochondria but also enhanced muscle mass through an increase in BCAAs contents, as to improve muscle strength, endurance and glucose tolerance in mice. In these ways, muscle mitochondrial activation with ALA is suggested to be useful for the treatment of sarcopenia and glucose intolerance.

Glucocorticoid causes hyperglycemia which is common in patients with or without diabetes. We experience prolonged hyperglycemia even after the discontinuation of glucocorticoid use. In the present study, we examined time course of blood glucose level in the patients of our hospital who received transient glucocorticoid treatment. In addition, the mechanism of prolonged hyperglycemia was investigated by using dexamethasone (Dexa)-treated mice and cultured cells. The blood glucose level in glucose tolerance test, level of insulin and glucagon-like peptide 1 (GLP-1) and the activity of dipeptidyl peptidase 4 (DPP-4) were examined during and after Dexa-loading in mice, with histone acetylation level of the promoter region. Mice showed prolonged hyperglycemia during and after transient Dexa-loading accompanied by persistently lower blood GLP-1 level and higher activity of DPP-4. The expression level of Dpp-4 was increased in the mononuclear cells and the promoter region of Dpp-4 was hyperacetylated during and after the transient Dexa treatment. In vitro experiments also indicated development of histone hyperacetylation in the Dpp-4 promoter region during and after Dexa treatment. The upregulation of Dpp-4 in cultured cells was significantly inhibited by a histone acetyltransferase inhibitor. Moreover, the histone hyperacetylation induced by Dexa was reversible by the treatment with a sirtuin histone deacetylase activator, nicotinamide mononucleotide. We identified persistent reduction in blood GLP-1 level with hyperglycemia during and after Dexa treatment in mice, associated with histone hyperacetylation of promoter region of Dpp-4. The results unveil a novel mechanism of glucocorticoid-induced hyperglycemia, and suggest therapeutic intervention through epigenetic modification of Dpp-4.

Purpose: Small fiber dysfunction is common in subjects with diabetic polyneuropathy (DPN). It is unsettled, however, whether marginal glucose intolerance is implicated in the onset and progression of small fiber dysfunction. Herein, we explored the relationship between glycated hemoglobin levels (HbA1c) and pain sensation in the Japanese population.Methods: A population-based study of 894 individuals (352 men, 542 women; average age 53.8 ± 0.5 years) and 55 subjects with impaired fasting glucose (IFG) in the 2017 Iwaki project were enrolled in this study. Individuals with diabetes were excluded. Relationships between pain threshold for intraepidermal electrical stimulation (P-IES) and parameters associated with metabolic syndrome were examined.Results: P-IES was elevated with increasing of age in women but not in men. Average P-IES (mA) was increased in IFG subjects (n = 55, 0.20 ± 0.03) compared with normoglycemic/non-IFG individuals (n = 894, 0.15 ± 0.11) (p < 0.01). It was comparable between IFG and a group of normal high HbA1c (5.9–6.4%). Univariate linear regression analyses showed no influence of sex, triglyceride, or cholesterol on the value of P-IES. In contrast, there were significant correlations between P-IES and serum HbA1c level (ß = 0.120, p < 0.001) Adjustments for the multiple clinical measurements confirmed positive correlation of P-IES with HbA1c (ß = 0.077, p = 0.046).Conclusion: Individuals with normal high HbA1c exhibited an elevated P-IES in a healthy Japanese population which may be useful for the screening of subclinical DPN.

Background: The renal tissue renin-angiotensin system is known to be activated by salt loading in salt-sensitive rats; however, the response in other organs remains unclear. Method: Spontaneously hypertensive rats were subjected to normal tap water or transient high-salt-concentration water from 6 to 14 weeks of age and were thereafter given normal tap water. From 18 to 20 weeks of age, rats given water with a high salt concentration were treated with an angiotensin II type 1 receptor blocker, valsartan. Results: Sustained blood pressure elevation by transient salt loading coincided with a persistent decrease in the fecal sodium content and sustained excess of the circulating volume in spontaneously hypertensive rats. Administration of valsartan sustainably reduced the blood pressure and normalized the fecal sodium levels. Notably, transient salt loading persistently induced the intestinal tissue renin-angiotensin system and enhanced sodium transporter expression exclusively in the small intestine of salt-sensitive rats, suggesting the potential connection of intestinal sodium absorption to salt sensitivity. Conclusion: These results reveal the previously unappreciated contribution of the intestinal tissue renin-angiotensin system to sodium homeostasis and blood pressure regulation in the pathophysiology of salt-sensitive hypertension.

Objective The management of blood pressure (BP) in hypertensive patients is the key to preventing a progression of organ damage. The brachial BP (bBP) has been used as the representative method for measuring the BP. The central BP (cBP), which is, different from the bBP due to the propagation and the reflection of the pulse wave in the arterial system, has recently received attention because it can now be estimated noninvasively. We examined the relationships between the difference in the central systolic BP (csBP) and the brachial systolic BP (bsBP) (Δ) and other factors in hypertensive patients. Methods The bsBP and csBP were measured in patients with essential hypertension and the relationships between the bsBP, csBP, or Δ and background factors including age, the brain natriuretic peptide (BNP) level, the estimated glomerular filtration rate (eGFR), flow-mediated vasodilation (an index of vascular endothelial function), the cardio-ankle vascular index (CAVI, an index of arteriosclerosis), and the carotid intima-media thickness (an index of atherosis) were investigated. Results The data of 191 patients were analyzed. Although there was no significant correlation between the CAVI and the bsBP; positive correlations were observed between the CAVI and the csBP (r=0.249, p=0.001). The Δ value showed significant positive correlations with age, and the BNP, eGFR, and CAVI values. Conclusion The csBP is more strongly associated with arteriosclerosis than the bsBP. Moreover, the Δ value is more strongly associated with cardiac function, renal function, and arteriosclerosis than the bsBP or csBP. These data suggested that the Δ value may have a greater prognostic value than the bsBP or csBP and may be worth calculating in the clinical setting.

The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-b mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-b mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.