Rosiglitazone improves insulin sensitivity and baroreflex gain in rats with diet-induced obesity

Obesity decreases baroreflex gain (BRG); however, the mechanisms are unknown. We tested the hypothesis that impaired BRG is related to the concurrent insulin resistance, and, therefore, BRG would be improved after treatment with the insulin-sensitizing drug rosiglitazone. Male rats fed a high-fat diet diverged into obesity-prone (OP) and obesity-resistant (OR) groups after 2 weeks. Then, OP and OR rats, as well as control (CON) rats fed a standard diet, were treated daily for 2 to 3 weeks with rosiglitazone (3 or 6 mg/kg) or its vehicle by gavage. Compared with OR and CON rats, conscious OP rats exhibited reductions in BRG (OP, 2.9 ± 0.1 bpm/mm Hg; OR, 4.0 ± 0.2 bpm/mm Hg; CON, 3.9 ± 0.2 bpm/mm Hg; P < 0.05) and insulin sensitivity (hyperinsulinemic euglycemic clamp; OP, 6.8 ± 0.9 mg/kg · min; OR, 22.2 ± 1.2 mg/kg · min; CON, 17.7 ± 0.8 mg/kg · min; P < 0.05), which were well correlated (r(2) = 0.49; P < 0.01). In OP rats, rosiglitazone dose-dependently improved (P < 0.05) insulin sensitivity (12.8 ± 0.6 mg/kg · min at 3 mg/kg; 16.0 ± 1.5 mg/kg · min at 6 mg/kg) and BRG (3.8 ± 0.4 bpm/mm Hg at 3 mg/kg; 5.3 ± 0.7 bpm/mm Hg at 6 mg/kg). However, 6 mg/kg rosiglitazone also increased BRG in OR rats without increasing insulin sensitivity, disrupted the correlation between BRG and insulin sensitivity (r(2) = 0.08), and, in OP and OR rats, elevated BRG relative to insulin sensitivity (analysis of covariance; P < 0.05). Moreover, in OP rats, stimulation of the aortic depressor nerve, to activate central baroreflex pathways, elicited markedly reduced decreases in heart rate and arterial pressure, but these responses were not improved by rosiglitazone. In conclusion, diet-induced obesity impairs BRG via a central mechanism that is related to the concurrent insulin resistance. Rosiglitazone normalizes BRG, but not by improving brain baroreflex processing or insulin sensitivity.     

5-Hydroxytryptamine lowers blood pressure in normotensive and hypertensive rats

Arterial hyper-responsiveness to 5-hydroxytryptamine (5-HT) is a hallmark of hypertension, and plasma levels of free 5-HT are elevated in hypertension. We hypothesized that chronic administration of 5-HT would cause blood pressure to 1) rise in normotensive rats and 2) rise significantly more in hypertensive rats. The deoxycorticosterone acetate (DOCA)-salt hypertensive and sham normotensive rat were used. Animals were implanted with minipumps that delivered 5-HT (or vehicle) at a rate of 25 microg/kg/min for 7 days. Free plasma 5-HT was elevated significantly by this protocol. Within 48 h, mean arterial blood pressure measured telemetrically decreased in sham (106 +/- 2 to 83 +/- 2 mm Hg) and in DOCA-salt hypertensive (166 +/- 9 to 112 +/- 3 mm Hg) rats; vehicle did not change blood pressure in either group. Ganglionic blockade (hexamethonium) reduced blood pressure to a greater magnitude in DOCA vehicle-administered rats (peak fall arterial pressure, 91 +/- 14 mm Hg) compared with DOCA 5-HT-administered rats (40 +/- 6 mm Hg). Maximal acetylcholine-induced (NO-dependent) relaxation in phenylephrine-contracted aortic strips was greater in 5-HT-administered (69.2 +/- 9.1% relaxation) versus vehicle-administered (39.7 +/- 14.2%) DOCA rats; aortic endothelial cell nitric oxide synthase expression was higher in the 5-HT- versus vehicle-administered DOCA-salt rats. In normotensive and DOCA-salt hypertensive rats, the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine (0.5 g/l in water) prevented the fall in blood pressure to 5-HT. We conclude that chronic exogenous 5-HT reduces blood pressure in normotensive and hypertensive rats through mechanisms critically dependent on NOS.     

Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lowers blood pressure in normal rats

Synthetic agonists of the peroxisomal proliferator-activated receptor subtype gamma (PPAR-gamma) are highly beneficial in the treatment of type II diabetes. However, they are also associated with fluid retention and edema, potentially serious side effects of unknown origin. These studies were designed to test the hypothesis that rosiglitazone (RGZ, PPAR-gamma agonist) may activate sodium- and water-reabsorptive processes in the kidney, possibly in response to a drop in mean arterial blood pressure (MAP), as well as directly through PPAR-gamma. Targeted proteomics of the major renal sodium and water transporters and channel proteins was used to identify potentially regulated sites of renal sodium and water reabsorption. RGZ (47 or 94 mg/kg diet) was fed to male, Sprague-Dawley rats (approximately 270g) for 3 days. MAP, measured by radiotelemetry, was decreased significantly in rats fed either level of RGZ, relative to control rats. Delta MAP from baseline was -3.2 +/- 1.2 mm Hg in rats fed high-dose RGZ versus + 3.4 +/- 0.8 for rats fed control diet. RGZ did not affect feed or water intake, but rats treated with high-dose RGZ had decreased urine volume (by 22%), sodium excretion (44%), kidney weight (9%), and creatinine clearance (35%). RGZ increased whole kidney protein abundance of the alpha-1 subunit of Na-K-ATPase, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), the sodium hydrogen exchanger (NHE3), the aquaporins 2 and 3, and endothelial nitric-oxide synthase. We conclude that both increases in renal tubule transporter abundance and a decrease in glomerular filtration rate likely contribute to the RGZ-induced sodium retention.     

Heparin lowers blood pressure and vascular calcium uptake in hypertensive rats

Increased calcium uptake by vascular tissue, leading to elevated cytosolic calcium, has been implicated in the pathophysiology of hypertension. Heparin treatment of hypertensive rats has been known to lower blood pressure but its mechanism is not known. This study examined the effect of chronic heparin treatment on systolic blood pressure, aortic calcium and 87Rubidium (86Rb) uptake of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Starting at 12 weeks of age SHR and WKY rats were given either sodium heparin 300 units s.c. or equal amounts of saline once a day for a period of 6 weeks. At 18 weeks, systolic blood pressure, uptakes of calcium and 86Rb by aortae were significantly higher (p less than 0.01) in saline-treated SHR compared with heparin-treated SHR and WKY. Heparin treatment lowered the elevated calcium and 86Rb Uptake and blood pressure in SHR but had no effect on WKY. The parallel increase in systolic blood pressure and vascular calcium uptake suggests that increased calcium uptake mechanisms are associated with hypertension in SHR. Heparin appears to lower elevated blood pressure in SHR by lowering elevated vascular calcium uptake.     

Specific insulin assays, insulin sensitivity and blood pressure

Serum insulin concentrations have been used as markers of insulin resistance in population studies examining the relationship between insulin resistance and blood pressure, but the relationship is variable among studies. We hypothesized that differences in cross-reactivity of insulin assays with proinsulin and its split/des-amino products might account for the variation. We therefore examined fasting and post- glucose load serum insulin concentrations (determined by both specific and conventional assays), insulin sensitivity (measured by the euglycaemic clamp technique), and blood pressure, in a group of 56 diabetic (NIDDM) and non-diabetic subjects. Insulin concentrations as measured by the two methods were highly correlated (r = 0.97, p < 0.0001), and the relationships among serum insulin concentrations, insulin sensitivity and blood pressure were independent of assay method; for example, in non-diabetic subjects the univariate correlation between log10AUC insulin and insulin sensitivity index was similar with both methods [r = -0.81 vs. r = -0.82, p < 0.0001 (specific vs. conventional assay)]. Discrepancies between studies in the relationship between serum insulin concentrations and blood pressure are unlikely to be due to cross-reactivity of conventional insulin assays with proinsulin-like molecules.      

Circadian blood pressure rhythms in elderly hypertensive patients

Blood pressure was recorded for 24 h in 121 essential hypertensive patients aged between 20 and 90 years. To characterize the circadian blood pressure rhythm, the differences between the daytime blood pressures (recorded at 8-min intervals between 8 a.m. and 10 p.m.) and the night-time blood pressures (recorded at 30-min intervals between 10 p.m. and 8 a.m.) were calculated. The difference between daytime and night-time blood pressures was significantly (P less than 0.01) decreased in elderly hypertensive patients aged between 65 and 90 years compared with in those aged 20-39 years. In patients with heart insufficiency the circadian blood pressure rhythmicity was significantly (P less than 0.05) further reduced compared with in uncomplicated hypertensives. This may be explained by increased sympathetic tonus in patients with heart insufficiency and reduced vascular compliance may be the cause of the overall reduced circadian blood pressure rhythmicity in elderly hypertensive patients.     

Abdominal and auricular acupuncture reduces blood pressure in hypertensive patients

IntroductionHypertension is an important risk factor of cardiovascular disease (CVD), which is associated with premature death, myocardial infarction, stroke, peripheral vascular disease, and renal disease. The goal of the present study was to use a randomized controlled clinical trial to explore and compare the effectiveness of abdominal and auricular acupuncture on blood pressure in 440 subjects with and without obesity.MethodsFour hundred participants were recruited and randomized to one of four groups: cases and controls receiving auricular acupuncture (204 subjects) and cases and controls receiving abdominal electroacupuncture (196 subjects). Blood pressure and anthropometric parameters were measured before and after the intervention period. In order to match the initial diet of the groups, participants were required to follow an isocaloric diet for two weeks before the trial, and a low-calorie diet for 6 weeks during the intervention period.ResultsWe observed a significant time dependent improvement in the systolic blood pressure measurements in the abdominal intervention group, although this improvement was more pronounce in the first period of study. Of note, in the auricular intervention group, a significant increasing in the level of SBP was detected. Importantly no statistically significant changes were found in the corresponding sham groups.ConclusionsOur findings demonstrated that abdominal electro-acupuncture for 6 weeks reduced both systolic and diastolic blood pressure and auricular acupuncture had a short-term adverse effect on both SBP and DBP.     

Daily blood pressure profile in patients with hypertensive encephalopathy

The purpose of the study was to study daily variations of blood pressure (BP) in patients with hypertensive encephalopathy (HE). Daily BP monitoring (DBPM) was made in 100 patients with different stages of HE. In HE, a proportion of patients from a non-dippers group substantially increased. An excessive nocturnal reduction in systolic BP (SBP) was more common. A dippers group was predominant in the controls. The daily index for SBP significantly decreased in patients with stage I HE; that for diastolic BP (DBP) reduced in those with stages I-II HE. The morning increase rate (MIC) of BP was studied. MIC of SBP was higher in patients with HE, which was most commonly observed in the non-dippers group. There was a more significant reduction in DBP in combination with high MIC in 10% of the examinees.     

高血压患者血压变异性与颈动脉粥样硬化的相关性

目的探讨高血压患者血压变异性(BPV)与颈动脉粥样硬化(CAS)的关系。方法 93例受试者依据血压分为试验组43例(高血压患者)和对照组50例(血压正常者)。统计2组血压情况,比较2组颈动脉内膜中层厚度(IMT)、BPV和硬化系数β值,并进行相关性分析。结果与对照组比较,试验组收缩压、收缩压BPV及舒张压BPV均升高,IMT及硬化系数β增大(P0.05或P0.01);Pearson相关性分析显示收缩压BPV与IMT、硬化系数β(r=0.77、0.53,P0.01)正相关;舒张压BPV与ITM及硬化系数β(r=0.59、0.33,P0.05)也正相关。结论高血压患者BPV与CAS密切相关。     

Fasting blood sample-based assessment of insulin sensitivity in kidney-pancreas-transplanted patients

OBJECTIVE: To ascertain whether simple indexes of insulin sensitivity based on a fasting blood sample may be reliable measures of insulin sensitivity in combined kidney-pancreas- transplanted patients. RESEARCH DESIGN AND METHODS: Estimates of insulin sensitivity based on fasting plasma glucose, insulin (homeostasis model assessment of insulin sensitivity [HOMA-IS], Quantitative Insulin Sensitivity Check Index [QUICKI]), and free fatty acid (revised QUICKI) concentrations were compared with insulin sensitivity as assessed with the gold standard technique (euglycemic-hyperinsulinemic clamp) in 22 patients who had undergone kidney-pancreas transplantation (KP-Tx) and 18 matched healthy subjects (NOR). RESULTS: In KP-Tx patients, indexes based on the glucose-insulin product, HOMA-IS (r = 0.47, P = 0.03) and QUICKI (r = 0.47, P = 0.03), were shown to be reliable measures of insulin sensitivity. The introduction of fasting plasma free fatty acid concentration in the revised QUICKI (r = 0.76, P < 0.0001) considerably improved the power of prediction of the clamp-based measure of insulin sensitivity as observed in the healthy control subjects (r = 0.83, P < 0.0001). CONCLUSIONS: This study shows that in KP-Tx patients, HOMA-IS and QUICKI are reliable measures of insulin sensitivity; the additional incorporation of fasting plasma free fatty acid concentration into the glucose-insulin product (revised QUICKI) resulted in a considerably more powerful index.     

高血压患者血压昼夜节律分析

目的探讨高血压患者血压昼夜节律的变化。方法采用24 h动态血压监测(ABPM)技术研究高血压患者昼夜节律变化特点并与正常人比较。结果单纯高血压组(EH)与正常组比较,血压昼夜节律改变两组无明显差异。而原发性高血压伴靶器官损害组(TOD)的昼夜节律与单纯高血压组或正常组比较差异有显著意义(P<0.01)。结论血压昼夜节律变化与TOD密切相关。     

Effects of beta-adrenoreceptor antagonists on sino-aortic baroreflex sensitivity and blood pressure in hypertensive man.

1. Sensitivity of the sino-aortic baroreflex was investigated before and after acute (23 patients) and chronic (23 patients) beta-adrenoreceptor antagonism in patients with essential hypertension. 2. Sensitivity was inversely related to age (r = -0.60) and systolic blood pressure (r = -0.46); a positive relationship was noted between sensitivity and initial pulse intervals (r = 0.40). 3. Sensitivity increased significantly in patients less than 40 years of age after chronic treatment. No change occurred after acute treatment or in older patients treated chronically. 4. The fall in ambulatory intra-arterial blood pressure after chronic treatment was unrelated to alteration of baroreflex sensitivity.     

Differences in age-independent effects of blood pressure on baroreflex sensitivity between normal and hypertensive subjects

Inter-relationship between age, systolic blood pressure and baroreflex sensitivity index derived from the Valsalva manoeuvre was investigated in either combined or separated groups of normal and hypertensive subjects. Both in the total population as a whole and in each blood pressure subgroup, the baroreflex sensitivity index was significantly inversely related to age and to systolic blood pressure. Furthermore, age was significantly related to systolic blood pressure except in the hypertensive group. Partial correlation analysis showed that, in the total and hypertensive population, the baroreflex sensitivity index was significantly related to age and systolic blood pressure independently of each other variable. In the normal group, however, the baroreflex sensitivity index was not related to systolic blood pressure after adjusting for the effect of age, but remained significantly related to age independently of systolic blood pressure. The estimates of relative effects of the two variables on baroreflex sensitivity by multiple regression analysis were consistent with these results. Thus a prevailing concept of the inhibitory effect of blood pressure on baroreflex function may be accurate exclusively in hypertensive patients, and baroreflex function appears to be more sensitive to age-related changes in this system than to those related to blood pressure level, particularly in non-hypertensive normal subjects.