Biphasic effect of epinephrine on blood glucose during hyperinsulinemiain borderline hypertensive young men

We aimed to study the glycemic response to epinephrine during hyperinsulinemia and infused epinephrine (0.03 μg/kg/min) for 30 min after 90 min of hyperinsulinemic glucose clamp in 14 borderline hypertensive young men. Plasma epinephrine was increased from 0.34 ± 0.08 to 2.33 ± 0.33 nmol/L while insulin and glucose infusions were kept constant with consequent changes in blood glucose. Initially (90 to 95 min), there was a decrease in blood glucose (P = .016) that correlated negatively with glucose disposal rate corrected for insulin (r = −0.55, P = .040) and positively with fasting insulin (r = 0.55). Thereafter, there was an increase in blood glucose (95 to 120 min) (P < .001) that persisted during the recovery period (120 to 140 min). The glucose increase (90 to 140 min) correlated positively with fasting insulin (r = 0.55), systolic blood pressure (r = 0.57), Δ epinephrine 90 to 120 min (r = 0.59), and baseline epinephrine (r = 0.57). Blood glucose remained unchanged (P = .207) in a saline control group (n = 6) with a significant group × treatment effect versus epinephrine (P = .003). Thus, epinephrine caused a biphasic response in blood glucose during hyperinsulinemia. The initial dip in glucose was more pronounced with higher insulin sensitivity, corresponding to previous observations during mental stress test. The following increment in blood glucose was positively related to insulin, systolic blood pressure, and epinephrine levels. These data suggest that insulin may modify the glycemic response to epinephrine in a potentially favorable direction and indicate some lag time before epinephrine gains effect. Subjects who are insulin sensitive and have low blood pressure and resting epinephrine levels seem to be less prone to hyperglycemia induced by epinephrine.     

Effect of Dietary Sodium on Insulin Sensitivity in Older,Obese, Sedentary Hypertensives

Increased dietary sodium intake has been associated with an increase in blood pressure as well as a decrease in insulin-mediated glucose disposal in young healthy adults. The purpose of this study was to determine whether dietary sodium intake is associated with changes in oral glucose tolerance, insulin sensitivity, and blood pressure in older, sedentary, overweight hypertensives. Eight older (70.0 ± 1.4 years, mean ± SEM), overweight (40.2 ± 3.1% body fat), mildly hypertensive (151 ± 8/82 ± 2 mm Hg) patients with a fasting plasma glucose < 7.8 mmol/L were studied after 2 weeks on low (3 g/day) and 2 weeks on high (10 g/day) sodium diets. To examine carbohydrate metabolism we performed a 2 h oral glucose tolerance test and a two-dose (240 and 600 pmol/m ²/min) hyperinsulinemic-euglycemic clamp at the end of each sodium diet. High sodium intake was associated with a significantly greater urinary sodium excretion (364 ± 45 mmol/day v 112 ± 21 mmol/day; P < .0001). The increase in dietary sodium from low to high did not result in significant differences in fasting plasma glucose (6.0 ± 0.2 v 5.8 ± 0.1 mmol/L, P = .20) or insulin (72.5 ± 7.8 v 69.9 ± 12.4 pmol/L, P = 0.71) levels or in the glucose (374.0 ± 50.8 v 493.2 ± 45.0 mmol/min/L, P = .12) and insulin (43,783 ± 10,278 v 44,110 ± 12,392 pmol/min/L, P = .96) areas determined during the oral glucose tolerance test. Similarly, there was no effect of dietary sodium on insulin-mediated glucose disposal at low (5.87 ± 1.02 v 5.60 ± 0.94 mg/kg LBM/min, P = .36) or high (12.15 ± 1.49 v 11.91 ± 1.49 mg/kg _LBM/min, P = .64) insulin infusion rates. Our findings suggest that, in insulin resistant hypertensives, increased dietary sodium does not affect either glucose or insulin responses during an oral glucose tolerance test or glucose disposal during a hyperinsulinemic euglycemic clamp.     

Ethnic differences in red blood cell sodium/lithium countertransport and metabolic correlates of hypertension: An international collaborative study

Arterial hypertension is frequently associated with metabolic abnormalities. An abnormal activity of the erythrocyte sodium/lithium countertransport (Na/Li CT), an ion transport system under strong genetic control, is also found in people with hypertension and concomitant metabolic abnormalities. However, little information exists with regard to these clinical associations in different racial groups. The aim of this international collaborative study was to investigate Na/Li CT and the metabolic correlates of hypertension in two comparable samples of normotensive and hypertensive populations in the cities of Naples, Italy, and Shanghai, China, using identical, carefully standardized techniques. Blood pressure, anthropometric and metabolic variables, Na/Li CT, and 24-h urinary Na and K excretion were measured in untreated essential hypertensive (HPT) and normotensive (NT) individuals selected by age (35–60 years), body mass index (BMI; < 30 kg/m²), and blood pressure (BP; HPT, DBP ≥ 95 mm Hg; NT, DBP < 90 mm Hg). The analysis of variance with adjustment for age was used to compare the groups. In the Neapolitan population, hypertensive individuals had higher serum triglyceride (P < .05) and uric acid levels (P < .001) than the normotensive group and also had a reduced glucose tolerance (P < .01) and an enhanced insulin response to the oral glucose tolerance test (OGTT) (P < .05). No such differences were seen between normotensive and hypertensive Chinese participants. The Neapolitan population (both NT and HPT) had a higher BMI (P < .01) than their Chinese peers. In the comparison of hypertensive patients in Shanghai and in Naples, the Neapolitans were heavier (P < .001), had a lower HDL/total cholesterol ratio (P < .01), an elevated fasting blood glucose (P < .05), and also a higher glucose (P < .001) and insulin response (P < .001) to OGTT. By contrast, they showed a significantly lower urinary Na/K ratio (P < .001). Na/Li CT was significantly increased in HPT both in Naples (286 ± 24 v 224 ± 13 μmol/L RBC × h; P < .05, M ± SE) and in Shanghai (388 ± 45 v 265 ± 30 μmol/L RBC × h; P < .05). Furthermore, Na/Li CT was significantly and inversely associated with HDL cholesterol both in the Neapolitan (P < .01) and in the Chinese (P < .05) population, whereas it was directly correlated with serum triglyceride (P < .001) and serum uric acid (P = .001) only in the Neapolitan population.These results indicate that essential hypertension is associated with a higher prevalence of obesity, impaired glucose tolerance, and hyperinsulinemia in Naples than in Shanghai; and Na/Li CT is linked to both high blood pressure and metabolic abnormalities in the Italian sample, whereas it is an isolated marker of hypertension in the Chinese sample.     

Strict dietary sodium reduction worsens insulin sensitivity by increasing sympathetic nervous activity in patients with primary hypertension

To assess the effects of sodium reduction on insulin sensitivity in hypertension, we examined the change of insulin sensitivity after two degrees of dietary sodium restriction by the euglycemic hyperinsulinemic glucose clamp method in 12 subjects with primary hypertension. A controlled period of 1 week, when the subjects were taking a normal sodium diet, was followed by a randomized crossover study in which the subjects were placed on either moderate or strict reduced sodium diets for 1 week. The result of the 1-week moderate dietary sodium reduction from 200 to 100 mmol/day showed significant decreases in systolic and diastolic blood pressure by 6.5 and 5.0 mm Hg, respectively. Strict dietary sodium reduction to 30 mmol/day for 1 week resulted in no further decrease in blood pressure, but it increased plasma insulin by 40.6% without changing plasma glucose. There were no changes in glucose infusion rate (GIR) or insulin sensitivity index (ISI), which is a measure of GIR divided by plasma insulin, after moderate dietary sodium reduction. However, strict dietary sodium reduction induced decreases in GIR by 19.8% (from 1318 ± 189 to 1057 ± 173 μmol/m²/min; P < .01), and ISI by 20.5% (from 16.6 ± 2.1 to 13.2 ± 1.9 μmol/m²/min/μU/mL; P < .01) with a paralleled increase of plasma norepinephrine by 90.0% (from 150.5 ± 61.6 to 287.3 ± 114.9 pg/mL; P < .01). These results indicate that dietary sodium restriction leads to a deterioration of insulin sensitivity when plasma norepinephrine levels increase, and suggest that moderate dietary sodium reduction may lower blood pressure without a distinct adverse effect on glucose metabolism in subjects with primary hypertension.     

Plasma homocysteine concentrations and insulin sensitivity in hypertensive subjects

Hyperhomocysteinemia is associated with several cardiovascular disease risk factors including endothelial dysfunction and abnormalities of clotting functions, which are also common features of insulin resistance syndrome observed in hypertensive patients. Recent study has shown that acute hyperinsulinemia can lower plasma homocysteine concentrations in nondiabetic but not in type 2 diabetic individuals, indicating that insulin may regulate homocysteine metabolism. To investigate the relationships between plasma homocysteine concentration and insulin sensitivity, we studied 90 Chinese hypertensive patients and a group of control subjects (n = 86) matched for age, gender, and body mass index. Fasting plasma homocysteine levels, plasma lipoprotein concentrations, plasma glucose, and insulin responses to oral glucose tolerance tests (OGTT) were determined. The results showed that fasting plasma homocysteine concentrations were significantly higher in subjects with hypertension than in those with normotension (mean ± SEM, 8.1 ± 0.6 v 6.8 ± 0.2 μmol/L; P < .05). Fasting plasma homocysteine levels correlated significantly with insulin secretion in response to OGTT even after adjustment for body mass index (P < .05) in hypertensive patients but not in normotensive individuals. However, fasting plasma homocysteine concentrations showed no correlations with steady-state plasma glucose concentration, a measurement of insulin sensitivity, during an insulin suppression test in groups of hypertensive (n = 42) and normotensive (n = 37) subjects. When the steady-state plasma glucose concentrations were divided into three tertiles, fasting plasma homocysteine concentrations showed no difference across these three groups in either hypertensive patients (8.6 ± 0.5 v 7.2 ± 0.5 v 8.4 ± 0.6 μmol/L; P = .148) or normotensive subjects (6.3 ± 0.4 v 8.0 ± 0.8 v 7.0 ± 0.8 μmol/L; P = .199). In conclusion, hypertensive Chinese subjects had higher fasting plasma homocysteine concentrations and a higher degree of insulin resistance when compared to a group of age-, gender-, and body mass index-matched normotensive individuals. Fasting plasma homocysteine levels were associated with insulin response to OGTT in hypertensives but not in normotensives. No correlation was observed between the degree of insulin resistance and plasma homocysteine levels in either the hypertensive or the normotensive group. The role of insulin in homocysteine metabolism deserves further investigation.     

Alterations in angiotensin II release and vascular reactivity in hypertensive men: a pilot study

Cold- and insulin-mediated release of angiotensin II (AII) and endothelin-1 (ET-1), as well as vascular reactivity to exogenous ET-1 and to insulin, were compared in hypertensive and normotensive subjects.Peripheral vascular release of AII and of ET-1 was investigated in 10 hypertensive (H; 29.2 ± 5.8 years) and 12 normotensive (N; 29.1 ± 4.6 years) men in two separate trials. Net transfemoral balance of AII and of ET-1 was calculated from the respective Arterio-Venous (A-V) differences in plasma concentrations (PC) of the peptides and the regional plasma flow (indocyanine-green dye method), both at baseline conditions and after a cold stimulus (immersion of one hand into ice water) in 7H and 6N, or during short-time hyperinsulinemia (hyperinsulinemic euglycemic clamp: biosynthetic human insulin, 1 mU/kg/min) in 7H and 7N. Moreover, hemodynamic changes to sequential exogenous ET-1 infusion (1, 2.5, 5, 10, 20, 40 ng/min) or during hyperinsulinemic clamp were studied in 7H and 6N and 7H and 7N, respectively.Baseline net-transfemoral balance of ET-1 and of AII were similar in the two subject groups. The cold stimulus provoked a similar increase in transfemoral ET-1 release in H and N (H: 257.0 ± 31.7 to 526.2 ± 393.7 pg/min; N: 280.2 ± 112.7 to 524.0 ± 393.7 pg/min, mean ± SD, P < .05). In contrast, the cold-induced increase in transfemoral AII release was somewhat more pronounced in H than in N (H: 162.2 ± 304.6 to 1081.7 ± 1037.7 pg/ min, P < .05; N: 83.9 ± 166.3 to 317.6 ± 187.8 pg/min, P < .02; maximum value H v N P < .05). During the hyperinsulinemic clamp the PC of insulin increased from 5.8 ± 2.8 to 69.1 ± 15.5 μU/mL in H and from 4.6 ± 1.7 to 67.5 ± 9,5 μU/mL in N; P < .0005. Hyperinsulinemia induced a similar elevation of norepinephrine PC in H and N, but an increase in transfemoral ET-1 release in N only (219.7 ± 161.2 to 512.2 ± 279.0 pg/min, P < .02). In contrast, hyperinsulinemia increased transfemoral AII formation in H (730.4 ± 554.3 to 1088.6 ± 597.9 pg/min, P < .05), but not in N. Insulin-mediated vasodilation was observed only in N, whereas ET-1-induced vasoconstriction was blunted in H.We conclude that the cold-induced increase in peripheral vascular release of AII is more pronounced in H than in N, whereas insulin provokes an increase in AII formation in hypertensives only. Moreover, insulin-mediated vasodilation and ET-1-dependent vasoconstriction are blunted in hypertensive subjects.     

Role of plasma and urinary endothelin-1 in early diabetic and hypertensive nephropathy

To evaluate the role of circulating and renal endothelin-1 (ET-1) in early diabetic nephropathy, plasma ET-1 levels and urinary ET-1 excretion were evaluated in lean, normotensive patients affected by non–insulin-dependent diabetes (NIDDM) either with (n = 9, NIDDM+) or without microalbuminuria (n = 18, NIDDM−); in never-treated, lean, essential hypertensive patients with (n = 12, EH+) or without microalbuminuria (n = 10, EH−); and in healthy volunteers (n = 12). Results showed higher plasma ET-1 levels in NIDDM+ (1.97 ± 0.58 pg/mL) than in NIDDM− (1.59 ± 0.14 pg/mL, P = .013), EH+ (1.40 ± 0.21 pg/mL, P = .005), EH− (0.91 ± 0.19 pg/mL, P < .0001), and controls (0.60 ± 0.10 pg/mL, P < .0001). The circulating ET-1 concentration was also higher in EH+ than EH− and controls (P < .0001).Urinary ET-1 excretion did not differ (P = .387, NS) between NIDDM+ (48.5 ± 20.1 pg/min) and NIDDM− (40.9 ± 21.6 pg/min), but was significantly reduced (P < .0001) in both groups compared with controls (70.0 ± 15.5 pg/min). Similar findings were observed in hypertensive subgroups. No correlations were found between urinary ET-1 and other variables, including plasma ET-1 levels, in all groups.In conclusion, NIDDM+ is accompanied by a significant increase in plasma ET-1 levels. A significant elevation of circulating ET-1 concentration was evident also in NIDDM−, suggesting that early abnormalities of ET-1 production might precede the microalbuminuric phase of diabetes-related renal damage.     

Plasma OLC is elevated in mild experimental uremia but is not associated with hypertension

Background:Little is known about the renal handling of endogenous ouabain-like compound (OLC). The aim of this study was to determine the normal renal clearance of OLC and the effect of mild experimental uremia on plasma OLC and its clearance.Methods:Male Wistar rats were studied 8 weeks after subtotal (5/6th) nephrectomy (n = 8) and compared with a control sham-operated group (n = 8).Results:Plasma creatinine and OLC were higher in uremic animals compared with controls (creatinine 76 ± 5.6 μmol/L v 45 ± 9.6 μmol/L, respectively, P < .00005; OLC 195 ± 62 pmol/L v 121 ± 62 pmol/L, P < .02). Creatinine clearance and OLC clearance were lower in uremic animals compared with controls (creatinine 1.06 ± 0.12 mL/min v 1.58 ± 0.32 mL/min, respectively, P < .002; OLC 23.6 ± 10.4 μL/min v 33.2 ± 11.4 μL/min, P < .05). There were no significant differences (all P > .05) between the uremic and control groups in the fractional clearance of OLC (uremic 2.3% ± 1.0% v control 2.2% ± 1.0%), OLC excretion rate (uremic 6.2 ± 2.4 pmol/24 h v control 5.0 ± 1.1 pmol/24 h) or in the mean systolic blood pressure (BP) (uremic 132 ± 13 mm Hg v control 126 ± 3 mm Hg). The amount of OLC excreted per unit of functioning nephron mass was 78% higher in uremic animals than in controls. The rate of tubular absorption varied linearly with filtered load, did not differ between groups, and showed no evidence of saturation.Conclusions:The kidneys are an important excretion route for plasma OLC and moderate but significant increases may occur without inducing hypertension in the short term. The low fractional clearance of OLC is most likely due to tubular absorption and/or catabolism.     

Blood Pressure and Metabolic Responses to Moderate Sodium Restriction in Isradipine-Treated Hypertensive Patients

This multicenter, randomized, controlled clinical trial assessed the influence of sodium chloride intake on the antihypertensive effect of the calcium channel blocker isradipine. Participants with uncomplicated hypertension controlled by isradipine entered a 4-week sodium-restricted (60 to 80 mmol/24 h) period. Participants with urinary sodium levels <120 mmol/24 h (n = 99) were randomized to placebo or sodium chloride (100 mmol/24 h) for 4 weeks, and then crossed over to the alternative treatment for an additional 4 weeks. Mean baseline systolic blood pressure was 151.9 ± 16.7 mm Hg (mean ± SD). During open-label isradipine treatment, systolic blood pressures for ad libitum sodium chloride and restriction were 134.1 ± 11.1 and 132.1 ± 12.2 mm Hg respectively; for double-blind sodium chloride restriction and supplementation: 133.6 ± 12.6 and 138.5 ± 12.8 mm Hg (P < .01). Urinary sodium excretion values for open-label isradipine ad libitum versus restricted were 140.6 ± 61.9 versus 76.9 ± 32.4 mmol/24 h; for double-blind restricted versus supplemented, sodium excretion was 120.5 ± 68.9 v 175.9 ± 68.7 mmol/24 h (P ≤ .0001). Changes in urinary sodium excretion were not predictive of variations in blood pressure. Urinary sodium excretion during sodium restriction correlated directly with HDL-cholesterol (P < .02) and inversely with total cholesterol:HDL-cholesterol (P = .02), despite decreased total and saturated fat intake (P < .01). Sodium restriction was associated with significant reductions (P < .01) in virtually all macronutrients and electrolytes, and thus had an adverse impact on overall nutrition. The antihypertensive action of isradipine was not enhanced by dietary sodium chloride restriction, and the lipoprotein profile was least favorable with sodium chloride restriction.     

Hyperinsulinemia in glucose-tolerant women with preeclampsia A controlled study

Essential hypertension is associated with insulin resistance and hyperinsulinemia. To assess whether hyperinsulinemia is also present in hypertensive disease induced by pregnancy, we studied the plasma glucose and insulin responses to 50 g of oral glucose in 10 women with definite, severe preeclampsia but normal glucose tolerance, and compared them with the responses observed in a well-matched control group of healthy pregnant women. Fasting plasma glucose concentrations were similar in healthy and preeclamptic pregnant mothers (4.1 ± mmol/L v 4.5 ± mmol/L, respectively, P =NS). Similar plasma glucose levels were also observed after glucose ingestion (5.5.0 ± 0.3 mmol/L v 6.2 ± 0.3 mmol/L in healthy and preeclamptic women, respectively P = NS). In contrast, fasting plasma insulin concentrations in the preeclamptic women were significantly higher than in normal pregnant mothers (175 ± 29 pmol/L v 101 ± 11 pmol/L, P < .05). Postload plasma insulin concentrations were nearly fourfold higher in the preeclamptic group as compared with the control group (1162 ± 70 pmol/L v 366 ± 39 pmol/L, P < .01).We conclude that preeclampsia is associated with marked hyperinsulinemia both in the fasting state and after oral glucose ingestion, suggesting that insulin resistance may play a role in pregnancy-induced hypertension.     

Cytochrome P-450 arachidonate metabolite inhibition improves renal function in Lyon hypertensive rats

The present study evaluated the effects of miconazole, a selective inhibitor of epoxygenase activity, on renal hemodynamics and the pressure-natriuresis response of saline-drinking, uninephrectomized Lyon hypertensive (LH) and Lyon low blood pressure (LL) rats. Infusion of miconazole (final concentration, 1 μmol/L) into the renal artery had no effect on the renal function of LL rats over a range of renal perfusion pressures (RPP) from 100 to 140 mm Hg. In contrast, miconazole lowered renal vascular resistance (RVR, 17.9 ± 1.1 v 26.3 ± 1.5 mm Hg/mL/min/g, P < .01) and increased urinary sodium excretion (6.4 ± 1.2 v 4.2 ± 0.8 μmol /min/g, P < .05) in LH rats at a RPP of 140 mm Hg. To determine whether the effects of epoxyeicosatrienoic acids were dependent on activation of the thromboxane A2-prostaglandin H2 (TP) receptor, we studied the effects of a TP receptor antagonist, GR 32191B (0.1 mg/kg/min), on the renal response to an infusion of miconazole into the renal artery in LH rats. GR 32191B decreased basal RVR and prevented the dilation induced by miconazole. It did not, however, alter its natriuretic effect. The renal metabolism of arachidonic acid was also compared in LH and LL rats. The production of epoxygenase metabolites was 25% lower in microsomes prepared from the renal cortex of LH versus LL rats. Miconazole (1 μmol /L) reduced epoxygenase activity similarly, by approximately 60%, in both strains. These results suggest that endogenously formed P450 metabolites of arachidonic acid may serve as a substrate for the formation of vasoconstrictor endoperoxides that interact with TP receptors in LH rats and contribute to the enhanced renal vascular tone but not the blunted pressure-natriuresis response.     

Vasorelaxant effects of cicletanine and its (+)- and (−)-enantiomers in isolated human pulmonary arteries

The purpose of the study was to investigate, in isolated human pulmonary artery, the ability of cicletanine and its (−) and (+)-enantiomers to attenuate the endothelin-1 (Et-1) induced vasoconstriction, and to potentiate vasorelaxation (relative to plateau of the effect of Et-1) by sodium nitroprusside (SNP) and human atrial natriuretic peptide (ANP). In pulmonary artery rings, Et-1 induced a concentration-dependent vasoconstriction with median effective concentration (EC₅₀ = 26 ± 2.8 nmol/L. Pretreatment of the vessels with 100 μmol/L (±)-cicletanine reduced the effect of Et-1 (EC₅₀ = 36 ± 3.5 nmol/L; P < .01). (−)-enantiomer displayed greater capacity to antagonize the vasoconstrictor action of Et-1 (EC₅₀ = 47 ± 4.2 nmol/L) v (+)-enantiomer (EC₅₀ = 29.9 ± 6.5 nmol/L; P < .01). In arterial rings, precontracted with 10 nmol/L Et-1, ANP caused vasorelaxation (EC₅₀ = 9.7 ± 1.9 nmol/L). The relaxant effect of ANP was potentiated by 100 μmol/L of (−)-(EC₅₀ = 4.2 ± 0.6 nmol/L; P < .01), but not (+)-cicletanine (EC₅₀ = 7.6 ± 0.7 nmol/L). Sodium nitroprusside relaxed pulmonary artery rings precontracted with 10 nmol/L Et-1 (EC₅₀ = 41 ± 11 nmol/L). The effect of SNP was potentiated by 10 μmol/L (±)-cicletanine (EC₅₀ = 9.0 ± 0.7 nmol/L; P < .05). The potentiating effect of 10 μmol/L (+)-cicletanine was weaker (EC₅₀ = 7.9 ± 1.8 nmol/L) than that of (−)-enantiomer (EC₅₀ = 3.3 ± 0.54 nmol/L; P < .05). The relaxant effect of SNP was not further potentiated by 100 μmol/L (±)-cicletanine. The present results demonstrate that, cicletanine antagonizes Et-1 induced vasoconstriction in an isolated human pulmonary artery and potentiates vasorelaxation by two guanylate cyclase activators, ANP and SNP. (−)-Cicletanine displays greater vasorelaxant activity v (+)-enantiomer.     

A novel mechanism of glipizide sulfonylurea action: decreased metabolic clearance rate of insulin

To examine whether sulfonylureas inhibit the metabolic clearance rate (MCR) of insulin, 19 healthy young subjects participated in two experiments. In the first protocol (n=10), a 3-h oral glucose load was performed with and without 2 mg of glipizide given 30 min before glucose ingestion. The total insulin response was 60% greater with than without glipizide (5.9±0.6 vs 3.7±0.5 μU/ml;P<0.001). However, the total C-peptide responses were virtually identical (4.7±0.5 vs 4.8±0.4 nmol/l) in both studies. In the second protocol (n=9), the MCR of insulin was measured during 4-h euglycemic insulin clamps performed with and without glipizide. In the study with glipizide, the subjects ingested 5 mg of glipizide at 120 min. The steady-state plasma insulin concentration during the 4th h, i.e., 1–2 h after glipizide ingestion, was significantly higher than during the 2nd h, i.e., before glipizide ingestion (99±22 vs 78±17 μU/ml;P<0.01). In addition, glucose uptake during the 4th h was greater (8.0±1.6 vs 6.4±1.5 mg/kg·min) and the MCR of insulin was reduced (503±126 vs 621±176 ml/m²·min;P<0.01). We conclude that glipizide augments plasma insulin levels both by enhancing its secretion and by decreasing the MCR of insulin.     

B族维生素在雄性小鼠高尿酸血症中的作用

目的研究B族维生素对高尿酸血症小鼠血尿酸水平的影响及其对高尿酸血症引起的内皮功能紊乱的作用。方法 SPF级昆明雄性小鼠63只,按体质量完全随机分成6组,A、B、C、D、E和F组。A组蒸馏水处理作为对照组,B组酵母膏+乙胺丁醇混合液灌胃处理建立小鼠高尿酸血症模型作为对照组;其余4组除建立模型外,还需在C组小鼠灌胃液中加入别嘌呤醇片,在D、E和F组中分别加入低、中、高剂量的叶酸+维生素B6+维生素B12混合溶液。3周后取血测定小鼠血尿酸水平及血清一氧化氮值。结果 3周后,6组小鼠的血清尿酸水平差异有统计学意义(F=14.7469,P<0.05)。与B组比较,D、E和F组小鼠的血清尿酸水平均能在一定程度上有所降低,且差异有统计学意义[D组(217.38±74.99)μmol/L,E组(228.19±65.25)μmol/L,F组(174.48±34.60)μmol/L比B组(302.93±56.99)μmol/L,均为P<0.05]。其中F组降低更显著,但其降低效果均低于C组[C组(105.52±49.32)μmol/L比F组(174.48±34.60)μmol/L,P<0.05]。6组小鼠的血清一氧化氮水平差异有统计学意义(F=7.0499,P<0.05)。与B组比较,E组和F组的血清一氧化氮水平均升高[E组(16.52±10.95)μmol/L,F组(18.63±10.77)μmol/L比B组(2.51±3.89)μmol/L,P<0.05],且与C组比较,F组升高更明显[C组(9.35±5.65)μmol/L比F组(18.63±10.77)μmol/L,P<0.05]。血清一氧化氮水平与尿酸水平呈负直线相关(r=-0.278,P<0.05)。结论叶酸、维生素B12及维生素B6可呈剂量依赖性降低高尿酸血症小鼠的血尿酸水平;同时较大剂量的B族维生素能够在一定程度上升高血清一氧化氮水平。     

Changes in plasma,erythrocyte, and platelet magnesium levels in normotensive and hypertensive obese subjects during oral glucose tolerance test

We evaluated the 75-g oral glucose tolerance test (OGTT)-induced modifications in glucose, insulin, and norepinephrine plasma concentrations, and in plasma, erythrocyte, and platelet magnesium levels in two groups of obese subjects (normotensive obese, NT-Ob, N = 19; hypertensive obese, HT-Ob, N = 15), and in a group of healthy control subjects (N = 12). During OGTT we detected a reduction in plasma magnesium concentrations and an increase in erythrocyte and platelet magnesium levels in the controls, whereas in both normotensive and hypertensive obese subjects, there was a reduction in plasma, erythrocyte, and platelet magnesium levels. Furthermore, no statistically significant difference was detected among the groups studied as regards Δ-plasma magnesium. On the other hand, Δ-erythrocyte magnesium and Δ-platelet magnesium were negative in the NT-Ob (Δ-erythrocyte magnesium: −0.24 ± 0.08 mmol/L; Δ-platelet magnesium: −0.49 ± 0.09 μmol/10⁸cells) and HT-Ob (Δ-erythrocyte magnesium: −0.20 ± 0.10 mmol/L; Δ-platelet magnesium: −0.50 ± 0.11 μmol/10⁸cells) groups, and positive in control subjects (Δ-erythrocyte magnesium: 0.40 ± 0.08 μmol/L; Δ-platelet magnesium: 0.47 ± 0.09 mmol/10⁸ cells). Finally, a direct correlation was found between Δ-norepinephrine and Δ-erythrocyte magnesium (r = 0.80, P < .01) in the control group, and a negative correlation was detected between Δ-norepinephrine and Δ-platelet magnesium (r = −0.58, P < .05) in the HT-Ob group. Our results seem to indicate that the insulin resistance status, the hyperglycemia, and the disregulation of the adrenergic system in obese subjects could be involved in the pathogenesis of the magnesium homeostasis impairment observed in the obese subjects.     

The effect of sodium supplementation on glucose tolerance and insulin concentrations in patients with hypertension and diabetes mellitus

Severe short-term sodium restriction or extreme sodium loading may alter glucose tolerance and insulin resistance in patients with hypertension, but it is unclear whether variations in sodium intake within the clinically observed range affect glucose tolerance. To examine this issue, 21 patients with primary hypertension with average sodium excretion of 116 ± 55 mEq/day were randomized to consecutive 4-week periods of placebo therapy and sodium chloride supplementation 2 g four times a day in a single-blind crossover study design. A 75-g oral glucose tolerance test (GTT) with simultaneous insulin levels was performed at the end of each intervention period.For the group as a whole, urinary sodium excretion increased on sodium chloride to 267 ± 118 mEq/day versus control (placebo) phase of 135 ± 53 mEq/day, P < .001. Total glycemic response in the oral GTT (area under the glucose curve) was 8.0% lower during sodium supplementation, P < .001. Secondary analysis revealed that the effect of sodium was noteworthy in 1) type 2 diabetic subjects (n = 8), 2) sodium-sensitive subjects (n = 10), and 3) nondiabetic subjects receiving antihypertensive drug treatment (n = 6). The total insulinemic response to oral GTT was also lowered by sodium loading among diabetic subjects. Thus, an abundant sodium intake may improve glucose tolerance and insulin resistance, especially in diabetic, salt-sensitive, and or medicated essential hypertensive subjects.     

Uridine preserves ATP during hypoxic perfusion of the rat heart

Background: The pyrimidine precursor, orotic acid, by minimising ischaemia-induced ATP loss, improves the functional performance of recently infarcted hearts that have been subjected to global ischaemia. However, we have also previously shown that orotic acid is not directly active in the heart but is preferentially taken up by the liver where it is metabolised to uridine. Aim: To investigate whether uridine itself can minimise hypoxia-induced ATP loss. Methods: Isolated Langendorff-mode perfused rat hearts were subjected to 4 protocols after 20 min normoxic stabilisation: normoxia for 30 min (n=12); hypoxia for 30 min (n=12); hypoxia in the presence of 17μM uridine for 30 min (n=12); and [U-¹⁴C]-uridine added directly to the hypoxic perfusate reservoir just prior to 30 min hypoxia (n=4). [U-¹⁴C]-uridine was used to assess the contribution of radiolabel to adenosine formation from adenine nucleotide hydrolysis. Coronary effluent was collected and hearts were freeze-clamped for metabolite assay. Results: Hypoxia reduced ATP, from 21.1±1.1 to 4.1±0.6 μmol/g dry weight (p<0.05), and reduced total adenine nucleotides (TAN) from 30±1.2 to 10.2±0.9 μmol/g dry weight (p<0.05). Uridine during hypoxia increased myocardial ATP by 94% to 8±0.9 μmol/g dry weight and TAN by 50% to 15.3±1.1 pmol/g dry weight (p<0.05). Uridine plus hypoxia increased total lactate release by 52% from 768.1± 86 μmol/g dry weight to 1148.4 ±146 μmol/g dry weight compared with hypoxia alone (p<0.05). Although the salvage of purine bases did occur, it was calculated that less than 0.01% of labelled ribose was transferred for salvage of purines. Conclusion: In the present experimental model, uridine protects the hypoxic heart by predominantly enhancing glycolytic energy production.     

微粒化非诺贝特调节老年代谢综合征患者血脂及尿酸代谢的研究

目的观察微粒化非诺贝特(非诺贝特)对老年代谢综合征患者血脂及尿酸代谢的影响,并探讨其潜在机制。方法入选131例老年代谢综合征患者,同时伴有高TG及高尿酸血症,每日顿服非诺贝特胶囊200 mg,疗程为4周。观察治疗前和治疗4周后主要血脂参数、血尿酸、24 h尿尿酸的变化及不良反应。结果非诺贝特治疗4周后:(1)患者血清TG下降最为显著,与基线比较下降49%,血清HDL-C水平升高18%,此外患者血清TC和LDL-C水平也有一定程度的下降(分别为11%和14%);(2)患者血尿酸水平由(472.5±74.8)μmol/L降至(325.0±82.1)μmol/L,下降幅度为31.2%。其中男性患者血尿酸水平下降32.6%,女性患者下降29.7%,差异均有统计学意义(P<0.01)。(3)患者24 h尿尿酸排泄明显增多,由(2 885.2±502.7)μmol/L增加至(3 701.7±768.2)μmol/L,排泄增加28.8%,其中男性24 h尿尿酸排泄高于女性(P<0.01)。结论非诺贝特具有同时改善老年代谢综合征患者的血脂及尿酸代谢异常的双重疗效,能明显促进尿尿酸排泄,且该作用与性别无关。     

Cystatin C is associated with the metabolic syndrome and other cardiovascular risk factors in a hypertensive population

Serum cystatin C has been associated with cardiovascular disease. We investigated whether cystatin C concentration is associated with the metabolic syndrome and with other cardiovascular risk factors in a hypertensive population. In this cross-sectional study, we prospectively included 611 essential hypertensive patients during a 12-month period. Cystatin C concentration was measured by nephelometry. The metabolic syndrome was present in 46% of the patients. Cystatin C was significantly higher in patients with the metabolic syndrome (0.94 ± 0.27 mg/L) than in those without (0.87 ± 0.23 mg/L) (P < .0001). Pearson partial correlation analysis showed a significant correlation between cystatin C and body mass index (r = 0.240; P = .001); waist circumference (r = 0.173; P = .012); microalbuminuria (r = 0.273; P < .0001); triglycerides (r = 0.138; P = .047); C-reactive protein (r = 0.190; P = .006); uric acid (r = 0.284; P < .0001); age (r = 0.409; P < .0001); and glomerular filtration rate (GFR) (r = -0.638; P < .0001). Multivariate analysis showed that GFR (B = -0.0061; 95% confidence interval [CI], -0.0073 to -0.0049; P < .0001), age (B = 0.0023; 95% CI, 0.0005–0.0041; P = .009), microalbuminuria (B = 0.0005; 95% CI, 0.0002–0.0007; P < .0001), uric acid (B = 0.0252; 95% CI, 0.0085–0.0418; P = .003), body mass index (B = 0.0051, 95% CI, 0.0012–0.0089; P = .011), and C-reactive protein (B = 0.0048; 95% CI, 0.0015–0.0082; P = .005) were independent determinants of cystatin C concentration. Measuring cystatin C concentration in hypertensive patients may be useful for evaluating their cardiovascular risk profile.     

Effects of l-arginine on blood pressure and metabolic changes in fructose-hypertensive rats

In the present study, we examined the effects of chronic l-arginine treatment on plasma insulin levels and systolic blood pressure (SBP) in fructose-fed (F) rats. Fructose feeding resulted in hyperinsulinemia and elevated blood pressure when compared with that in controls (plasma insulin, 311.3 ± 11.4 v control 164.4 ± 11.8 pmol/L, P < .05; SBP, 135.4 ± 4.2 v control 105.5 ± 1.3 mm Hg, P < .05). l-arginine treatment of fructose-hypertensive rats prevented the development of hyperinsulinemia and hypertension (plasma insulin, 200.1 ± 7.5 pmol/L; P < .05 compared with that in F rats; SBP, 108.0 ± 0.9 mm Hg; P < .05 compared with F rats). However, treatment with l-arginine did not influence any of these parameters in control rats. Statistical analysis of the data of plasma insulin level and SBP, revealed a significant correlation between these two variables. On the other hand, l-arginine treatment of F rats prevented the increased glucose and insulin concentrations in response to oral glucose challenge. l-arginine treatment also prevented the decrease in insulin sensitivity of F rats. These results indicate that l-arginine treatment is able to prevent fructose-induced hypertension and hyperinsulinemia. Our data also suggest a strong relationship between hyperinsulinemia and hypertension in this hypertensive rat model. Therefore, the antihypertensive effect of l-arginine could be, at least in part, the result of the restoration of plasma insulin levels by its vasodilator ability to increase blood flow to insulin sensitive tissues.