Rilmenidine normalizes fructose-induced insulin resistance and hypertension in rats

OBJECTIVE: The aim of this study was to determine the effects of rilmenidine (an antihypertensive drug that lowers blood pressure by decreasing sympathetic outflow) in an animal model of hypertension associated with insulin resistance, i.e. rats fed on a high-fructose diet. DESIGN: Wistar rats were fed for 4 weeks either on a standard diet (S group) or on a high-fructose diet (F group; 34.5% fructose). In half of the rats in the F group, rilmenidine (1 mg/kg per day) was added to the drinking water for the last 2 weeks of the diet (FR group). RESULTS: Body weight gain was higher in the F than in the S rats (66+/-8g versus 45+/-8g, P< 0.05), but was prevented by rilmenidine treatment (32+/-2g). Arterial systolic blood pressure was increased in F rats (162+/-2 versus 155+/-2 mmHg, P< 0.05), rilmenidine reduced this value to normal (149+/-3 mmHg). Glucose tolerance, glucose turnover rate, and insulin secretion were not modified by the diet or by the drug. However, during a euglycemic hyperinsulinemic clamp, glucose utilization was lower (10+/-1 versus 14+/-1.5 mg/min per kg; P< 0.05) and hepatic glucose production higher (1+/-0.01 versus 0 mg/min per kg, P< 0.01) in F than in S rats. These changes in insulin action were totally abolished by rilmenidine. CONCLUSIONS: These data demonstrate that rilmenidine can ameliorate the deleterious effects of a high-fructose diet, i.e. weight gain, hypertension, and resistance to the effects of insulin.     

Insulin therapy could prevent salt-induced high blood pressure in diabetes mellitus

The effectiveness of insulin replacement therapy in the prevention of salt-induced hypertension in diabetes mellitus was examined using Alloxan diabetic rats. Early daily (eight units/day) treatment with insulin prevented the development of high blood pressure after six weeks of high-salt feeding. The mean arterial pressure (MAP) for the early insulin-treated and salt-fed group (DET-SF) was 123.37 +/- 6.37 mmHg which was close to the value for normal (control) rats 128.17 +/- 4.84 mmHg, but significantly (p < 0.001) less than that of the untreated diabetic salt-fed group (DSF) which was 164.58 +/- 8.33 mmHg. The nondiabetic salt-fed (NDSF) group had MAP of 150.27 +/- 4.24 mmHg. Late commencement of insulin therapy did not significantly affect the sensitivity of the diabetic rats to high-salt diet. The results suggest that early commencement of insulin therapy could prevent the development of high blood pressure in diabetic rats.     

Effects of rilmenidine (hyperium) on lipid balance in hyperlipidemic hypertensive patients. Randomized, controlled, double-blind 8-week study vs. captopril in parallel groups

Rilmenidine (dose of 1 mg once or twice a day) is the first oxazoline compound with antihypertensive properties. Its effects on lipid parameters [total cholesterol, HDL and LDL fractions, triglycerides, apolipoprotein A1 and B, lipoprotein (a)] were compared under double-blind conditions and in parallel groups to those of captopril (50 to 100 mg per day, in 2 divided doses) over a period of 8 weeks, in 51 hyperlipidaemic hypertensive patients [age: 56.3 +/- 1.5 years, systolic and diastolic blood pressure (SBP/DBP): 165.1 +/- 2.0/99.1 +/- 0.6 mmHg, LDL cholesterol: 5.38 +/- 0.16 mmol/L]. No significant difference was demonstrated between the groups on inclusion for any of the clinical parameters (SBP, DBP, heart rate (HR)) and laboratory parameters, apart from apolipoprotein A1, for which the mean value was higher in the rilmenidine group than in the captopril group (p < 0.05). No difference between the groups was demonstrated during the 8 weeks of treatment for the course of blood pressure: SBP and DBP decreased by 20.5 and 13.9 mmHg, respectively, in the rilmenidine group and by 21.3 and 13.1 mmHg in the captopril group (no significant difference: NS). HR decreased by 0.3 beats per minute (bpm) in the rilmenidine group and by 4.1 bpm in the captopril group (NS). No statistically significant difference in lipid parameters was observed between the two groups. No clinically significant variation in any of the lipid parameters was observed after 8 weeks of treatment with rilmenidine or captopril. These results confirm the antihypertensive efficacy and neutrality of rilmenidine on lipid metabolism over a period of 8 weeks. Rilmenidine therefore represents a useful alternative in the first-line treatment of hypertension in hyperlipidaemic hypertensive patients.     

52 cases of apoplexy treated with scalp acupuncture by the slow-rapid reinforcing-reducing method

The objective of this study was to investigate the effect of Losartan (NK-954, DuP-753), a new selective angiotensin II receptor antagonist, on insulin sensitivity and sympathetic nervous system activity in patients with severe primary hypertension. Five patients with a record of diastolic blood pressure (DBP) > or = 115 mmHg, currently either untreated or with DBP > 95 mmHg on antihypertensive treatment, were examined in an open study with the euglycemic glucose clamp examination before and after being treated with Losartan for an average of 6 weeks. The glucose disposal rate increased from 6.2 +/- 2.6 to 7.9 +/- 2.6 mg/kg x min (27%, p < 0.05) during treatment with Losartan. The insulin sensitivity index (glucose disposal rate divided by mean insulin concentration during clamp) increased from 7.7 +/- 4.5 to 10.1 +/- 4.1 arbitrary units (30%, p < 0.05). Plasma noradrenaline decreased from 1.87 +/- 0.53 to 1.11 +/- 0.13 nmol/l (40%, p < 0.05), while plasma adrenaline was unchanged (0.23 +/- 0.10 vs. 0.22 +/- 0.11 nmol/l, n.s.). Mean blood pressure decreased from 132 +/- 10 to 119 +/- 13 mmHg (p < 0.05) and heart rate was unchanged during treatment with Losartan. Thus, antihypertensive treatment with the new selective angiotensin II receptor antagonist Losartan seems to improve insulin sensitivity. A decrease in plasma noradrenaline on Losartan suggests a sympathicolytic effect which together with vasodilation may explain the fall in blood pressure and the improvement in insulin sensitivity.     

Mechanism of the diabetogenic action of cyclosporin A

To investigate the mechanism of diabetogenic action of cyclosporin A (CsA), 7 male Wistar albino rats received 10 mg/kg/day of the drug for 4 weeks (CsA). The results were compared with controls (C); blood CsA levels measured weekly remained stable throughout the experiment (mean +/- SEM) (X = 2657.9+/-155.1 ng/ml). Intravenous glucose load (0.75 g/kg) performed after 2 weeks of CsA therapy showed glucose intolerance in treated animals as evaluated by the glucose area under the curve (CsA = 409.2+/-17.8 vs. C = 313.3+/-12.6 umol x ml(-1) x min(-1)) (p < 0.05) with insulin levels being similar in the two groups (CsA = 8603.9+/-1645.5 vs. C = 9571.9+/-828.5 pmol x ml(-1) x min(-1)). After 4 weeks of CsA administration, glucose intolerance was maintained (CsA = 398.6+/-35.6 vs. C = 301.7+/-23.0 umol x ml(-1) x min(-1)) (p < 0.05) associated with a significant decrease in insulin secretion (CsA = 4404.9+/-2392.0 vs. C = 10075.9+/-2861.0 pmol x ml(-1) x min(-1) (p < 0.05). These results suggest that CsA induced a state of insulin resistance preceding the failure of insulin secretion. After 4 weeks, the pancreatic insulin content was also decreased (CsA = 0.7+/-0.1 vs. C = 1.4+/-0.5 mU/mg) (p < 0.05). Maximal insulin binding to isolated adipocytes was not affected by CsA (CsA = 7.4+/-2.6 vs. C = 6.4+/-2.0%), although glucose transport and oxidation decreased after CsA treatment (p < 0.05). In conclusion, glucose intolerance induced by CsA in Wistar albino rats is due to decreased insulin production and impaired insulin action by a post-binding mechanism.     

The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity

OBJECTIVE: To investigate the metabolic effects of losartan (Cozaar) in patients with essential hypertension. METHODS: Twenty patients with mild hypertension (office blood pressure > 140/95 mmHg and home diastolic blood pressure > 90 mmHg) were examined in a double-blind, placebo-controlled cross-over study of 4 weeks of treatment with 50-100 mg losartan. The effects on glucose metabolism were assessed by euglycaemic glucose clamp examinations [glucose disposal rate (GDR, mg/kg per min)] and oral glucose-tolerance tests (OGTT). RESULTS: Supine blood pressure was reduced from 146 +/- 3/90 +/- 3 mmHg on placebo to 134 +/- 4/83 +/- 3 mmHg on losartan and the difference was maintained during 120 min of insulin infusion and glucose clamping. GDR was 6.2 +/- 0.5 mg/kg per min on placebo and 6.4 +/- 0.5 mg/kg per min on losartan. The glucose and insulin responses (the area under the curve) during OGTT were similar with placebo and losartan (0.86 +/- 0.3 versus 0.88 +/- 0.4 and 341 +/- 60 versus 356 +/- 60, respectively; arbitary units). Serum cholesterol was 5.3 +/- 0.2 mmol/l on placebo and 5.1 +/- 0.2 mmol/l losartan treatment. High-density lipoprotein cholesterol and triglycerides were, respectively, 1.1 +/- 0.1 and 1.5 +/- 0.2 mmol/l with placebo, and 1.1 +/- 0.1 and 1.4 +/- 0.1 mmol/l with losartan treatment. CONCLUSION: In mildly hypertensive patients, selective angiotensin II receptor antagonism with losartan for 4 weeks lowers blood pressure at rest and during 120 min of glucose clamping, and has neutral effects on insulin sensitivity, glucose metabolism and serum lipids.     

Regression of left ventricular hypertrophy in hypertensive patients after 1 year of treatment with rilmenidine: a double-blind, randomized, controlled (versus nifedipine) study

OBJECTIVE: To assess the effect of 1-year treatment with rilmenidine, an oxazoline compound that exerts its antihypertensive effects through binding to imidazoline receptors in the brainstem, on left ventricular hypertrophy (LVH) secondary to essential, mild-to-moderate hypertension [supine diastolic blood pressure (DBP)95-115 mmHg]. METHODS: We performed a double-blind, randomized, controlled (versus slow-release nifedipine) trial. Adjustment of treatment took place every month (M) between inclusion (MO) and an evaluation after 6 months (M6), then during M9 and after 1 year (M12) to achieve supine DBP values < or = 90 mmHg. Patients were dropped from our study if they had DBP> 95mmHg during two consecutive visits or DBP>115 mmHg on one occasion. The daily dosage of rilmenidine was 1 mg, and could be increased to 2 mg/day. The daily dosage of slow-release nifedipine was started from the beginning at the maximum dosage of 40 mg/day, so that there was no true adjustment of treatment despite the allocation of patients to a different unit in the case of DBP> 95 mmHg. The primary criterion was the change in left ventricular mass index (LVMI, g/m2), assessed by echocardiography, between MO and M12 for patients who completed the trial. RESULTS: After a 1-month placebo run-in period, 76 patients were selected and 73 were included (35 treated with rilmenidine and 38 treated with nifedipine). Fifteen patients withdrew from the study and two completed the study with a major deviation from protocol, leaving 56 patients (24 treated with rilmenidine and 32 treated with nifedipine) for a per-protocol analysis. Baseline demographic characteristics and history of arterial hypertension for the rilmenidine and nifedipine groups were similar, for included patients and for those taken into account for the per-protocol analysis. Between MO and M12, DBP in members of the per-protocol population was adequately controlled for those in the rilmenidine group (102.7+/-4.6 versus 88.5+/-7.1 mmHg, respectively) and for those in the nifedipine group (102.7+/-5.1 versus 85.6+/-79 mmHg, respectively). During MO, LVMI of patients in the rilmenidine group (176.9+/-41.3 g/m2) was slightly higher than that of patients in the nifedipine group (172.6+/-35.1 g/m2). During M12, LVMI was observed to have decreased both for patients in the rilmenidine group (to 154.8+/-40.2 g/m2, a decrease of 22.1+/-23.3 g/m2, P< 0.001) and for those in the nifedipine group (to 145.6+/-36.4 g/m2, a decrease of 26.9+/-29.5 g/m2, P< 0.001) but the difference between these two groups was not significant (P= 0.5). CONCLUSION: One-year treatment with a daily dosage of 1 or 2 mg rilmenidine achieves a significant reduction of left ventricular mass, which is not statistically different than that occurring with a daily dosage of 40 mg of slow-release nifedipine.     

Dynamic left intraventricular obstruction after reconstructive mitral valve surgery

To investigate the effect of pioglitazone, a thiazolidinedione oral antidiabetic agent, on the glucose and insulin metabolism in insulin resistance, a perfusion study of the liver and hindquarter was performed in high-fructose-fed rats. Male Wistar albino rats were assigned randomly to one of the following diets for 2 weeks: (1) normal chow (control group), (2) a diet high in fructose (fructose group), or (3) a high-fructose diet plus pioglitazone (pioglitazone intake of approximately 10 mg/kg body weight; pioglitazone group). The elevated levels of plasma insulin, triglyceride, and free fatty acids (FFA) in the fructose group were normalized by pioglitazone administration. In the perfused liver, the glucagon-induced increment in the glucose output of the fructose (57.1+/-9.1 micromol/g liver/20 min) and pioglitazone (44.7+/-10.1 micromol/g liver/20 min) groups was significantly (P < .01) higher than that in the control group (27.6+/-5.7 micromol/g liver/20 min). The level in the pioglitazone group was significantly (P < .05) lower than that in the fructose group. In the presence of 100 or 500 microU/mL insulin, the insulin-mediated decrement in the glucagon-induced glucose output of the fructose group (29.8+/-7.8 or 38.9+/-9.3 micromol/g liver/20 min) was significantly (P < .05) lower than that in the control (45.8+/-14.2 or 54.5+/-8.5 micromol/g liver/20 min) and pioglitazone (44.4+/-9.2 or 56.2+/-10.8 micromol/g liver/20 min) groups, respectively. In the perfused hindquarter, glucose uptake in the fructose group (8.2+/-2.0 micromol/g muscle/30 min) was significantly (P < .05) lower than that in the control (12.1+/-2.3 micromol/g muscle/30 min) and pioglitazone (11.8+/-3.1 micromol/g muscle/30 min) groups. In the presence of 100 or 500 microU/mL insulin, glucose uptake in the fructose group (12.0+/-5.2 or 17.4+/-3.0 micromol/g muscle/30 min) was significantly (P < .05) lower than that in the control (20.2+/-2.4 or 23.0+/-3.1 micromol/g muscle/30 min) and pioglitazone (17.8+/-2.4 or 20.7+/-2.0 micromol/g muscle/30 min) groups, respectively. Insulin uptake by the liver and hindquarter was not significantly different in the control, fructose, and pioglitazone groups. These results indicate that pioglitazone improves the increased glucagon-induced hepatic glucose output and decreases insulin-induced muscular glucose uptake without altering insulin uptake in high-fructose-fed insulin-resistant rats.     

Twenty-four hour time and frequency domain variability of systolic blood pressure and heart rate in an experimental model of arterial hypertension plus obesity]

Modifications of heart rate (HR) and systolic blood pressure (SBP) variabilities (V) have been reported in the human syndrome arterial hypertension plus insulin-resistance. The aim of this study was to characterize the 24 h SBPV and HRV in both time and frequency domains during weight increase in dogs fed ad libitum with a high fat diet. Implantable transmitter units for measurement of blood pressure and heart rate were surgically implanted in five beagle male dogs. BP and HR were continuously recorded using telemetric measurements during 24 hours, before and after 6 and 9 weeks of hypercaloric diet in quiet animals submitted to a 12h light-dark cycle. To study nychtemeral cycle of SBP and HR, two periods were chosen: day (from 6.00 h to 19.00 h) and night (from 23.00 h to 6.00 h). Spontaneous baroreflex efficiency was measured using the sequence method. Spectral variability of HR and SBP was analyzed using a fast Fourier transformation on 512 consecutive values and normalized units of low (LF: 50-150 mHz, reflecting sympathetic activity) and high (HF: respiratory rate +/- 50 mHz, reflecting parasympathetic activity) frequency bands were calculated. The energy of total spectrum (from 0.004 to 1 Hz) was also studied. Body weight (12.4 +/- 0.9 vs 14.9 +/- 0.9 kg, p < 0.05). SBP (132 +/- 1 vs 147 +/- 1 mmHg, p < 0.05) significantly increased after 9 weeks of hypercaloric diet. A nycthemeral HR rhythm was present at baseline (day: 79 +/- 1 vs night: 71 +/- 1 bpm) but not after 9 weeks (day: 91 +/- 4 bpm ; night: 86 +/- 2 bpm). Concomitantly, the efficiency of spontaneous baroreflex decreased at 6 weeks (36 +/- 1 vs 42 +/- 2 mmHg/ms, p < 0.05). A significant decrease in HF energy of HRV was found after 6 but not after 9 weeks. LF energy of SBPV was increased at 6 but not at 9 weeks (table). [table: see text] In conclusion, this study shows that an hyperlipidic and hypercaloric diet induces transient variations in autonomic nervous system activity which could be the physiopathological link between obesity, insulin-resistance and arterial hypertension.     

Comparative study of the effects of ouabain and digoxin on blood pressure of rats

OBJECTIVE: To compare the effect of ouabain on the blood pressure of rats with that of digoxin to find the evidences of the relationship between endogenous ouabain (EO) and development of hypertension. METHODS: Sprague-Dawley rats, which were divided into 3 groups, were infused with ouabain (23 x 75 micrograms.kg-1/day, i.p.), digoxin (36 x 84 micrograms.kg-1/day, i.p.) and normal saline (NS) once a day respectively. Systolic blood pressure and body weight were recorded weekly. Five weeks later, rats of ouabain group were randomly assigned to three infusion subgroups: Oc group, continued with ouabain infusion; Od group, added digoxin (73 x 68 micrograms.kg-1/day, i.p.) and Os group, stopped administration of ouabain. Another week later, direct blood pressure was recorded in aorta. Systolic and diastolic cardiac function, plasma renin activity and aldosterone levels of all the rats were measured. RESULTS: After a latent period of one week, blood pressure of Ouabain group increased significantly [95.4 +/- 11.8 mmHg (1 mmHg = 0.133 kPa) at the beginning of the experiment vs 122.5 +/- 16.9 mmHg at the end of week 6, P < 0.05] with normal plasma renin activity and higher aldosterone (1.28 +/- 0.45 ng/ml vs 0.69 +/- 0.27 ng/ml, P < 0.05). The blood pressure decreased after either withdrawal of ouabain or addition of digoxin (116.3 +/- 14.4 mmHg vs 100 +/- 10.7 mmHg, P < 0.05; 123.9 +/- 13.9 vs 103.3 +/- 10.5 mmHg, P < 0.05, respectively). No difference of blood pressure was found between the digoxin and NS group. CONCLUSIONS: Our results suggested that EO might be one of the causes of the development of hypertension. Aldosterone might play some role in the mechanism of ouabain-induced hypertension. Digoxin can not induce hypertension. There is a great difference between the effect of ouabain and digoxin on the blood pressure. Moreover, digoxin can reverse the hypertension induced by ouabain.     

Autonomic contribution to the blood pressure and heart rate variability changes in early experimental hyperthyroidism

A great deal of uncertainty persists regarding the exact nature of the interaction between autonomic nervous activity and thyroid hormones in the control of heart rate (HR) and blood pressure (BP). Thyrotoxicosis was produced by a daily intraperitoneal (i.p.) injection of L-thyroxine (0.5 mg/kg body wt in 1 ml of 5 mM NaOH for 5 days). Control rats received i.p. daily injections of the thyroxine solvant. Autonomic blockers were administered intravenously: atropine (0.5 mg/kg), atenolol (1 mg/kg), atenolol + atropine or prazosin (1 mg/kg). Eight animals were studied in each group. Thyroxine treatment was sufficient to induce a significant degree of tachycardia (423 +/- 6 vs 353 +/- 4 bpm; p < 0.001, unpaired Student's tests), systolic BP elevation (142 +/- 3 vs 127 +/- 2 mmHg; p < 0.001), pulse pressure increase (51 +/- 2 vs 41 +/- 2 mmHg, p < 0.01), cardiac hypertrophy (1.165 +/- 0.017 vs 1.006 +/- 0.012 g, p < 0.001), weight loss (-21 +/- 2 g; p < 0.001) and hyperthermia (37.8 +/- 0.1 vs 37.0 +/- 0.1 degrees C, p < 0.001). The intrinsic HR observed after double blockade (atenolol + atropine) was markedly increased after treatment with thyroxine (497 +/- 16 vs 373 +/- 10 bpm, p < 0.05). Vagal tone (difference between HR obtained after atenolol and intrinsic HR) was positively linearly related to intrinsic HR (r = 0.84; p < 0.01). Atenolol neither modified HR nor BP variability in rats with hyperthyrodism. The thyrotoxicosis was associated with a reduction of the 0.4 Hz component of BP variability (analyses on 102.4 sec segments, modulus 1.10 +/- 0.07 vs 1.41 +/- 0.06 mmHg; p < 0.01). Prazosin was without effect on this 0.4 Hz component in these animals. These data show a functional diminution of the vascular and cardiac sympathetic tone in experimental hyperthyroidism. Increased intrinsic HR resulting from the direct effect of thyroid hormone on the sinoatrial node is the main determinant of a tachycardia leading to a subsequent rise in cardiac output. The resulting BP elevation could reflexly induce a vagal activation and a sympathetic (vascular and cardiac) inhibition.     

Reflex sympathetic function in cortisol-induced hypertension in humans

Nine healthy male subjects underwent measurement of reflex sympathetic function, pressor responsiveness and baroreflex sensitivity to phenylephrine (PE) and glyceryltrinitrate (GTN) before (C1) and following six days of treatment (E6) with cortisol (F), 200 mg/day. Seven subjects had washout studies (W) performed at least two weeks following the end of treatment. The BP responses to head tilt, isometric exercise and mental arithmetic were unaltered by F, however, there was a significant diminution of the diastolic BP response to cold pressor stimulus (delta DBP: 19 +/- 3 vs 25 +/- 5 vs 27 +/- 5 mmHg; E6 vs C1 vs W, p < 0.05 C1 vs E6 and W). Baroreflex sensitivity to PE was increased (28 +/- 3 vs 19 +/- 2 ms/mmHg, E6 vs C1, p = 0.03). These data demonstrate that increased BP during F treatment is not attributable to increased SNS activity, and suggest that SNS activity may be decreased by F.     

Neonatal de-afferentation of capsaicin-sensitive sensory nerves increases in vivo insulin sensitivity in conscious adult rats

Sensory neuropeptides, released from the peripheral nervous system, might modulate glucose homeostasis by antagonizing insulin action. The effects of de-afferentation of functional small diameter unmyelinated C-fibres (sensory nerves) on in vivo insulin-mediated intracellular glucose metabolism were investigated by using euglycaemic insulin (6 and 18 mU/kg x min) clamps with [3-(3)H]-glucose infusion in 24 adult rats, treated neonatally with either capsaicin (CAP) (50 mg/kg) or vehicle (CON). Following the clamp, skeletal muscle groups, liver and adipose tissue were freeze-clamped. At plasma insulin levels of approximately 90 mU/l, CAP-rats showed a 21% increase in whole body glucose uptake compared with CON (24.4 +/- 1.6 vs 20.1 +/- 0.8 mg/kg min, p < 0.02), which was paralleled by a 20% increase in whole body glycolysis (12.6 +/- 0.8 vs 10.5 +/- 0.5 mg/ kg.min p < 0.05) (concentration of 3H2O in plasma). Whole body skeletal muscle glycogenesis was increased by 80% in CAP-rats (5.7 +/- 0.7 vs 3.1 +/- 0.7 mg/kg x min, p < 0.05) with increased muscle glycogen synthase activity. Whole body (muscle, liver and adipose tissue combined) de novo lipogenesis also was increased in CAP-rats compared with CON (0.69 +/- 0.10 vs 0.44 +/- 0.06 mg/kg x min, p < 0.05) (incorporation of [3-(3)H]-glucose counts into glycogen or fat). Hepatic glucose production was lower in CAP-rats compared with CON (0.6 +/- 0.6 vs 2.1 +/- 0.7 mg/kg x min, p < 0.05). Plasma glucagon, corticosterone, epinephrine and norepinephrine levels were reduced in CAP-rats: 43 +/- 2 compared with 70 +/- 6 pg/ml, 855 +/- 55 compared with 1131 +/- 138 nmol/l, 513 +/- 136 compared with 1048 +/- 164 pmol/l and 928 +/- 142 compared with 1472 +/- 331 pmol/l, respectively, p < 0.05. At plasma insulin levels of approximately 400 mU/l, CAP-rats showed no differences in peripheral and hepatic insulin action compared with CON. We conclude that the removal of endogenous sensory neuropeptides, by de-afferentation of capsaicin-sensitive sensory nerves, increases in vivo insulin sensitivity, but not responsiveness: 1) primarily through an increased sensitivity of skeletal muscle glycogen synthesis to insulin; 2) through a reduction in the levels of counter-regulatory hormones, thereby creating a milieu which favours overall in vivo insulin sensitivity with respect to glucose uptake, glucose production, glycolysis, glycogenesis and lipogenesis.     

Left ventricular repercussion of obesity-induced arterial hypertension in the dog

Obesity and hypertension are frequently associated. The aim of our study was to assess the effects of high fat diet on weight, blood pressure and left ventricule in dogs. We studied 6 male Beagle dogs before and after 7 weeks of hypercaloric hyperlipidic diet. Echocardiography was used to measure left ventricular wall thickness, volumes, ejection fraction and mass. Results are expressed as % of variation of initial values. After 20 weeks, dogs presented abdominal obesity with increased body weight (11.9 +/- 2.3 to 15.2 +/- 2 kg; p < 0.03) associated with an increasing of systolic (196.5 +/- 14.6 to 260.1 +/- 17.5 mmHg; p < 0.03), diastolic (76.6 +/- 9 to 110.6 +/- 10.2; p < 0.004) and mean blood pressure (128.8 +/- 7 to 152.7 +/- 7.6 mmHg; p < 0.004). There were non significant changes concerning diastolic thickness of septum and posterior wall. Left ventricular volumes increased in diastole (41.1 +/- 4.5 to 48.9 +/- 10.3 cm3; p < 0.03) and systole (12.2 +/- 1.7 to 14.9 +/- 3.2 cm3; p < 0.03). So, despite any changes in wall thickness, we observed an increased of ventricular mass (67 +/- 15 to 80 +/- 24.3 g; p < 0.03). Ejection fraction remained unchanged. CONCLUSION: it appears that hight fat diet induces obesity and hypertension in dogs; changes in left ventricule suggest a volodependent hypertension.     

Blood-to-brain glucose transport and cerebral glucose metabolism are not reduced in poorly controlled type 1 diabetes

Clinical and epidemiological studies suggest that thiazide diuretics can prevent bone loss and decrease the incidence of hip fractures. However, the mechanism of the effect of diuretics on bone is not clearly established. Indapamide (IDP), a sulfonamide diuretic related to thiazides, is used to treat hypertension. Sixty spontaneously hypertensive rats (SHRs) were divided into four groups and treated with or without IDP (1.5 mg/kg/day) during 8 weeks in the presence or absence of a high sodium load (8% NaCl supplementation in the diet). Sodium and calcium excretions were increased in the rats receiving the high sodium load (SHR + 8% NaCl) comparatively with control rats (SHR). IDP decreased and increased, respectively, calcium and sodium excretions. Serum parathyroid hormone (PTH) was unchanged in any group. Bone density was measured at the femur, tibia, and vertebrae, and bone morphometry was performed at the metaphysis of the femur to evaluate bone architecture. Rats fed a high sodium diet had an average 5.5% decreased bone density at every site except the femoral diaphysis. The trabecular bone volume was also decreased (SHR + 8% NaCl vs. SHR, 11.99+/-0.78 vs. 17.51+/-1.5%, p < 0.05). An increase in trabecular separation suggested that these changes were due to increased bone resorption. In the SHR + 8% NaCl + IDP group, IDP increased bone density and trabecular bone volume (SHR + 8% NaCl + IDP vs. SHR + 8% NaCl, 16.52+/-1.04 vs. 11.99+/-0.78%, p < 0.05). Trabecular separation and pyridinoline/creatinine excretion (SHR + 8% NaCl + IDP vs. SHR + 8% NaCl, 136.39+/-9.62 vs. 195.18+/-22.34 nmol/mmol, p < 0.05) were also decreased by IDP. These results show that in rats receiving a high sodium diet, IDP can reverse sodium-induced bone loss and increased bone resorption independently of changes in serum PTH.     

A study of laboratory based faecal occult blood testing in Melbourne, Australia. The Faecal Occult Blood Testing Study Group

The effects of chromium (Cr) supplementation on diet-induced insulin resistance produced by feeding a high-fat, low-Cr diet were studied in rats to ascertain the role of Cr in insulin resistance. Wistar male rats were maintained for 16 weeks after weaning on a basal diet containing 40% lard, 30% sucrose, and 25% casein by weight and adequate vitamins and minerals without added Cr (-Cr). Fasting levels of insulin, glucose, and triglycerides and the responses during an intravenous glucose tolerance test (IVGTT) were compared as indices of insulin resistance and the effectiveness of dietary Cr. IVGTTs and blood sampling for data analyses were performed over a 40-minute period after IV glucose injection (1.25 g/kg body weight) in overnight-fasted animals under pentobarbital anesthesia (40 mg/kg body weight). All animals were normoglycemic (-Cr, 109 +/- 3 mg/dL; +Cr, 119 +/- 5), with fasting insulin levels elevated in the -Cr group (65 +/- 10 microU/mL) versus the +Cr group (31 +/- 4 microU/mL). Increases in plasma triglycerides in the -Cr group were not significant. Following glucose injection, the rate of glucose clearance was lower in the -Cr group (1.74 +/- 0.22 v2.39 +/- 0.11%/min), and 40-minute glucose areas in the -Cr group tended to be higher than in the +Cr group. The insulin response to glucose injection was 20% higher in the -Cr group. Forty-minute plasma triglyceride areas were lower in +Cr rats (875 +/- 62 v 1,143 +/- 97 mg/dL.min in -Cr rats). These data demonstrate that the insulin resistance induced by feeding a high-fat, nutrient-stressed diet is improved by Cr.     

Chronic hypertension leads to hyperinsulinemia in Sprague-Dawley rats treated with nitric oxide synthase inhibitor

Insulin resistance and hypertension, as well as dyslipidemia, frequently cooccur. Evidence that nitric oxide (NO) plays a crucial role in the long-term regulation of systolic blood pressure led us to examine whether enhanced vasoconstriction and hypertension induced by NO synthase inhibitor could lead to insulin and lipid disorders. NG-Nitro-L-arginine methyl-ester (L-NAME), an inhibitor of NO synthase, was given for 4 weeks in drinking water (100 mg/kg/day) to 12 Sprague-Dawley rats. Another nine rats received both L-NAME and verapamil (100 mg/kg/day), whereas 12 animals fed rat chow only served as controls. Systolic blood pressure was measured weekly by the indirect tail cuff method. Blood samples were taken at the beginning of the experiment, and after 2 and 4 weeks from all rats. The samples were assayed for insulin, glucose, and triglyceride concentrations. L-NAME treatment resulted in a marked and sustained increase in systolic blood pressure from 130+/-7 to 171+/-3 mm Hg by the second week, which was succeeded by a significant elevation in insulin level at the end of 4 weeks, from 2.3+/-1.8 to 5.4+/-2.0 ng/mL. Triglycerides and glucose were unaffected throughout the experiment. The combination of L-NAME and the NO-independent vasodilator, verapamil, attenuated the hypertension induced by L-NAME and prevented the following rise in insulin level. Data suggest that chronic elimination of NO after chronic inhibition of NO synthase may lead to a state of hyperinsulinemia, possibly as an outcome of insulin resistance.     

Etiological role of cadmium in hypertension in an animal model

Dahl hypertension-resistant (R) and hypertension-sensitive (S) lines of rats were used to determine whether cadmium plays an etiological role in hypertension. In Study I, weanling (3-week-old) R and S rats of both sexes were given a low-salt (0.4% NaCl) diet and were divided into two groups. Rats in the cadmium group were injected with cadmium (2 mg/kg body weight, ip), whereas the controls received identical volumes of saline. Three weeks after the first injection, no elevations of systolic blood pressure were detected. A second dose of cadmium (1 mg/kg) produced hypertension in S females but not in S males or in R rats of either sex. Also, female S cadmium rats manifested significant (p less than 0.01) mild to moderate renal vascular changes. The concentrations of cadmium in hepatic and renal tissues of S cadmium rats were significantly higher (p less than 0.001) than in R rats. In Study II, weanling (3-week-old) female S rats on a high-salt (4% NaCl) diet were given cadmium (2 mg/kg body weight, ip) at week 3 followed by second and third injections of cadmium (1 mg/kg) at weeks 6 and 23. S controls received the same volumes of saline. Cadmium enhanced the rate and the degree of salt-induced hypertension development. Pathological lesions of periarteritis nodosa in the mesenteric arteries and renal vascular lesions occurred to the same extent in the cadmium and control groups. These data indicate that differences in genetic background influence the development of cadmium-induced hypertension in weanling rats, and that cadmium exacerbates the severity of salt-induced hypertension.     

Lack of association between both insulin resistance and plasma insulin levels with blood pressure values in essential hypertension

AIM: To evaluate the role of insulin resistance and hyperinsulinaemia in the genesis of essential arterial hypertension (EAHT). SUBJECTS AND METHODS: We studied 49 patients (age 44 +/- 8 y., body mass index (BMI: 29.5 +/- 3.2 kg.m-2) with mild or moderate EAHT (systolic blood pressure: 156 +/- 13 mmHg, diastolic blood pressure: 100 +/- 6 mmHg). Patients with BMI > 27 kg.m-2 were classed as obese. Arterial pressure was measured with a mercury sphygmomanometer after the patient had been lying down for 15 min. For each patient, the results of a frequently sampled intravenous glucose tolerance test (FSIGT) were used to estimate insulin sensitivity (using the minimal model of glucose metabolism) and to characterize insulin secretion in response to intravenous glucose (area of the insulin curve above basal during the 180 min of the FSIGT test). Correlations were evaluated by means of Spearman's correlation coefficient. RESULTS: Neither fasting insulinaemia, glucose-induced insulin secretion nor insulin sensitivity correlated significantly with arterial pressure, either in the whole sample or in the obese and non-obese subsamples. CONCLUSIONS: These results suggest that neither insulin nor insulin sensitivity are important physiological regulators of arterial pressure, and lend no support to the hypothesis that insulin is related to essential arterial hypertension.     

Short-term effects of a high-sucrose diet on plasma lipid, lipoprotein cholesterol, tissue lipoprotein lipase and hepatic triglyceride lipase in rats

Short-term (2 weeks) effects of a high-sucrose diet on plasma lipids, lipoproteins, tissue lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities were investigated in rats. Three days of sucrose feeding significantly increased plasma TG (42 +/- 3 mg/dl vs. 56 +/- 2 mg/dl, p = 0.032), while TC increased significantly after 10 days of the diet (50 +/- 2 mg/dl vs. 62 +/- 2 mg/dl, p = 0.0001). HDL-C increased significantly after 3 days of sucrose feeding (36.2 +/- 0.9 mg/dl vs. 42.4 +/- 2.7 mg/dl, p = 0.011). Although LDL-C tended to decrease on days 3, 7 and 10, these changes were not significant. The plasma glucose level did not change during the study. Increased LPL activity in adipose tissue and decreased enzyme activities in skeletal and heart muscles were observed. Adipose tissue LPL returned to the baseline value after 14 days of the diet treatment, while LPL in skeletal and heart muscles remained at the decreased level. HTGL and HTGL/total liver lipase activities were significantly increased after 14 days of the diet. The different responses of lipase activities in various tissues may help to regulate serum lipid and lipoprotein levels in sucrose-fed rats.