Tomoko Gomi

Improvement of Insulin Sensitivity Contributes to Blood Pressure Reduction After Weight Loss in Hypertensive Subjects With Obesity

To access the role of insulin resistance in obesity hypertension, we examined the change of insulin sensitivity after weight loss in 24 obese hypertensive subjects by the euglycemic hyperinsulinemic glucose clamp method. The results of the 4-week calorie-restricted diet were a weight loss of 10.2% (from 74 +/- 12 to 67 +/- 11 kg, P < .01) and a decrease in mean blood pressure of 13.1% (from 124 +/- 7 to 107 +/- 9 mm Hg, P < .01). A decrease in plasma norepinephrine (from 208 +/- 74 to 142 +/- 52 pg/mL, P < .01) was associated with decreases in plasma renin activity (from 1.06 +/- 0.98 to 0.62 +/- 0.63 ng/mL per hour, P < .01) and serum aldosterone (from 70 +/- 28 to 57 +/- 24 pg/mL, P < .05). Glucose infusion rate increased significantly (42.9%), from 809 +/- to 1155 +/- 251 mumol/m2 per minute. The insulin sensitivity index, which is a measure of the glucose infusion rate divided by plasma insulin, increased significantly (42.6%), from 10.8 +/- 3.5 to 15.4 +/- 4.4 (mumol/m2 per minute)/(microU/mL). Stepwise multiple linear regression analysis showed that changes of plasma norepinephrine, insulin sensitivity index, plasma renin activity, and age were significant predictive factors for the change of mean blood pressure after weight loss. These results indicate a distinct relation between an improvement of insulin sensitivity and a decrease in blood pressure after weight loss in obese hypertensive subjects. The decrease in blood pressure after weight loss is probably related to the suppression of sympathetic nervous activity.

Long-Term Inhibition of Renin-Angiotensin System Sustains Memory Function in Aged Dahl Rats

The Dahl salt-sensitive (DS) rat, a genetic model of salt-induced hypertension in humans, is more likely to develop severe vascular injuries than a rat with spontaneous hypertension. We designed an experiment to scrutinize the effects of renin-angiotensin inhibition on cognitive dysfunction in the aged, normotensive DS with a passive avoidance test. Eighteen months of treatment with a very low dose of the angiotensin-converting enzyme (ACE) inhibitor cilazapril (2.5 microg/mL in drinking water) or the angiotensin II type 1 receptor antagonist E4177 did not reduce blood pressure throughout the experiment, although in the low dose cilazapril group (12.5 microg/mL in drinking water), blood pressure dropped within 6 months after treatment began. The cilazapril treatments dose-dependently improved memory function in the aged, normotensive DS fed a low-salt diet compared with the untreated, control rats. This improvement was associated with significant increases in hippocampal CA1 cells and capillary densities in the CA1 regions compared with those in the untreated DS. Similarly, E4177 slightly improved the memory dysfunction observed in the aged DS. The cells in the hippocampal CA1 region were restored slightly, but the capillary densities were not influenced by the receptor antagonist. On the other hand, the ACE inhibitor and receptor antagonist both attenuated urinary protein excretions with an improvement of glomerular sclerosis. These data suggest that long-term treatment with an ACE inhibitor improves memory dysfunction probably through restoration of capillary and hippocampal cells. The effects are due to the inhibition of the angiotensin II type 1 receptor and probably to the enhancement of the kallikrein-kinin system.

Urinary Prostaglandin D Synthase (β-Trace) Excretion Increases in the Early Stage of Diabetes mellitus

Objective: Circulating levels of lipocalin-type prostaglandin D synthase (L-PGDS)/β-trace reportedly increase in renal failure as well as in cardiovascular injuries. We investigated the alterations of L-PGDS in urine and plasma in the early stage of type-2 diabetic patients. Method: Thirty-six type-2 diabetic patients and 29 normal subjects were studied. Overnight spot urine and plasma samples were obtained in the morning. L-PGDS was measured by ELISA method using anti-L-PGDS antibody. Variables indicating renal function were determined. Results: Plasma L-PGDS concentration was slightly higher in the patients with diabetes mellitus than in the control subjects, whereas the urinary L-PGDS excretion almost doubled in the diabetic patients as compared with that in the control subjects. Plasma L-PGDS was determined by plasma creatinine (Cr) concentration while urinary L-PGDS excretion was correlated solely with urinary protein excretion. There was no relationship between plasma L-PGDS concentration and urinary L-PGDS excretion. The averaged plasma concentration of L-PGDS in the diabetics with a normal Cr level in plasma, corresponding to that in the controls, was determined by the plasma Cr concentration. On the other hand, the urinary L-PGDS excretion was determined by the amount of proteinuria and greater in the diabetics with a normal Cr level in plasma than in the controls even when the patients exhibited urinary protein excretion equal to that in the control subjects. Conclusions: Urinary L-PGDS excretion increased in the early stage of kidney injury in patients with type-2 diabetes mellitus. The urinary excretion was correlated independently with urinary protein excretion even when there was no difference in urinary protein or albumin excretions, thereby suggesting that urinary L-PGDS excretion is possibly a more sensitive indicator of renal injuries than proteinuria. Urinary L-PGDS may thus predict the progression of renal injuries in diabetic patients.

Mechanistic analysis of renal protection by angiotensin converting enzyme inhibitor in Dahl salt-sensitive rats

Objective To investigate whether and how renin-angiotensin inhibition attenuates renal injury seen in salt-induced hypertension in Dahl salt-sensitive (Dahl-S) rats. Methods Dahl-S rats fed a high-salt (4% sodium chloride) diet for 6 weeks were treated with the angiotensin converting enzyme (ACE) inhibitor alacepril or the angiotensin receptor antagonist losartan for 4 weeks. Functional and morphological alterations in the kidney were investigated. Results Alacepril decreased systolic blood pressure (SBP). This SBP reduction was associated with the attenuation of cardiac and aortic wall hypertrophy and that of proteinuria and urinary N-acetyl-β-D-glucosaminidase excretion. Kidney injuries, e.g. glomerular, arterial and tubular damage, were improved with alacepril treatment. Losartan decreased SBP to the same extent as alacepril, but neither renal function nor morphological structure was improved as was the case with alacepril. The response of the renal eicosanoid system to alacepril was inadequate, but cyclic GMP excretion, an indicator of nitric oxide formation, was significantly enhanced and lipid peroxidation in the kidney was decreased. Conclusions The beneficial effects of ACE inhibition on the renal injury in Dahl-S rats outrange those induced by the receptor antagonism. This might be due to multiple factors including an increased vasodepressor eicosanoid system, enhanced nitric oxide formation and possible inhibition of oxygen radical generation in the injured renal tissues.

Subpressor dose of angiotensin II increases susceptibility to the haemodynamic injury of blood pressure in Dahl salt-sensitive rats

Objective To investigate the effects of subpressor doses of angiotensin II (Ang II) on the progression of renal injuries in Dahl salt-sensitive (Dahl-S) rats with hypertension. Methods Rats were fed a high-salt (4% NaCI) diet and given an Ang II infusion (10 or 50 ng/kg per min, subcutaneously) for 4 weeks. Results The plasma Ang II concentration achieved in the high-dose Ang II infusion was lower than that in low-salt (0.3% NaCI) normotensive rats. The Ang II infusion did not affect systolic blood pressure, cardiac hypertrophy or weight of thoracic aorta. However, the high-dose Ang II infusion increased proteinuria by 58%, enhanced the urinary N-acetyl-β-D-glucosaminase index by 77% and reduced the glomerular filtration rate by 37%. The impaired renal function was associated with a progression of glomerulosclerotic lesions. Neither tubular nor arterial lesions were exacerbated. The infusion did not influence prostacyclin production or urinary cyclic GMP excretion. Conclusion A subpressor dose of Ang II infusion impairs renal function with progression of glomerulosclerosis, and these alterations may be due to increased susceptibility of the glomerulus in Dahl-S rats to Ang II-induced injuries. Such a mechanism might underlie a predisposition to hypertension-induced organ damage seen in Dahl-S rats with salt-induced hypertension.

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 micromol/m2/ min; P < .01), and ISI by 20.5% (from 16.6+/-2.1 to 13.2+/-1.9 micromol/m2/min/microU/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.

Captopril, an Angiotensin I-Converting Enzyme Inhibitor, Decreases Proteinuria in Hypertensive Patients with Renal Diseases

A crossover study was planned in order to compare the effects of captopril and slow channel calcium entry blocker (Ca antagonist) on urinary protein excretion in 7 hypertensive patients with renal diseases, including 4 with IgA nephropathy, 2 with lupus nephritis and 1 with benign nephrosclerosis. Captopril decreased urinary protein excretion by 52% without any change in creatinine clearance, while Ca antagonist was having a slight effect on proteinuria even though the drug showed an equivalent antihypertensive effect as captopril. These results suggest that the attenuation of proteinuria induced by captopril may be related to an inhibition of angiotensin II formation and/or a direct action of this drug on protein permeability of glomerular basement membrane.

Morning Rise of Blood Pressure Assessed by Home Blood Pressure Monitoring Is Associated with Left Ventricular Hypertrophy in Hypertensive Patients Receiving Long-Term Antihypertensive Medication

To assess the influence of morning rise of systolic blood pressure (SBP) as assessed by home blood pressure monitoring on the left ventricular mass index (LVMI) in relation to the blood pressure control status, we evaluated M-mode cardiac echocardiography in 626 hypertensive subjects (412 men and 214 women; mean age, 61.3±10.1 years) who were receiving antihypertensive medication. The subjects were requested to measure their blood pressure at home in the morning and evening over a 3-month period. They were distributed into the following four groups by the average (ME Ave) and the difference (ME Dif) of the morning and evening SBP. The well-controlled hypertensives with a morning rise of SBP (ME Ave<135 mmHg and ME Dif ≥10 mmHg; n=45; 7.2%) had a greater LVMI (122.9±22.7 vs. 92.7±15.6 g/m2, p<0.001) than the well-controlled hypertensives without a morning rise of SBP (ME Ave<135 mmHg and ME Dif<10 mmHg; n=367; 58.6%). The uncontrolled hypertensives with a morning rise of SBP (ME Ave≥135 mmHg and ME Dif≥10 mmHg; n=91; 14.5%) also had a greater LVMI (136.8±21.9 vs. 100.2±17.5 g/m2, p<0.001) than the uncontrolled hypertensives without a morning rise of SBP (ME Ave≥135 mmHg and ME Dif<10 mmHg; n=123; 19.6%). A stepwise multivariate regression analysis revealed that the ME Dif was the most important factor related to the LVMI (r2=35.1% for all subjects, p<0001; r2=39.7% for men, p<0.001; and r2=18.7% for women, p<0.001). These results suggest that morning rise of blood pressure is an important factor influencing the development of left ventricular hypertrophy in hypertensive patients on antihypertensive medication.

Blood Sugar Control Reverses the Increase in Urinary Excretion of Prostaglandin D Synthase in Diabetic Patients

Background/Aims: We investigated basal levels of serum and urinary lipocalin-type prostaglandin D synthase/β-trace (L-PGDS) in type-2 diabetic patients and explored whether glycemic control affects L-PGDS status in another 55 diabetic inpatients with normoalbuminuria. Methods: Fifty-five type-2 diabetic outpatients (HbA1c, 9.14 ± 0.20%; creatinine (Cr), 85.1 ± 2.4 µmol/l), and 55 age-matched healthy control subjects were recruited. Serum and urinary levels of L-PGDS were determined with respect to the stage of diabetic nephropathy. The L-PGDS was localized by immunohistochemistry. Results: The urinary L-PGDS index increased in diabetic patients, compared with the controls (234.8 ± 27.4 vs. 73.8 ± 7.8 µg/mmol Cr, p < 0.001). Even in normoalbuminuric patients as well as in microalbuminuric patients, urinary L-PGDS indexes were higher than the controls (166.0 ± 21.1, p < 0.0001 and 338.6 ± 62.5 µg/mmol Cr, p < 0.0001, respectively), although the serum L-PGDS level was equal to that in the control subjects. Multiple regression analysis revealed that the urinary L-PGDS index was predicted solely by glucose levels and type-IV collagen index, whereas the serum L-PGDS was determined mainly by age and serum Cr. Glycemic control reduced the urinary L-PGDS index towards the normal range in diabetic patients with normoalbuminuria (172.3 ± 6.6 vs. 118.1 ± 2.6 (SE) µg/mmol Cr, p < 0.0001). Immunohistochemistry showed that L-PGDS was uniquely present in the renal tubules in diabetes while in nondiabetics, L-PGDS occurred solely in the peritubular interstitium, not in the tubular cells. Conclusion: Inadequate glycemic control is responsible for urinary L-PGDS excretion in the diabetic patients. Urinary L-PGDS is useful to predict subclinical renal injury associated with type-2 diabetes.

Add-on effect of bedtime dosing of the alpha(1)-adrenergic receptor antagonist doxazosin on morning hypertension and left ventricular hypertrophy in patients undergoing long-term amlodipine monotherapy.

High morning blood pressure is related to target organ damage and future cardiovascular events. Chronobiologic therapies focusing on the early morning period may be an important strategy for antihypertensive therapy. The aim of this study was to clarify the add-on effects of bedtime dosing of the α1-adrenergic receptor antagonist doxazosin on morning blood pressure in patients with essential hypertension who were under long-acting calcium channel blocker amlodipine monotherapy. The add-on effects of doxazosin at the maximum dose of 6 mg at bedtime on home blood pressure and left ventricular geometry for 1 year were investigated in 49 subjects (37 men and 12 women, aged 57.5±9.1 years) with morning hypertension who had been treated with amlodipine alone for more than 1 year. Doxazosin induced a significant decrease in morning blood pressure (145.6±5.6/91.5±5.4 to 132.4±3.7/83.6±5.6 mmHg, p≤0.001/<0.001) without a change of evening blood pressure (128.9±5.1/79.8±5.1 to 127.7±6.0/78.8±6.2 mmHg, p=0.056/0.051). Left ventricular mass index (LVMI; 124.8±19.8 to 95.6±15.7 g/m2, p<0.001), relative wall thickness (0.457±0.061 to 0.405±0.047, p<0.001) and homeostasis model assessment of the insulin resistance index (HOMA-IR; 2.62±1.43 to 1.33±0.75, p<0.001) were decreased after doxazosin therapy. A stepwise multivariate regression analysis revealed that the changes in morning systolic blood pressure (adjusted r2=34.9%, p<0.001) and HOMA-IR (adjusted r2=4.5%, p=0.046) were significant contributory factors to the change in LVMI after doxazosin therapy. These results suggest that bedtime dosing of doxazosin is useful for the control of morning blood pressure and regression of left ventricular hypertrophy.