Simonetta Coassin

Circulating endothelin-1 levels increase during euglycemic hyperinsulinemic clamp in lean NIDDM men.

OBJECTIVE To evaluate whether or not insulin stimulates endothelin (ET)-l secretion in vivo. RESEARCH DESIGN AND METHODS Plasma ET-1 levels were evaluated in 16 lean normotensive men with non-insulin-dependent diabetes mellitus (NIDDM) (mean age 50.3 ±4.1 years) during either a 2-h euglycemic hyperinsulinemic clamp (40 mU insulin · m−2 · min−1) or placebo infusion (50 ml isotonic saline) according to a single-blind randomized crossover protocol. RESULTS Circulating ET-1 levels increased during the euglycemic hyperinsulinemic clamp (from 0.88 ± 0.38 pg/ml at time 0 to 1.66 ± 0.22 pg/ml and 1.89 ± 0.99 pg/ml at 60 and 120 min, respectively [P < 0.05 vs. time 0]) and returned to baseline levels after the discontinuation of insulin infusion (0.71 ± 0.22 pg/ml after a 30-min period of recovery [NS]). Compared with placebo, the euglycemic hyperinsulinemic clamp induced a significant increase in plasma ET-1 levels at 60 min (P < 0.0001) and 120 min (P < 0.0001). Changes in basal insulin levels and corresponding changes in circulating ET-1 levels after a 2-h euglycemic hyperinsulinemic clamp were significantly correlated (r = 0.771, P < 0.0001). A possible unfavorable effect of ET-1 on the tissue sensitivity to insulin-stimulated glucose uptake was suggested by the presence of a negative correlation between total glucose uptake and baseline ET-1 levels (r = –0.498, P < 0.05). CONCLUSIONS Our findings indicate that circulating ET-1 levels significantly increase during euglycemic hyperinsulinemic clamp in men with NIDDM. The negative correlation between total glucose uptake and circulating ET-1 levels suggests that the peptide might exert negative effects on the insulin sensitivity of target tissues. The consequent increase in insulin secretion as well as the insulin-related ET-1 release from endothelial cells could favor the development of diabetes-related vascular lesions.

High plasma endothelin-1 levels in hypertensive patients with low-renin essential hypertension.

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide derived from endothelial cells and may be important in the control of systemic blood pressure (BP) and local blood flow. Immunoreactive ET-1 plasma levels may be normal or elevated in human arterial hypertension, although the exact pathophysiological role of ET-1 remains to be established. The aim of our study was to determine the relationship between the components of the renin-angiotensin-aldosterone system and plasma ET-1 levels in patients with low, normal or high-renin essential hypertension. The study groups included 13 patients with low-renin essential hypertension (average age 43.5 ± 16.2 years), 16 patients with normal-renin essential hypertension (46.5 ± 13.4 years), 11 patients with high-renin essential hypertension (40.7 ± 13.8 years) and 12 healthy subjects (43.1 ± 11.4 years). Our results demonstrated that the mean ET-1 values of all patients with essential hypertension were 10.4 ± 3.4 pg/ml; there was not a statistical correlation between plasma renin activity (PRA) and the ET-1 levels of hypertensives; instead there was a statistically significant correlation between plasma ET-1 and plasma aldosterone (PA) (r = 0.393; P < 0.026). in particular mean plasma et-1 values in patients with low-renin essential hypertension (12.6 ± 2.1 pg/ml) were significantly higher (anova = 0.000, P < 0.05) than those of normotensive subjects (7.7 ± 1.7 pg/ml), patients with normal-renin essential hypertension (8.5 ± 2.8 pg/ml), and patients with high-renin essential hypertension (9.9 ± 3.8 pg/ml), respectively. there was a statistical correlation between pa and et-1 levels in patients with low-renin essential hypertension (r = 0.619, P < 0.024). Our study demonstrated that there was an increase of circulating ET-1 levels in patients with low-renin essential hypertension and ET-1 plasma levels correlated with PA. The results suggest that ET-1 may play an important role in this particular form of human essential hypertension.

Abnormal atrial natriuretic peptide and renal responses to saline infusion in nonmodulating essential hypertensive patients.

BackgroundNonmodulation seems to represent an inheritable trait characterized by abnormal angiotensin-mediated control of aldosterone release and renal blood supply and salt-sensitive hypertension. Recently, we demonstrated that atrial natriuretic peptide (ANP) response to angiotensin II also is altered in nonmodulators. Moreover, an abnormal ANP response to acute volume expansion has been shown by others in hypertensive patients displaying some features of nonmodulators. These data induced us to hypothesize that nonmodulators. These data induced us to hypothesize that nonmodulation could be characterized by an abnormal ANP response to saline load. Methods and ResultsForty-three essential hypertensive men were subdivided into low-renin patients (n = 12), nonmodulators (n = 15), and modulators (n = 16) according to their renin profile and ability to modulate aldosterone and p-aminohippurate clearance responses to a graded angiotensin II infusion (1.0 ng.kg-1·min−1 and 3.0 ng·kg−1.min−1 for 30 minutes each) on both a low- (10 mmol Na+ per day) and a high- (210 mmol Na+ per day) Na+ intake. The intravenous saline load (0.25 mL.kg−1−min−1 for 2 hours) performed on a low-Na+ diet increased plasma ANP levels in low-renin (from 14.30 ± 4.68 to 23.30 ± 7.52 fmol/mL at 120 minutes, P < .05) and modulating patients (from 10.95 ± 3.55 to 18.21 ± 5.42 fmol/mL at 120 minutes, P < .05), whereas it did not change the hormone levels in nonmodulators (from 10.77 ± 3.25 to 13.83 ± 5.70 fmol/mL at 120 minutes, P = NS). When patients switched from a low- to a high-NaCl diet, plasma ANP levels increased significantly in all groups. However, when the saline load was repeated on a high-NaCl intake, ANP levels increased in both low-renin and modulating patients (P < .05), whereas it failed to increase in nonmodulators. ConclusionsNonmodulating hypertensive patients showed a reduced ANP response to saline infusion in the presence of a normal increase of plasma ANP with dietary NaCl load. The impaired ANP response to saline infusion could be due to a different distribution of volume load and contribute to determining the reduced ability to excrete sodium that is commonly described in nonmodulators.

Dynamic Exercise Induces Elevation of Plasma Levels of Endothelin-1 in Patients with Coronary Artery Disease

In this investigation the response of endothelin-1 plasma levels to dynamic exercise in patients with coronary artery disease (CAD) was studied. The study population consisted of 20 patients with CAD, 16 men and 4 women (mean age 53 ±8.6 years). Seven normal volunteers all men (mean age 53.4 ±4.4 years) were studied as a control group. Seven patients had prior myocardial infarction. All patients and controls exercised on a multi stage bicycle ergometer; plasma endothelin-1 levels and hemodynamic indices were measured at rest, at peak exercise, and at two and six minutes after exercise. Of the 20 patients examined, 7 (35%) showed electrocardiographic (ECG) signs of myocardial ischemia during the stress test. The mean plasma endothelin-1 concentration increased significantly from 7.8 ±3.0 to 13.6 ±3.5 pg/mL at exercise peak (P < 0.05) only in patients who did not show ECG signs of myocardial ischemia and returned to baseline values during recovery (six minutes) (9.4 ±2.1 pg/mL). In normal subjects baseline endothelin-1 levels (9.4 ±4.2 pg/mL) were not significantly altered at peak exercise (10.8 ±4.7 pg/mL) and at recovery (11.3 ±3.6 pg/mL). The hemodynamic parameters were not correlated with the plasma endothelin-1 levels before, during, and after exercise in all groups. The present study demonstrated that the plasma levels of endothelin-1 in patients with CAD increased significantly during stress testing.

Adrenomedullin Levels are High in Primary Aldosteronism due to Adenoma and Decline after Surgical Cure

The aim of the study was to evaluate the possible changes in plasma adrenomedullin (AM) levels in patients with primary aldosteronism before and after surgical resection. The study included 13 patients affected by aldosterone-producing adenoma (9 women, 4 men; mean age 36.2+/-14.2 years) and 20 healthy control subjects (7 women, 13 M; mean age 31.8+/-12.4 years). Unilateral adrenalectomy was performed in all patients and adrenal mass consisted of a benign adrenal cortical adenoma. The mean plasma AM concentrations in patients with primary aldosteronism (36.2+/-19.3 pg/ml) were significantly (p < 0.0001) higher than those of normal subjects (13.2+/-6.2 pg/ml). In these patients the plasma AM levels significantly (p < 0.0001) reduced after surgical removal of the tumours (14.9+/-7.6 pg/ml). In all patients with aldosterone-producing adenoma, tumour diameter correlated with the plasma AM concentrations (r=0.631; p < 0.021). In conclusion, the present investigation shows that in primary aldosteronism due to adrenal adenoma plasma AM levels are higher at the moment of diagnosis and decline after successful adrenal operation.

Unilateral adrenal hypersecretion of both aldosterone and cortisol in two first cousins with a syndrome of mineralocorticoid excess but without signs of hypercortisolism

A 38 year old woman and her first cousin, a 41 year old man, presented both with hypertension, hypokalemia, hyperaldosteronism, and low plasma renin activity in our Hospital. In both patients, plasma and urine aldosterone were constantly above the normal range, even on a high NaCl diet (250 mEq/day), while the plasma aldosterone response to postural changes was normal. In the female patient abdominal ultrasonic scan, CT scan, MRI, and adrenal gland phlebography were normal, but blood from the left adrenal vein contained 1002 pg/ml of aldosterone, versus 91 pg/ml in the contralateral one. Interestingly, the secretion of cortisol was also lateralized (plasma cortisol levels being of 28.8 mcg% in the left, 2.3 mcg% in the right adrenal gland), although neither clinical nor laboratory signs of hypercortisolism were present. Spironolactone treatment (100 mg/daily) completely reversed the syndrome of mineralocorticoid excess. After 2 years, patient has normal blood pressure and serum K+ levels.

Renal Sodium Excretory Function during Acute Oxygen Administration

To evaluate the effect of O2 administration and O2 removal on renal Na+ excretion, 12 hypoxemic eucapnic patients affected by chronic obstructive pulmonary disease (COPD) and 9 normal subjects were studied. After 1 h in the supine position, O2 was administered for 3 h by a tight-fitting face-mask. Urine and blood samples for renal Na+ excretion evaluation were taken at times 0, 60 and 180 min. After O2 removal both the blood and the urine samples were taken again for a further 3 h. In normal subjects, urinary Na+ excretion did not vary after both O2 administration and removal. On the contrary, in patients affected by COPD renal Na+ excretion significantly increased during O2 administration (from basal values of 0.08 +/- 0.01 to 0.17 +/- 0.02 mEq/min at 180 min, p < 0.05), and returned to baseline levels (0.13 +/- 0.03 mEq/min) after 3 h from O2 removal. The basal fractional excretion of filtered Na+ was significant lower in hypoxemic patients than in normal subjects (0.72 +/- 0.3% in patients with COPD vs. 0.95 +/- 0.7% in normal subjects, p < 0.05), while, at the end of O2 administration, it became higher in patients with COPD than in controls (1.62 +/- 0.4% in patients with COPD vs. 0.89 +/- 0.5 in control subjects, p < 0.001). In conclusion, our findings showed an oxygen-related increase of both the urinary Na+ excretion and the fractional excretion of filtered sodium in patients affected by COPD.

SERUM CONCENTRATIONS OF OSTEOCALCIN IN PREGNANT WOMEN WITH MULTINODULAR THYROID GOITER UNDERGOING TREATMENT WITH LEVOTHYROXINE

In this study we measured serum osteocalcin (Bone Gla-Protein) to investigate bone metabolism in pregnant women with multinodular thyroid goiter undergoing treatment with levothyroxine (L-T4). Serum concentration of BGP was measured in 18 pregnant women and in 20 non-pregnant women (ages raging from 21-34 years) receiving L-T4 (75-125 micrograms/day). Venous blood samples for RIA determination of serum BGP, plasma thyroid hormone (T3, T4, free T3, free T4) and TSH were collected from the two groups. The samples of the pregnant women group were collected before pregnancy (at the moment the disease was diagnosed without L-T4 therapy) during pregnancy (at the 3rd, 6th and 9th month) and one month after delivery. The normal TSH levels (measured with Irma method) before pregnancy, were significantly reduced during treatment with L-T4 during pregnancy and after delivery (p < 0.005), respectively. Also in the control group TSH levels were reduced during treatment. Serial measurement of serum BGP before pregnancy, (3.4 +/- 1 ng/ml) during pregnancy (3rd: 4.2 +/- 1.5 ng/ml; 6th: 4.2 +/- 1.4 ng/ml; 9th: 2.8 +/- 1.6 ng ml, month respectively) and one month after delivery (3.5 +/- 1.3 ng/ml) did not demonstrate significant variations. Furthermore, in the control group the BGP levels were 3.2 +/- 1.7 ng/ml. There was no correlation between BGP, thyroid hormones and TSH in these groups. These data indicate that the administration of moderate doses of L-T4 in pregnant and in non-pregnant women did not modify the serum BGP levels.

Influence of the Renin Profile on the Blood Pressure Response to Different Doses of Hydrochlorothiazide plus either Quinapril or Captopril

SummaryThe antihypertensive efficacy and safety of quinapril 20mg plus hydrochlorothiazide 6.25mg were compared over 8 weeks with Captopril 50mg plus hydrochlorothiazide 15mg in 52 patients with mild to moderate essential hypertension (27 men and 25 women age 49.7 ±8.4 years). The study also evaluated the relationship between antihypertensive efficacy and plasma renin activity/blood pressure sensitivity to changes in dietary sodium intake. The combination of quinapril or Captopril with hydrochlorothiazide showed similar antihypertensive effects and tolerability. Neither blood pressure salt sensitivity nor renin profile were predictive of blood pressure response to either therapy. These results suggest that the antihypertensive efficacy of an angiotensin converting enzyme inhibitor when administered in fixed ratio with a thiazide diuretic is independent of salt sensitivity in hypertension.