Roberta Baldoncini

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.

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.

Elevated plasma endothelin-1 levels as an additional risk factor in non-obese essential hypertensive patients with metabolic abnormalities.

Summary Circulating endothelin-1 concentration was evaluated in 93 lean patients with essential hypertension, of whom 16 had impaired glucose tolerance and hyperlipidaemia, 25 had impaired glucose tolerance, 28 had hyperlipidaemia and 24 had no metabolic abnormalities; we also studied 22 control subjects. All groups were age- and sex-matched. Plasma endothelin-1 levels were higher (p < 0.05) in hypertensive patients with impaired glucose tolerance and hyperlipidaemia than in the remaining groups, and were directly correlated with fasting insulin levels (r = 0.506, p = 0.045). Therefore, circulating endothelin-1 concentrations are elevated in hypertensive patients with a high-risk profile due to the presence of metabolic abnormalities, and might favour the development of vascular damage. [Diabetologia (1997) 40: 100–102]

Plasma endothelin-1 levels in patients with systemic sclerosis: influence of pulmonary or systemic arterial hypertension.

OBJECTIVES--To investigate the behaviour of circulating endothelin-1 (ET-1) in patients affected by systemic sclerosis and to elucidate the relationship between systemic and pulmonary plasma peptide and arterial pressure levels. METHODS--Plasma ET-1 concentrations were determined in 48 patients affected by systemic sclerosis (41 women, seven men; mean age 47.2 (SD 5.5) years) with or without systemic or pulmonary hypertension (or both). A group of 18 normal volunteers served as controls (15 women, three men; mean age 45.0 (10.1) years). RESULTS--Plasma ET-1 levels were significantly greater in patients affected by systemic sclerosis (1.65 (0.29) pg/ml) than in controls (0.63 (0.19) pg/ml) (p < 0.0001). Pulmonary artery systolic hypertension alone was present in 14 patients with systemic sclerosis (50.5 (8.49) mm Hg, range 37-67 mm Hg), and systemic hypertension alone (160.7 (5.9)/100.6 (3.2) mm Hg) was present in 11 patients. Both conditions were present in 12 patients, while 11 patients had systemic hypertension. There were no significant differences in plasma ET-1 levels between patients with pulmonary hypertension alone (1.62 (0.21) pg/ml) and those with systemic hypertension alone (1.65 (0.43) pg/ml). In particular, patients with normal pulmonary artery and systemic pressures (n = 11) had plasma ET-1 concentrations identical to those found in patients (n = 12) with both pulmonary and systemic hypertension (1.70 (0.15) v 1.64 (0.35) pg/ml, respectively). No correlations were observed between plasma ET-1 and either pulmonary or systemic pressures. CONCLUSION--Systemic sclerosis is characterised by increased plasma ET-1 levels, but neither pulmonary nor systemic hypertension are accompanied by further increase in plasma peptide levels.

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.

Elevated Albumin Excretion in Nonmodulating Essential Hypertensive Patients

Nonmodulating (NM) essential hypertensives are characterized by abnormal renal and aldosterone responses to angiotensin II. Recently, hyperinsulinemia, hypercholesterolemia, and an increased prevalence of family history of hypertension and myocardial infarction have been shown in NM hypertensives. Since an elevated urinary albumin excretion (UAE) has been indicated as a negative prognostic marker for cardiovascular diseases in essential hypertensives, we evaluated UAE in 50 male patients with mild to moderate essential hypertension (mean age 46.3 +/- 4.4 years), characterized as low renin (LR) (n = 14), modulating (M) (n = 20), and NM patients (n = 16) according to their renin profile and ability to modulate the aldosterone response to a graded infusion of angiotensin II. A group of 14 healthy male subjects (mean age 43.3 +/- 3.9 years) served as control. Resulting data showed that NM had significantly higher UAE (30.7 +/- 10.7 microg/min) than controls (11.9 +/- 2.7 microg/min, p < 0.0001), LR (22.1 +/- 8.4 microg/min, p < 0.05), and M patients (19.7 +/- 6.6 microg/min, p = 0.0001) when all fed a 200-mmol NaCl/day diet. On the contrary, differences in UAE disappeared when all subjects were on a low sodium regimen (10 mmol NaCl/day). Compared to LR and M patients, the NM ones also manifested higher low-density lipoprotein cholesterol levels (p < 0.05). Furthermore, these latter and UAE were positively correlated in NM patients (r = 0.579, p < 0.05) but not in the other subgroups. In conclusion, the current study demonstrates elevated UAE in NM patients, suggesting the NM phenotype is combined to an increased cardiovascular risk.

Hormonal and renal responses to atrial natriuretic peptide infusion in low-renin hypertension

Although atrial natriuretic peptide (ANP) levels are often elevated in low-renin hypertensives, the renal and hormonal effects of ANP infusion have never been evaluated in these patients. To address this topic, 27 lean nondiabetic men affected by uncomplicated essential hypertension were studied. Low-renin patients (n = 9, age 42 +/- 3 years) were defined as those individuals in balance on a low NaCl intake (10 mmol NaCl/day for 1 week) who had a plasma renin activity <0.30 ng angiotensin I/l/s, in both the supine and the upright positions. The remaining hypertensives (n = 18, age 41 +/- 4 years) were classified into the normal-renin group. Six age-matched healthy men (age 40 +/- 2 years) served as controls. After plasma renin activity determinations, both patients and controls were replaced on a normal NaCl intake (120 mmol NaCl/day). After 1 week, either ANP (99-126), at a dose (0.7 pmol/kg/min for 3 h) which is known to induce changes in plasma ANP confined to the range of normality, or its vehicle were infused at 1-week intervals, according to a randomized double-blind crossover design. At time 0, low-renin patients had significantly higher (p < 0.05) levels of plasma ANP (12.4 +/- 2.5 fmol/ml) than normal-renin patients (7.2 +/- 2.4 fmol/ ml) and normotensives (7.4 +/- 3.3 fmol/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.