Clinical presentation and management of patients with primary hyperparathyroidism in Italy.

PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 ± 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13  years), the remaining 38 (6.3%, age 41 ± 17  years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.

The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

OBJECTIVE: To evaluate the basal/total ratio of daily insulin dose (b/T) in outpatients with diabetes type 1 (DM1) and type 2 (DM2) on basal-bolus regimen, by investigating whether there is a relationship with HbA1c and episodes of hypoglycemia. METHODS: Multicentric, observational, cross-sectional study in Italy. Adult DM1 (n = 476) and DM2 (n = 541) outpatients, with eGFR >30 mL/min/1.73 m2, on a basal-bolus regimen for at least six months, were recruited from 31 Italian Diabetes services between March and September 2016. Clinicaltrials.govID: NCT03489031. RESULTS: Total daily insulin dose was significantly higher in DM2 patients (52.3 ± 22.5 vs. 46 ± 20.9 U/day), but this difference disappeared when insulin doses were normalized for body weight. The b/T ratio was lower than 0.50 in both groups: 0.46 ± 0.14 in DM1 and 0.43 ± 0.15 in DM2 patients (p = 0.0011). The b/T was significantly higher in the patients taking metformin in both groups, and significantly different according to the type of basal insulin (Degludec, 0.48 in DM1 and 0.44 in DM2; Glargine, 0.44 in DM1 and 0.43 in DM2; Detemir, 0.45 in DM1 and 0.39 in DM2). The b/T ratio was not correlated in either group to HbA1c or incidence of hypoglycemia (<40 mg/dL, or requiring caregiver intervention, in the last three months). In the multivariate analysis, metformin use and age were independent predictors of the b/T ratio in both DM1 and DM2 patients, while the type of basal insulin was an independent predictor only in DM1. CONCLUSION: The b/T ratio was independent of glycemic control and incidence of hypoglycemia.

Correction to: The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

[This corrects the article DOI: 10.1007/s40200-018-0358-2.].

Circulating BRAFV600E in the diagnosis and follow-up of differentiated papillary thyroid carcinoma.

CONTEXT: Cell-free nucleic acids circulating in plasma are considered a promising noninvasive tool for cancer monitoring. BRAF(V600E) mutation in cell-free DNA (cfDNA) could represent an appropriate marker for papillary thyroid carcinoma (PTC). OBJECTIVE: Our aim is to investigate the role of BRAF(V600E)-mutated allele in cfDNA as a marker for the diagnosis and follow-up of PTC. STUDY DESIGN: BRAF(V600E) allele was detected and quantified by an allele-specific real-time quantitative PCR assay in plasma from 103 patients affected by nodular goiter. As control populations, we enrolled 49 healthy subjects and 16 patients with non-nodular thyroid diseases. RESULTS: The percentage of circulating BRAF(V600E) was significantly different between patients and controls and throughout different cytological categories of ultrasound-assisted fine-needle aspiration. Patients with a histopathological diagnosis of PTC showed a higher percentage of circulating BRAF(V600E) (P = .035) compared to those with benign histology. In 19 patients, a second blood draw, taken 3-6 months after surgery, showed a lower percentage of BRAF(V600E) in cfDNA than the presurgical sample (P < .001). The diagnostic performance of circulating BRAF(V600E) was assessed by receiver operating characteristic curve analysis resulting in an area under the curve of 0.797. A cutoff value was chosen corresponding to maximum specificity (65%) and sensitivity (80%). On this basis, we evaluated the predictive value of BRAF(V600E) in Thy 3 patients with a resulting positive predictive value of 33% and a negative predictive value of 80%. CONCLUSIONS: The results of the present study provide encouraging data supporting the possibility to take advantage of circulating BRAF(V600E) in the management of PTC.

A simple ultrasound score for the identification of candidates to fine needle aspiration of thyroid nodules.

BACKGROUND: Cytological examination of fine needle aspirates (FNA) is the standard procedure for discriminating potentially malignant thyroid nodules to be referred to surgery. In a fraction of cases, ultrasound (US) examination could provide information theoretically sufficient to avoid FNA, when typical US features suggesting malignancies are lacking. AIM: The aim of this study was to construct a simple US score predicting malignant nodules so as to reduce the number of unnecessary FNA. SUBJECTS AND METHODS: In a series of 1632 consecutive patients undergoing US-guided FNA (1812 nodules), echostructure, echogenicity, margins, halo, microcalcification, and vascularization were assessed. RESULTS: At multivariate analysis, the following parameters showed a strong predictive value for positive cytology (Thy 4 and Thy 5, suspicious and diagnostic for malignancy, respectively, according to the Thyroid British Association): solid echostructure, irregular margins and hypoechogenicity [adjusted odd ratio (OR) 5.13 (1.58-16.66), 3.03 (1.70-5.39), 2.05 (1.17-3.57), respectively]. A 10-point Thyroid Risk Ultrasound Score (TRUS) was constructed on the basis of the adjusted OR. A TRUS≥6 identified malignant nodules with sensitivity and specificity of 73% and 65%, respectively. Among the patients with follicular lesions (Thy 3) and final diagnosis of carcinoma, about 65% had a TRUS≥6.0. CONCLUSIONS: The sensitivity of TRUS, although higher than that of other scores, could still be insufficient for the identification of patients who could avoid FNA in routine clinical practice, whereas its predictive value for Thy 3 lesions deserves further investigations.

Cardiovascular effects of parathyroid hormone: a study in healthy subjects and normotensive patients with mild primary hyperparathyroidism.

The aim of the study was to evaluate: 1) the cardiovascular function and the autonomic drive to the heart in patients affected by primary hyperparathyroidism (pHPT) with no evidence of renal and cardiovascular complications; 2) the cardiovascular effects of acute administration of PTH in normal subjects. In 14 patients affected by mild asymptomatic pHPT echocardiographic assessment of cardiovascular function and of the mechanic properties of the brachial and carotid artery, heart rate variability and the dispersion of QT interval were performed before and 6 months after successful surgery. Twenty age- and sex-matched healthy subjects were included in the study. Five healthy volunteers underwent a single blind, placebo-controlled, random order, cross-over study with infusion of PTH (hPTH 1-34, 200 U in saline over 5 min) or placebo. Echocardiographic assessment of cardiovascular function, heart rate variability, and QT interval were performed between 20 and 25 min after the start of the infusion and repeated after 15 min of tilting at 60 degrees. In pHPT patients the echocardiographic parameters were normal; left ventricular isovolumetric relaxation time was always in the normal range, but significantly shorter than in control subjects, suggesting an increased sympathetic stimulation. Arterial diameters and thickness, blood pressure, and QT interval were not significantly different with respect to normal subjects and were unchanged 6 months after surgery. pHPT patients lacked the circadian rhythm of the low frequency to high frequency ratio, suggesting an increased sympathetic drive to the heart at nighttime. In normal subjects there were no significant differences in basal echocardiographic measurements during PTH infusion with respect to placebo and in the hemodynamic response to tilt. These results suggest that cardiovascular function is substantially normal in normotensive pHPT patients with mild hypercalcemia. A modulation of the adrenergic control of circulation seems to be associated with hypercalcemia and/or chronic PTH excess, but its biological relevance needs further investigations.

Parathyroid glands: combination of (99m)Tc MIBI scintigraphy and US for demonstration of parathyroid glands and nodules.

PURPOSE: To determine the appropriate choice of imaging techniques for localization of nodular lesions of parathyroid glands. MATERIALS AND METHODS: First, computed tomographic (CT), magnetic resonance (MR), ultrasonographic (US), and technetium 99m methoxyisobutyl-isonitrile (MIBI) scintigraphic images in 49 patients with primary hyperparathyroidism were retrospectively evaluated. A single-blind, prospective study that included 16 patients with primary hyperparathyroidism was then conducted. MR, US, scintigraphic, and color Doppler US images of the neck were obtained and analyzed. RESULTS: In the retrospective study, CT, MR imaging, and US had low sensitivity (13%, 17%, and 27%, respectively) and specificity (39%, 65%, and 65%, respectively). Scintigraphy had 57% sensitivity and 85% specificity. In the prospective study, the use of latest-generation MR and US equipment and the participation of experienced operators led to improved sensitivity and specificity for these techniques. The combination of US and scintigraphy resulted in improved sensitivity (96%), specificity (83%), and positive and negative predictive values (88% and 94%, respectively), relative to the results obtained with either method alone. Doppler US was of little help in the setting of small glands. CONCLUSIONS: The combination of (99m)Tc MIBI scintigraphy and US performed by well-trained operators with up-to-date instruments appeared to be the best diagnostic tool for the preoperative diagnosis of parathyroid disease.

Different effects of atrial and C-type natriuretic peptide on the urinary excretion of endothelin-1 in man.

1. Following the observation that brain natriuretic peptide enhances the urinary excretion rate of endothelin-1, the relationship between natriuretic peptides and urinary endothelin-1 was further investigated. Six healthy volunteers received, on three different occasions, increasing doses of atrial or C-type natriuretic peptide (0, 2 and 4 pmol.min-1.kg-1 for 1 h each), or placebo.2. Atrial natriuretic peptide caused significant increases in the urinary excretion of cGMP, sodium and endothelin-1, without affecting plasma endothelin-1, renal plasma flow, glomerular filtration rate and urine flow rate. C-type natriuretic peptide did not modify any of these parameters. During atrial natriuretic peptide infusion, urinary endothelin-1 directly correlated with plasma atrial natriuretic peptide, urinary cGMP and sodium excretion.3. These results indicate that enhancement of the urinary excretion of endothelin-1 by natriuretic peptides is dose-dependent and somewhat related to their ability to bind to natriuretic peptide receptors A, activate guanylate cyclase and induce a natriuretic response.

Urinary endothelin-1 excretion is enhanced by low-dose infusion of brain natriuretic peptide in normal humans.

To evaluate the functional relationship between cardiac natriuretic peptides and endothelin-1 within the human kidney, we studied the effects exerted by infusion of brain natriuretic peptide on urinary endothelin-1 excretion. We studied twice in a single-blind manner five normal volunteers who received a constant infusion of 5% dextrose (250 mL/h) or human brain natriuretic peptide-32 at a dose of 4 pmol/kg per minute. Blood samples were drawn at intervals for measurement of hematocrit and concentrations of creatinine, electrolytes, brain natriuretic peptide, and endothelin-1. Urine was collected an intervals for measurement of flow rate and concentrations of creatinine, sodium, cGMP, and endothelin-1. Blood pressure and heart rate were measured every 15 minutes. Placebo administration did not change blood pressure, heart rate, or any of the other parameters measured in plasma and urine. As expected, brain natriuretic peptide infusion caused significant increases in its own plasma levels (basal versus peak levels [mean +/- SD], 1.45 +/- 0.20 versus 50.5 +/- 6.0 pmol/L, P < .01), in urinary cGMP (0.75 +/- 0.16 versus 1.92 +/- 0.81 fmol/min, P < .05), and in urinary sodium excretion (140.0 +/- 38.7 versus 624.2 +/- 181.6 mumol/min, P < .01). In addition, it caused an increase in urinary endothelin-1 excretion (4.32 +/- 2.11 versus 19.67 +/- 9.52 fmol/min, P < .05), without modifying plasma endothelin-1, blood pressure, heart rate, creatinine clearance, and urinary flow rate. Our data indicate that brain natriuretic peptide, at plasma levels comparable to those observed in patients with heart failure, causes a significant increase in urinary but not plasma endothelin-1, thus demonstrating a functional link between cardiac natriuretic peptides and renal release of endothelin-1.

Systemic hemodynamics and renal function during brain natriuretic peptide infusion in patients with essential hypertension.

We assessed the cardiovascular and renal effects of human brain natriuretic peptide (BNP) infused at a dose inducing an increase in plasma BNP to pathophysiologic levels, in eight hypertensive patients in a randomized, placebo-controlled, cross-over study. Left ventricular performance, cardiac output (echocardiography), heart rate, arterial pressure, glomerular filtration rate (GFR; creatinine clearance), sodium excretion, intrarenal sodium handling (lithium clearance method), and urine flow rate were measured in the infusion and postinfusion periods (1 h each), together with plasma BNP and the urinary excretion rate of cGMP. Plasma BNP levels increased from 2.90 +/- 0.74 to 36.43 +/- 5.51 pmol/L (P < .01) at the end of the infusion and were still elevated at the end of the postinfusion period (7.03 +/- 1.41 pmol/L, P < .05). The urinary excretion of cGMP was also significantly higher during BNP infusion. Left ventricular performance, cardiac output, arterial pressure, and peripheral vascular resistance were not affected by BNP. Peptide infusion induced a significant increase in GFR (placebo, 115 +/- 24; BNP, 147 +/- 19 mL/min), sodium excretion (placebo, 129 +/- 40; BNP, 243 +/- 60 mumol/min), and urine flow rate. All these effects were observed also in the postinfusion period. The natriuretic effect of BNP was attributable to both an increase in filtered sodium load and a reduction of distal sodium reabsorption. These results suggest that BNP may contribute to maintain renal function and sodium excretion in patients with essential hypertension.

Natriuretic hormone receptors and actions on bone endothelial cells.

[125I]Atrial natriuretic peptide (ANP) was used to identify ANP receptors on a clonal line of bovine bone endothelial (BBE) cells. Specific binding of [125I]ANP was saturable and of high affinity. Computer analysis of the equilibrium binding data indicated that the Scatchard plots are best fit by a straight line (Kd = 69.3 +/- 20.9 pM; binding capacity = 37.9 fmol/10(6) cells). The order of potency for competing with [125I]ANP binding was human ANP (hANP) > rat atriopeptin-1 (rAP-1) > porcine brain natriuretic peptide (pBNP) > porcine C-type natriuretic peptide. Affinity cross-linking studies indicated the presence of two major 130- and 70-kilodalton bands that specifically bound to hANP, rAP-1, pBNP, and porcine C-type natriuretic peptide. The binding of natriuretic peptides to BBE cells resulted in an increase in cGMP production and a significant decrease in Na+/K+/Cl- cotransport, without effects on cAMP intracellular accumulation. hANP, rAP-1, and pBNP at 100-nM concentrations, significantly inhibited PTH-induced cAMP production. Treatment with natriuretic hormones was also associated with an increase in 6-keto-prostaglandin F1 alpha levels in the culture medium of BBE cells and a higher cell growth rate. These studies demonstrate that bone endothelial cells bear receptors for natriuretic hormones associated with changes in PTH-induced cAMP production, prostaglandin production, and cell proliferation.

Thromboxane-receptor blockade increases water diuresis in cirrhotic patients with ascites.

This study was undertaken to investigate the role of increased renal thromboxane (TX) A2 production in modulating renal hemodynamics and sodium and water retention in cirrhotic patients with ascites. In a randomized, double-blind, placebo-controlled, crossover trial, 15 nonazotemic cirrhotic patients with ascites and elevated urinary TXB2 excretion received the thromboxane-receptor antagonist ONO-3708 (3 micrograms.kg-1.min-1) in a 4-hour continuous infusion. Administration of ONO-3708 significantly blocked TXA2 receptors; bleeding time showed a twofold increase (432 +/- 65 vs. 131 +/- 17 seconds; P less than 0.005), and platelet aggregation to U-46619 (an agonist of TXA2 receptors) was abolished in all patients studied. The drug induced a significant increase in free water clearance (3.06 +/- 0.70 vs. 1.72 +/- 0.57 mL/min; P less than 0.001) and diuresis (4.74 +/- 0.79 vs. 3.94 +/- 0.66 mL/min; P less than 0.05) compared with placebo, as well as a significant (14%) increase in renal plasma flow. The increases in both free water clearance and diuresis induced by ONO-3708 were directly related to basal urinary TXB2 excretion. These results suggest a role for renal TXA2 as a modulator of water handling in cirrhotic patients with ascites.

Plasma levels of brain natriuretic peptide in patients with cirrhosis.

Plasma levels of brain natriuretic peptide, a recently identified cardiac hormone with natriuretic activity, were measured in 11 healthy subjects, 13 cirrhotic patients without ascites, 18 nonazotemic cirrhotic patients with ascites and 6 patients with cirrhosis, ascites and functional kidney failure. Plasma levels of brain natriuretic peptide were similar in healthy subjects and cirrhotic patients without ascites (5.56 +/- 0.65 and 7.66 +/- 0.68 fmol/ml, respectively). In contrast, cirrhotic patients with ascites, with and without functional kidney failure, had significantly higher plasma concentrations of brain natriuretic peptide (19.56 +/- 1.37 and 16.00 +/- 1.91 fmol/ml, respectively) than did healthy subjects and patients without ascites (p less than 0.01); no significant difference was found between the two groups of cirrhotic patients with ascites with respect to this parameter. In the whole group of cirrhotic patients included in the study, brain natriuretic peptide level was directly correlated with the degree of impairment of liver and kidney function, plasma renin activity and plasma levels of aldosterone and atrial natriuretic peptide. The results of this study indicate that brain natriuretic peptide is increased in cirrhotic patients with ascites and suggest that sodium retention in cirrhosis is not due to deficiency of this novel cardiac hormone.

Natriuretic peptide receptors regulate endothelin synthesis and release from parathyroid cells.

Cloned rat parathyroid cells (PTr cell line) that produce parathyroid hormone-related peptide plus endothelin 1 and primary cultures of human parathyroid cells were tested for growth and differentiation responses to atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). High- and low-affinity binding sites for ANP were found on PTr cells; BNP appeared to bind to the same receptors with similar affinities. Either ANP or BNP stimulated production of cGMP and caused a 30% decrease in Na(+)-K(+)-Cl- cotransport. Each peptide increased synthesis and secretion of endothelin 1 by PTr cells in a dose-dependent fashion, but cell growth was not affected. Human parathyroid cells (normal and pathological) also responded to ANP or BNP with an increase in cGMP production. The finding of receptors for natriuretic hormones on parathyroid cells with consequent effects on release of endothelin 1 might be of relevance in understanding the clinical association between hyperparathyroidism and hypertension.

[The effects of the acute administration of atrial natriuretic peptide on the mechanisms regulating diuresis and natriuresis in the essential hypertension patient]. / Effetti della somministrazione acuta di peptide atriale natriuretico su alcuni meccanismi di regolazione della diuresi e della natriuresi nell'iperteso essenziale.

The authors investigated the role of atrial natriuretic peptide (alpha-hANP 99-126) in essential hypertension by evaluating some hemodynamic and renal effects of acute peptide infusion (1 micrograms/kg for 1 min + 50 ng/kg for the following 20 min) in fourteen subjects: eight mild to moderate, untreated, essential hypertensives (EH) and six normotensive (N) controls, during 2 hour-clearance periods, the 1st after ANP infusion, the 2nd during placebo (PL) administration. The double-blind study was carried out after the patients had rested and fasted overnight. It showed no significant changes in heart rate (HR); instead, compared with placebo, mean blood pressure (MBP) decreased significantly in both groups, beginning from the 3rd min after ANP infusion was begun (N: PL = 87.04 +/- 1.7 mmHg, ANP = 80.9 +/- 3.7 mmHg, p less than 0.0001; EH: PL = 102.6 +/- 3.2 mmHg, ANP = 97.7 +/- 5.9 mmHg, p less than 0.01). Among the urinary parameters we considered, cyclic GMP (cGMP) increased after ANP infusion in all subjects (N: PL = 129.1 +/- 56.3 pmol/mL, ANP = 199.2 +/- 85.4 pmol/mL; EH: PL = 106.55 +/- 56.2 pmol/mL, ANP = 220.03 +/- 92.7 pmol/mL, p less than 0.05); diuresis showed a prompt and significant increase in EH (N: PL = 837 +/- 368 mL, ANP = 1066 +/- 340 mL; EH: PL = 713 +/- 286 mL, ANP = 1043 +/- 280 mL, p less than 0.005), and so did natriuresis (N: PL = 23 +/- 14.3 mEq/L, ANP = 33 +/- 14.6 mEq/L; EH: PL = 25.6 +/- 8.9 mEq/L, ANP = 41.9 +/- 13.8 mEq/L, p less than 0.01); urinary potassium excretion was significantly reduced in EH (N: PL = 18.7 +/- 12.9 mEq/L, ANP = 14.2 +/- 6.9 mEq/L; EH: PL = 16.5 +/- 7.9 mEq/L, ANP = 10.7 +/- 4.8 mEq/L, p less than 0.005), while no changes were noted in glomerular filtration rate (GFR), estimated as creatinine clearance, urinary magnesium, albumin and aldosterone excretion. To investigate other potential mechanisms involved in renal effects of ANP, the urinary excretion of both prostaglandins 6-cheto PGF1-alpha and thromboxane B2 (TXB2), and dopamine were studied. The results showed only a significant decrease of dopamine urinary excretion in EH after ANP administration (N: PL = 50.4 +/- 28.7 micrograms/L, ANP = 45.0 +/- 29.7 micrograms/L; EH: PL = 47.3 +/- 21.5 micrograms/L, ANP = 27.1 +/- 12.7 micrograms/mL, p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of the effects of torasemide and furosemide in nonazotemic cirrhotic patients with ascites: a randomized, double-blind study.

In a randomized double-blind trial we compared the effects of torasemide, a new loop diuretic, and furosemide in nonazotemic cirrhotic patients with ascites during a 3-day period in association with potassium canrenoate (200 mg/day) administration. Doses of loop diuretics administered in this trial (10 and 25 mg/day of torasemide and furosemide, respectively) had been shown to be equipotent in healthy subjects. Torasemide induced significantly greater natriuresis than furosemide (p less than 0.02), with a twofold greater percentage increase in basal values (day 1: 130% vs. 50%; day 2: 104% vs. 42%; and day 3: 65% vs. 26%, respectively). Body weight loss was significantly higher during torasemide (p less than 0.02) administration, and the overall decrease at the end of the treatment was twice as high for furosemide (2.5 +/- 0.6 kg vs. 1.3 +/- 0.4 kg, respectively). Diuresis was also higher during torasemide administration, but the difference was not significant (p = 0.08). The extent of kaliuresis observed during the two treatments was almost identical despite the striking differences in the natriuretic response. The effects of the two treatments on plasma electrolytes, creatinine clearance, blood urea nitrogen, mean arterial pressure, heart rate and plasma arginine vasopressin concentration were similar. Both drugs caused increases in plasma renin activity at the end of the treatment, whereas plasma aldosterone concentration slightly increased only after torasemide administration. Despite the presence of a trend toward a more pronounced effect on these parameters after torasemide administration, no significant difference between the two treatments was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of repeated atrial natriuretic peptide bolus injections in cirrhotic patients with refractory ascites.

The renal and hormonal effects of repeated atrial natriuretic peptide (ANP) boli (1 microgram/kg of body weight) were studied in eight cirrhotic patients with refractory ascites. Under basal conditions the patients showed a striking activation of the renin-angiotensin-aldosterone system (plasma renin activity 19.3 +/- 3.0 ng/ml.h, plasma aldosterone concentration 3.87 +/- 0.58 ng/ml) and a tenfold elevation in plasma ANP levels compared to healthy subjects (131.7, range 47.0-288.6, vs. 9.8, range 5.0-15.0, fmol/ml, p less than 0.001). The first ANP injection was followed by a remarkable increase in plasma ANP levels and by a slight increase in urinary cyclic guanosine-monophosphate excretion (from 1050.8 +/- 454.8 to 1446.6 +/- 822.2 pmol/min). A significant reduction of mean blood pressure (MBP) occurred 5 min after the first injection (from 86.7 +/- 7.2 to 79.9 +/- 5.8 mmHg, p less than 0.05), but values gradually returned to the baseline after 30 min. Heart rate (HR) increased 10 min after the first bolus injection (from 83.75 +/- 4.7 to 88.1 +/- 4.6 beats/min) and reached baseline values after 30 min. Similar behaviour of MBP and HR was observed after the second, third and fourth bolus injections. Urinary sodium excretion, urinary flow, glomerular filtration rate, plasma renin activity, and plasma aldosterone concentration did not show any significant modification during ANP administration, nor did these parameters change in the following 12-h recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous dopamine (DA) and DA2 receptors: a mechanism limiting excessive sympathetic-adrenal discharge in humans.

We studied the effects of presynaptic dopamine (DA) 2 receptor blockade on the sympathetic-adrenal response to graded exercise in seven normal men. DA2 receptor blockade was achieved by means of domperidone (DMP) administration. The exercise consisted of progressive cycling activity, from 30-80% of the predetermined maximal oxygen consumption for each man. Systolic, diastolic, and mean arterial pressures; heart rate; and plasma norepinephrine (NE), epinephrine (E), PRL, glucose, lactate, FFA, sodium, potassium, cortisol, and PRA were measured at rest, during exercise, and during recovery after placebo or DMP administration. Graded exercise caused significant increases in systolic and mean arterial pressures and plasma NE, E, lactate, sodium, potassium, FFA, cortisol, and PRA. DMP administration before exercise caused a significant increase in plasma PRL (P = 0.0009), a greater increase in plasma NE at the end of the exercise (P = 0.002), and an overall increase in plasma E (P = 0.02) and FFA (P = 0.02) concentrations. These results strongly suggest that endogenous DA limits catecholamine release during sympathetic-adrenal stimulation by activating DA2 receptors.

Measurement of catecholamines, met-enkephalin, somatostatin and substance P-like immunoreactivities in 12 human pheochromocytomas.

The present study was designed to evaluate the simultaneous presence of epinephrine (E), norepinephrine (NE), met-enkephalin (ME)-, somatostatin (SRIF)- and substance P (SP)- like immunoreactivities (LI) in extracts of 12 pheochromocytomas obtained at the time of surgery from 10 patients. Moreover, catecholamines and ME-LI levels were measured in peripheral plasma of each patient. Each pheochromocytoma was characterized by a high variability of ME-LI, SRIF-LI, SP-LI, E and NE levels. The highest E concentrations were found in tumors from patients with Multiple Endocrine Adenomatosis (MEA) IIa syndrome, whereas in sporadic pheochromocytomas NE was the main catecholamine. Among the neuropeptides ME-LI showed the highest intratumoral concentration, and SP-LI the lowest. No correlations were found between intratumoral levels of catecholamines and any of the neuropeptides or between any of the different neuropeptides measured. Plasma catecholamine levels were not correlated with intratumoral catecholamine levels. Plasma ME-LI was higher than normal in only one patient. No correlation was observed between tumoral CA or peptide content and the clinical picture. Our study confirms that human pheochromocytoma cells can synthetize different neuropeptides. The variability of the clinical picture very likely depends on the biochemical and biological heterogeneity of this chromaffin tumor.