atrial-natriuretic-factor and Hyperinsulinism

The cause of primary (essential) hypertension remains unknown, but a number of circulating hormones and endothelium-derived factors are probably involved. This review summarizes recent evidence on the roles of hyperinsulinemia, the renin-angiotensin system, atrial natriuretic factor, and three endothelium-derived factors--prostacyclin, endothelium-derived relaxing factor, and endothelin.

Topics: Animals; Atrial Natriuretic Factor; Epoprostenol; Hormones; Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Models, Biological; Muscles; Nitric Oxide; Renin-Angiotensin System

Endothelial dysfunction occurs in hyperinsulinemia (HI). Coronary microcirculation responses to vasoactive agents are examined in 57 patients with angiographically normal coronary arteries. Patients were divided into 2 groups, 37 with normoinsulinemia (NI) and 20 with HI based on results of a 75-g oral glucose tolerance test. Epicardial artery vasoactivity in response to acetylcholine chloride is measured to assess endothelial function. Coronary microcirculation function is evaluated by intracoronary administration of 50 microg of adenosine triphosphate, 1 mg of isosorbide dinitrate, and 0.05 mg/kg of atrial natriuretic peptide. Epicardial artery vasoconstriction in response to 100 microg of acetylcholine is mildly reduced in HI (P = .04). Coronary flow reserve in response to adenosine triphosphate in NI is similar to that in HI. In NI, the resting mean (SD) peak velocity in response to isosorbide dinitrate (40.7 [10.9] cm/s) vs atrial natriuretic peptide (39.6 [10.9] cm/s) is similar. In contrast, the resting mean (SD) peak velocity in response to atrial natriuretic peptide (31.3 [9.3] cm/s) vs isosorbide dinitrate (43.5 [10.0] cm/s) in HI is statistically significantly blunted (P < .001). Atrial natriuretic peptide may have a pathologic effect on coronary microcirculation even in mild endothelial dysfunction among patients with HI.

Topics: Acetylcholine; Adenosine Triphosphate; Aged; Atrial Natriuretic Factor; Coronary Vessels; Endothelium, Vascular; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Isosorbide Dinitrate; Male; Microcirculation; Middle Aged; Vasoconstriction; Vasodilator Agents

Increased plasma atrial natriuretic peptide (ANP) levels and impaired ANP action have been reported in patients with diabetes or insulin resistance. The aim of this study was to assess the interaction between insulin and ANP in type 2 diabetes. In 12 normotensive, normoalbuminuric type 2 diabetics, we infused insulin at a high (6.6 pmol/min/kg) or, on a different day, at a low rate (0.6 pmol/min/kg) during 4 hours of isoglycemia under isovolumic, isoosmolar conditions. The normal response was established in 12 healthy volunteers using an identical protocol. Despite higher baseline ANP levels (17.7 +/- 2.8 vs. 10.8 +/- 1.8 pg/ml, p = 0.04), urinary sodium excretion was similar in diabetics and controls (113 +/- 8.5 vs. 102 +/- 8.8 mEq/24 hours, p = ns). In both groups, hyperinsulinemia caused a decrease in blood volume (0.33 +/- 0.10 l, p < 0.01), diastolic blood pressure (6 %, p < 0.02), and natriuresis. However, plasma ANP decreased in controls (from 12.7 +/- 1.9 to 8.6 +/- 1.4 pg/ml, p = 0.01) but not in type 2 diabetics (15.1 +/- 2.7 vs. 17.2 +/- 3.8 pg/ml, p = ns). We conclude that ANP release is resistant to volume stimulation in type 2 diabetic patients, and natriuresis is resistant to ANP action. This dual disruption of ANP control may play a role in blood pressure regulation in diabetes.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Glucose; Blood Volume; Body Mass Index; Diabetes Mellitus, Type 2; Electrolytes; Female; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Natriuresis; Renin

To evaluate the influence of salt-sensitivity on the plasma insulin and glucose response to infusion of ANP, we studied 22 men with essential hypertension, who were between 40 and 60 years old. After 1 month under normal Na+ intake (120 mmol Na+ per day), patients were randomly assigned to receive either ANP (0.04 micrograms.kg-1.min-1) (n = 15) or vehicle (50 ml saline) (n = 7) over a 60-min period, while in the supine position. Plasma insulin and glucose were measured at time -60, 0, 20, 40, 60, 120, 180, 240 min. Ten days after ANP infusion, blood pressure sensitivity to changes in dietary salt intake was assessed according to a randomized double-blind crossover protocol. Patients were classified into two groups either salt-sensitive (n = 8) or salt-resistant (n = 7). Our results showed that plasma insulin and glucose did not change during ANP infusion in both groups. However, both plasma insulin (from 75.6 +/- 45.1 pmol/l at 60 min to 121.2 +2- 48.6 pmol/l at 240 min, p < 0.05 vs time 0) and glucose levels (from 4.86 +/- 0.73 mmol/l at 60 min to 6.56 +/- 1.03 mmol/l at 240 min, p < 0.01 vs time 0) rose after discontinuation of ANP in salt-sensitive patients, but did not change at all in salt-resistant patients. In conclusion, this randomized vehicle-controlled study demonstrates that plasma insulin and glucose levels increase in salt-sensitive hypertensive patients after the infusion of ANP. The increase of plasma insulin levels observed after ANP discontinuation, if occurring under physiologic conditions, could influence the blood pressure sensitivity to dietary Na+ intake.

Topics: Adult; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Double-Blind Method; Heart Rate; Humans; Hyperglycemia; Hyperinsulinism; Hypertension; Infusions, Intravenous; Insulin; Male; Middle Aged; Sodium Chloride, Dietary

Corin is a protease that converts pro-atrial natriuretic peptide (pro-ANP) to ANP. While the involvement of ANP in the cardiovascular regulation is well established, there is increasing evidence that the pregnant uterus produces ANP, which promotes spiral artery remodeling. The present study examines the alterations in corin and PCSK6, a key enzyme in the conversion of pro-corin to corin, in the placenta of hyperinsulinemic dams (HD) featuring pregnancy-induced hypertension (PIH).. The study was conducted on female Wistar rats. Rats were rendered hyperinsulinemic by subcutaneous insulin pellet, mated and followed to the twenty-first day of pregnancy. Normal pregnant dams (NPD) served as controls. Both groups were sacrificed on day 21 of gestation and their placentas were dissected along with the mesometrial triangle (MT). The tissue was then sectioned from the maternal surface to the base of the MT, and processed for histological and molecular biology analysis of Corin, PCSK6 and ANP expression/immunoreactivity.. Hyperinsulinemic dams developed PIH, along lower placental and fetal weights. Corin expression and immunoreactivity were significantly decreased in the placenta by ~40-50%, but not in the MT. Similarly, placental but not MT PCSK6 immunoreactivity was lower in HD. Concomitantly with the downregulation of corin/PCSK6, proANP levels increased in the placenta of HD.. Corin and PCSK6 are expressed in the placenta and MT. The decline in these two enzymes in the placenta of HD suggests a role of corin/PCSK6 machinery in the development of PIH and intrauterine growth restriction characterizing hyperinsulinemia.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Down-Regulation; Female; Humans; Hyperinsulinism; Placenta; Pre-Eclampsia; Pregnancy; Proprotein Convertases; Rats; Rats, Wistar; Serine Endopeptidases

Gut hormones affect cardiac function and contractility. In this study, we examined whether insulin affects the cardiac atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression and release of proANP-derived peptides in pigs. Anaesthetized pigs were included in an experimental study comparing the effect of hyperinsulinemia in 15 pigs submitted to two different protocols versus 11 control pigs receiving saline infusion. Phosphorylation of Akt on Thr308 was determined by western blotting with a pAkt-Thr308 antibody. The mRNA contents of ANP and BNP were determined with real-time PCR; plasma and cardiac tissue proANP was measured with an immunoluminometric assay targeted against the mid-region of the propeptide and a processing-independent assay. Insulin stimulation increased phosphorylation of Akt Thr308 in both left atrium and left ventricle of porcine hearts (p < 0.005). No change was observed in ANP and BNP mRNA contents in the right or left atrium. BNP mRNA contents in the left ventricle, however, decreased 3-fold (p = 0.02) compared to control animals, whereas the BNP mRNA content in the right ventricle as well as ANP mRNA content in the right and left ventricle did not change following hyperinsulinemia. Moreover, the peptide contents did not change in the four cardiac chambers. Finally, proANP concentrations in plasma did not change during the insulin infusion compared to the control animals. These results suggest that insulin does not have direct effect on atrial natriuretic peptide expression but may have a role in the left ventricle.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Female; Gene Expression Regulation; Glucose Clamp Technique; Heart Atria; Heart Ventricles; Hyperinsulinism; Infusions, Intravenous; Insulin; Natriuretic Peptide, Brain; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA, Messenger; Swine

Topics: Adult; Aged; Atrial Natriuretic Factor; Glucose; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Thinness

Pioneer studies have proposed that multiple metabolic abnormalities, such as insulin resistance, increased Na(+)-H(+) exchanger activity and abnormal intracellular calcium homeostasis, are frequently associated with a subset of essential hypertensive patients with low plasma renin activity (PRA). However, it is unclear whether insulin resistance is related to the low renin status in the very early phase of genetical hypertension. Besides, there is controversy on the subject of the in vivo effect of acute hyperinsulinaemia on sodium-related factors. We investigated the relationship between sodium-related parameters and insulin sensitivity, and the effects of euglycaemic hyperinsulinaemia on cyclic guanosine monophosphate (cGMP) and atrial natriuretic peptide (ANP) levels in 17 young, lean, normotensive male subjects, who displayed extreme predispositions for the development of hypertension. PRA was significantly lower in the positive than in the negative family history group (P < 0.05). Insulin sensitivity (M-value) was correlated with PRA before euglycaemic hyperinsulinaemic clamping (r = 0.577, P < 0.05), and was also inversely correlated with fractional excretion of sodium (FE(Na)) before clamping (r = -0.51, P < 0.05). Euglycaemic hyperinsulinaemia significantly decreased PRA (P < 0.0001) and increased cGMP (P < 0.05) and ANP levels (P < 0.01). In conclusion, insulin sensitivity may be partially determined by PRA levels and FE(Na) before clamping in young, lean, normotensive male subjects. Acute euglycaemic hyperinsulinaemia decreases PRA, and increases cGMP and ANP levels from the fasting condition.

Topics: Adult; Atrial Natriuretic Factor; Cyclic GMP; Glucose Clamp Technique; Homeostasis; Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Male; Predictive Value of Tests; Renin; Sensitivity and Specificity; Sodium; Thinness

Aim of this study was to verify the existence of a correlation between the insular hormones and the atrial natriuretic factor (ANF). We studied 70 subjects (20 control, 20 obese, 20 non insulin-dependent diabetic obese, 10 insulin-dependent diabetic subjects) submitted to a glucagon test (1 mg i.v.). Blood samples were collected at -15, 0, 3, 6, 12, 15, 30, 60, 120, 150 minutes to assay insulin, C-peptide, serum electrolytes and ANF levels. The results to point out are: the ANF basal values are significantly higher (p < 0.01) in non insulin-dependent obese patients than in controls; the obese subjects also present a significant difference (p < 0.05). After glucagon injection no variations have been found in the ANF values until the 15th minute; then the controls, the obese and, above all, the non insulin-dependent diabetic obese subjects showed a significant increase of the ANF values between 60' and 90' (basal values 38 +/- 4 ng/ml; 90' values 85 +/- 7 ng ml). As these high values appear only after the induction of hyperinsulinism in our experiment and are not present in the type-1 diabetic subjects, it's probable that insulin, rather than glucagon, stimulates, directly or indirectly, the ANF secretion. If this hypothesis is confirmed, the correlation between insulin and ANF should deserve attention from a therapeutic point of view in subjects with glycometabolic imbalance.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Obesity; Potassium; Secretory Rate; Sodium

Insulin-dependent diabetic patients have a large exchangeable body sodium pool, secondary to sodium retention. The pathogenesis of impaired natriuresis in insulin dependent diabetes remains to be elucidated. The present study examines the role of hyperinsulinemia, impaired atrial natriuretic release, and resistance to atrial natriuretic peptide action in determining sodium retention in normotensive and hypertensive insulin-dependent diabetic patients. Eight insulin-dependent diabetic patients had significantly higher daily sodium excretion rate (147 +/- 16 mmol/day; mean +/- SE) during conventional insulin treatment (daily plasma glucose: 11.6 +/- 1.2 mmol/liter; daily plasma insulin: 27 +/- 3 microU/ml) than during intensified insulin treatment (daily sodium excretion rate: 91 +/- 12, P less than 0.01; daily plasma glucose: 6.8 +/- 0.7, P less than 0.01; daily plasma insulin: 44 +/- 4, P less than 0.01). Daily sodium excretion rate was also significantly lower (107 +/- 13, P less than 0.01) in the same diabetic patients during intensified insulin treatment along with hyperglycemic clamp (daily plasma glucose: 12.8 +/- 0.3, NS; plasma insulin 48 +/- 4, P less than 0.01). Seven control subjects had lower extracellular liquid volume than eight insulin-dependent diabetic patients (11.0 +/- 0.8 l/1.73 m2 vs. 14.8 +/- 0.9, P less than 0.05) and also had baseline plasma atrial natriuretic peptide concentrations (18 +/- 5 pg/ml vs. 37 +/- 4, P less than 0.05). Atrial natriuretic peptide response to saline challenge was blunted in insulin-dependent diabetic patients when saline was administered on the basis of body surface area (90 mmol/1.73 m2.90 min) but not when administered on the basis of extracellular liquid volume (ECV) (8.2 mmol/liter ECV.90 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Glucose; Cilazapril; Diabetes Mellitus, Type 1; Humans; Hyperinsulinism; Hypertension; Insulin; Isotonic Solutions; Natriuresis; Plasma Substitutes; Pyridazines

The effects of insulin on renal haemodynamics and renal sodium handling were studied in 10 healthy males. Using the euglycaemic insulin clamp technique, insulin was infused on separate days resulting in two levels of hyperinsulinaemia (41 +/- 3 and 90 +/- 7 mU/l, respectively). Renal haemodynamics and the proximal and distal tubular sodium handling were studied using inulin, para-amino-hippuric acid, sodium and lithium clearances. Low- and high-dose insulin infusions were followed by a fall in sodium clearance from 1.6 +/- 0.1 ml/min to 1.2 +/- 0.1 and 1.0 +/- 0.1 ml/min, respectively. Both levels of hyperinsulinaemia resulted in increased distal tubular sodium reabsorption. The distal antinatriuretic effect of insulin was associated with dose- and time-dependent decline in proximal tubular sodium reabsorption. The changes in proximal tubular sodium handling occurred without any significant changes in natriuretic factors, such as renal dopamine and plasma atrial natriuretic peptide levels. However, hyperinsulinaemia resulted in time- and dose-dependent increases in renal plasma flow, and renal vasodilatation could, possibly via changes in renal interstitial pressure, have contributed to the fall in the proximal tubular sodium reabsorption. The results also suggest that decreased proximal sodium reabsorption may be a compensatory mechanism counteracting the insulin-induced sodium retention.

Topics: Adult; Atrial Natriuretic Factor; Biological Transport; Dopamine; Hemodynamics; Humans; Hyperinsulinism; Insulin; Kidney; Kidney Tubules, Distal; Kidney Tubules, Proximal; Male; Sodium

Blood pressure, plasma concentration of triglyceride, aldosterone, renin activity (PRA), and atrial naturietic peptide (ANP), and red blood cell, urine, and plasma sodium and potassium concentration were determined in 24 healthy individuals divided into two groups defined as being either hyperinsulinemic or normoinsulinemic. The results demonstrated that the hyperinsulinemic group had significantly higher values for both systolic (P less than .01) and diastolic (P less than .05) blood pressure. In addition, plasma concentrations of triglyceride (P less than .02), aldosterone (P less than .05) and potassium (P less than .05) were higher in hyperinsulinemic individuals as compared to those who were normoinsulinemic. Furthermore, red cell potassium was lower (P less than .01) and red cell sodium higher (P less than .01) in the hyperinsulinemic group. Finally, the magnitude of hyperinsulinemia correlated directly with systolic (r = 0.50, P less than .01) and diastolic (r = 0.44, P less than .05) blood pressure, concentration of plasma triglyceride (r = 0.55, P less than .01) and aldosterone (r = 0.46, p less than .05), and erythrocyte sodium concentration (r = 0.57, p less than .01). In contrast, plasma insulin response was negatively correlated with erythrocyte potassium concentration (r = 0.40, P less than 0.05). These observations provide further support for the view that hyperinsulinemia, presumably secondary to resistance to insulin-stimulated glucose uptake, is associated with a cluster of variables that may play important roles in the etiology and clinical course of hypertension.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cations; Erythrocyte Count; Erythrocytes; Humans; Hyperinsulinism; Potassium; Renin; Sodium; Triglycerides

Because insulin shows an antinatriuretic effect in healthy humans, insulin therapy resulting in circulating hyperinsulinemia may lead to sodium retention and in turn to hypertension in individuals with insulin-dependent diabetes mellitus (IDDM). Moreover, it has been proved that atrial natriuretic peptide (ANP) plays a major role in modulating natriuresis in humans. This study investigated the relationship between insulin and ANP in modulating sodium metabolism in normotensive and hypertensive IDDM subjects compared with control groups of normotensive and hypertensive nondiabetic subjects. IDDM normotensive and hypertensive subjects had mean +/- SE duration of IDDM of 7 +/- 2 and 8 +/- 2 yr, respectively, and had no clinical features of diabetic nephropathy. All subjects received a saline infusion (2 mmol.kg-1.90 min-1) during euglycemia. IDDM normotensive and hypertensive subjects received a subcutaneous insulin infusion (15 mU.kg-1.h-1), resulting in twofold higher plasma free-insulin levels (16 +/- 2 and 19 +/- 3 microU/ml, respectively) than in nondiabetic normotensive and hypertensive subjects (7 +/- 2 and 8 +/- 2 microU/ml, respectively). During saline challenge, sodium excretion increased by 22 +/- 4% in normotensive and 49 +/- 9% in hypertensive nondiabetic subjects but by only 11 +/- 0.4% in normotensive (P less than 0.01) and 8 +/- 2% in hypertensive (P less than 0.01) IDDM subjects. The impaired natriuretic response to saline challenge was mainly due to greater rates of sodium reabsorption by kidney proximal tubules in IDDM than nondiabetic subjects. At baseline, plasma ANP concentrations were significantly higher in both IDDM groups than in control groups (normotensive IDDM and control subjects: 38 +/- 4 and 19 +/- 2 pg/ml, respectively, P less than 0.01; hypertensive IDDM and control subjects: 45 +/- 6 and 27 +/- 4 pg/ml, respectively, P less than 0.05). After saline challenge, ANP concentrations rose to 39 +/- 4 pg/ml in normotensive and 49 +/- 5 pg/ml in hypertensive control subjects, whereas no significant change above baseline value was seen in IDDM subjects. Both IDDM groups showed a 10-12% greater exchangeable Na+ pool than control subjects regardless of the presence of hypertension. Subcutaneous insulin infusion, resulting in circulating plasma free-insulin levels in normotensive control subjects comparable to those in IDDM patients, inhibited natriuresis, increased proximal tubule sodium reabsorption at the level of the kidney, and in

Topics: Adult; Atrial Natriuretic Factor; Diabetes Mellitus, Type 1; Female; Humans; Hyperinsulinism; Hypertension; Insulin; Isotonic Solutions; Male; Sodium; Sodium Chloride