atrial-natriuretic-factor and Hyperglycemia

To examine the effect of acute hyperglycaemia on atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations in Type 1 diabetes.. The study was two limb, randomized, and single-blind. Eight Type 1 diabetes subjects were clamped at euglycaemia by intravenous infusion of insulin. When euglycaemia was established, the insulin infusion rate was left unaltered for the remainder of the protocol, and an intravenous infusion of either 500 ml 0.9% saline or 500 ml 10% dextrose was administered over 1 h. Blood was collected for estimation of plasma glucose, ANP and BNP concentrations at 30 min intervals for 2 h from the start of the infusion period. One week later, each subject received the alternate infusion. Results are expressed as mean +/- standard deviation, and were analysed by ANOVA.. Baseline plasma glucose (P = 0.8), ANP (P = 0.8) and BNP (P = 0.8) concentrations were similar on the study days. Plasma glucose rose with dextrose (6.1 + 0.5-15.1 + 2.8 mmol/l, P = 0.9). Plasma ANP concentrations were unaltered by saline infusion (76.5 +/- 14.7-77.7 +/- 15.2 pg/ml, P = 0.9), but increased with dextrose infusion (79 +/- 14-134 +/- 17.1 pg/ml, P < 0.0001), and were higher with dextrose than saline infusion (P < 0.0001). Plasma concentrations of BNP were not significantly altered by infusion of either dextrose (5.1 +/- 3.9-9.3 +/- 5.4 pg/ml, P = 0.63) or saline (4.3 +/- 3.5-6 +/- 5.2 pg/ml, P = 0.84).. Plasma concentrations of ANP, but not BNP, rise in response to acute hyperglycaemia in Type 1 diabetes.

Topics: Adult; Atrial Natriuretic Factor; Blood Glucose; Diabetes Mellitus, Type 1; Glucose Clamp Technique; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Male; Natriuretic Peptide, Brain; Single-Blind Method

To elucidate the mechanism behind the increased plasma atrial natriuretic factor (ANF) reported in Type 1 diabetic patients with glomerular hyperfiltration and incipient nephropathy, we studied the effects of a short-term moderate hyperglycemia with concomitant hyperinsulinaemia on plasma ANF concentrations and glomerular filtration rate (GFR) in healthy male volunteers. Following a 2-hour basal run-in period, blood glucose level was clamped at 12.2 mmol/l for 4 hours by infusing 20% glucose solution (hyperglycaemia study) or the level was kept normal by infusing isotonic saline over the 4 hours (saline control study). Plasma ANF increased slightly both in the hyperglycaemia phase (from 25.7 +/- 6.3 to 32.1 +/- 7.5 ng/l at 3 hours [p < 0.02] and 31.0 +/- 6.6 ng/l at 4 hours [p = 0.058, mean +/- SD]) and in the control phase (from 17.7 +/- 6.1 to 26.1 +/- 13.5 ng/l at 3 hours [p < 0.05] and 25.4 +/- 11.7 ng/l at 4 hours [p < 0.05]) as compared with the respective baseline values. GFR remained unchanged both in the hyperglycaemia (from 108 +/- 8 to 104 +/- 13 ml/min/1.73 m2) and the saline control phases (from 106 +/- 7 to 101 +/- 7 ml/min/1.73 m2), respectively. The results of this short-term study showed no association between the moderate hyperglycaemia with a concomitant hyperinsulinaemia and plasma ANF concentration in non-diabetic normotensive subjects.

Topics: Adult; Atrial Natriuretic Factor; Glomerular Filtration Rate; Glucose; Humans; Hyperglycemia; Insulin; Male; Time Factors

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

Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 μL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6-8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT-qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cardiomyopathies; Collagen; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Fibrosis; Hyperglycemia; JNK Mitogen-Activated Protein Kinases; Mice; Mitogen-Activated Protein Kinase 10; Natriuretic Peptide, Brain; Receptors, Leptin; RNA, Messenger; Signal Transduction; Sirtuin 1

Several mechanisms have been proposed for the heart dysfunction during hyperglycemia. The aim of the present in vitro study is to elucidate the role of alterations in redox homeostasis in the induction of apoptosis during hyperglycemia in H9c2 cells via dysfunction in mitochondria and polyol pathway and evaluation of the beneficial effect of cinnamic acid against the same. The H9c2 cells were incubated with 33 mM glucose for 48 h to simulate the diabetic condition. Cell injury was confirmed with a significant increase of atrial natriuretic peptide and lactate dehydrogenase release. Alterations in the innate antioxidant system, polyol pathway, mitochondrial integrity, dynamics and apoptosis were investigated. Hyperglycemic insult has significantly affected redox homeostasis via depletion of superoxide dismutase, glutathione and enhanced reactive oxygen species generation. It also caused dysregulation in mitochondrial dynamics (fusion, fission proteins), dissipation of mitochondrial transmembrane potential and increased sorbitol accumulation. Finally, apoptosis was observed with upregulation of Bax, activation of caspase-3 and downregulation of Bcl-2. Cinnamic acid cotreatment increased the innate antioxidant status, improved mitochondrial function and prevented apoptosis in H9c2 cardiomyoblasts. Moreover, this in vitro model is found to be ideal for the elucidation of mechanisms at the cellular and molecular level of any physiological, pharmacological and toxicological incidents in H9c2 cells.

Topics: Animals; Atrial Natriuretic Factor; Cell Line; Cell Survival; Cinnamates; Glucose; Homeostasis; Hyperglycemia; Hypoglycemic Agents; L-Lactate Dehydrogenase; Membrane Potential, Mitochondrial; Mitochondrial Dynamics; Oxidation-Reduction; Polymers; Rats; Reactive Oxygen Species

Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such toxicity can be reversed by reducing circulating glucose levels by fasting or insulin. Furthermore, glucose injections alone reversed the fasting-dependent protection against DXR in mice, indicating that elevated glucose mediates, at least in part, the sensitizing effects of rapamycin and dexamethasone. In yeast, glucose activates protein kinase A (PKA) to accelerate aging by inhibiting transcription factors Msn2/4. Here, we show that fasting or glucose restriction (GR) regulate PKA and AMP-activated protein kinase (AMPK) to protect against DXR in part by activating the mammalian Msn2/4 ortholog early growth response protein 1 (EGR1). Increased expression of the EGR1-regulated cardioprotective peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in heart tissue may also contribute to DXR resistance. Our findings suggest the existence of a glucose-PKA pathway that inactivates conserved zinc finger stress-resistance transcription factors to sensitize cells to toxins conserved from yeast to mammals. Our findings also describe a toxic role for drugs widely used in cancer treatment that promote hyperglycemia and identify dietary interventions that reverse these effects.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Atrial Natriuretic Factor; Cardiotoxins; Cyclic AMP-Dependent Protein Kinases; Cytoprotection; Dexamethasone; Diet; Early Growth Response Protein 1; Fasting; Female; Glucose; Hyperglycemia; Metformin; Mice; Mice, Inbred C57BL; Natriuretic Peptide, Brain; Stress, Physiological; Time Factors

The present study was aimed to investigate whether hyperglycemia may alter the regulation of vascular natriuretic peptide receptors (NPR). The hyperglycemia was induced in rats by the treatment with streptozotocin (50 mg/kg, i.v.). The expression of different subtypes of NPR was determined in the thoracic aorta by reverse transcriptase-polymerase chain reaction and quantitative in vitro receptor autoradiography. The isometric tension and the guanylyl cyclase activity of the isolated thoracic aorta in response to natriuretic peptides were also determined. Following the treatment with streptozotocin, the plasma concentration of atrial natriuretic peptide (ANP) was significantly increased. The expression of NPR-A was increased, while that of NPR-C was reduced. The receptor binding study demonstrated an increased maximal binding capacity of NPR, with its affinity not significantly altered. The magnitude of vasodilation and guanylyl cyclase activity in response to ANP was significantly increased. On the other hand, the vasodilator response as well as the tissue formation of cGMP in response to acetylcholine or sodium nitroprusside was significantly reduced. These results indicate that the hyperglycemia may cause an altered regulation of vascular NPR.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Blood Glucose; Body Weight; Carrier Proteins; Gene Expression; Guanylate Cyclase; Hyperglycemia; Intracellular Signaling Peptides and Proteins; Iodine Radioisotopes; Isometric Contraction; Male; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Streptozocin; Time Factors; Vasodilation

Hypertension is commonly associated with diabetes mellitus. The aim of the present study was to explore the pathophysiological significance of the natriuretic peptide (NP) system in hypertension associated with genetically obese/hyperglycemic Wistar fatty rats. The messenger RNA (mRNA) levels of the two biologically active NP receptors, NP-A receptor [more specific for atrial natriuretic peptide (ANP)] and NP-B receptor [more specific for C-type natriuretic peptide (CNP)], and CNP mRNA levels were determined in the aorta and kidney by ribonuclease protection assay. Plasma ANP levels were determined by RIA. Both NP-A and NP-B receptor mRNA levels in the aortae of Wistar fatty rats were double those in Wistar lean rats. Plasma ANP levels and CNP mRNA levels in the aorta of Wistar fatty rats were also significantly higher than those in Wistar lean rats. In contrast, there was no significant difference in renal levels of the mRNA for both NP receptors and CNP between the two strains. Administration of a NP-A and -B receptor antagonist, HS-142-1, to Wistar fatty rats resulted in a significant increase in systolic blood pressure and a larger decrease in plasma cGMP level than that in Wistar lean rats, with no difference in the extents of decrease in urine volume and urinary sodium excretion between the two strains. These results suggest that both the ANP/NP-A system and the CNP/NP-B system in vessels are up-regulated at the level of gene expression and may, thus, play an important role in counteracting the hypertension associated with diabetes mellitus.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Vessels; Cyclic GMP; Diuresis; Guanylate Cyclase; Hyperglycemia; Hypertension; Kidney; Male; Natriuresis; Natriuretic Peptide, C-Type; Obesity; Polysaccharides; Proteins; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; RNA, Messenger

The effect of alloxan monohydrate-induced diabetes on the resting plasma atrial natriuretic peptide (ANP) level was investigated in 22 male New Zealand white rabbits. Alloxan monohydrate (100 mg/kg) dissolved in saline at a concentration of 50 mg/ml was administered by a single intravenous injection 3 months before the experimental analysis. The diabetic state was examined 72 h later by quantitative determination of blood glucose levels of >350 mg/dl. Beginning on day 3, 14 animals (Group 1) received a daily subcutaneous injection of 1 U insulin having moderate hyperglycemia (blood glucose concentration [BGC] between 300 and 400 mg/dl). Eight animals (Group 2; normoglycemic controls) received 3.2 U of insulin daily to maintain the BGC below 100 mg/dl. Eight healthy rabbits were included in the study as controls (Group 3). Blood samples for ANP analysis were obtained three months after administration of alloxan monohydrate. The plasma ANP levels in moderately diabetic rabbits (328 +/- 43 pg/ml) were significantly higher than those in normoglycemic (98.5 +/- 20 pg/ml) and healthy (76.6 +/- 18 pg/ml) controls (p < 0.001 for both). In addition, we found a significant correlation between plasma levels of glucose and levels of ANP (r = 0.665, p < 0.001). Our data indicate that further experiments need to be performed to investigate what is responsible for the elevation of plasma ANP levels in diabetic rabbits.

Topics: Alloxan; Animals; Atrial Natriuretic Factor; Blood Glucose; Diabetes Mellitus, Experimental; Electrolytes; Hyperglycemia; Male; Rabbits

Evidence that an increase in plasma atrial natriuretic peptide (ANP) concentrations mediates, at least in part, glomerular hyperfiltration in diabetic rats prompted us to study the relationship between ANP and renal haemodynamics in hyperfiltering type 2 diabetic patients in association with other hormones implicated in the control of glomerular filtration rate (GFR) (catecholamines, vasopressin, renin) and in sodium tubular transport (aldosterone, ouabain-displacing factor, ODF). Since hyperglycaemia is also associated to hyperfiltration, diabetic patients who presented with secondary drug failure were studied both in hyperglycaemic and in normoglycaemic condition. For this purpose, 11 normotensive non-macroproteinuric hyperfiltering patients with type 2 diabetes were treated with an 8-day continuous insulin infusion (days 0-7). Dehydration was prevented or corrected and natriuresis was on day 0 above 100 mmol/day. The following parameters were determined on days 0 and 7: GFR and renal plasma flow (RPF) by 99mTc-DTPA and 131I-hippuran clearances; the extracellular volume, assimilated to the DTPA diffusion volume; urinary ODF by receptor-binding assay and urinary as well as plasma catecholamines by HPLC after extraction on alumin. Plasma ANP and antidiuretic hormone (ADH) were measured by radioimmunoassay after extraction on phenyl-silylsilica (ANP) and with ether (ADH). Unextracted plasma was used for radioimmunological measurement of plasma renin activity and aldosterone. When correcting hyperglycaemia to normoglycaemia GFR decreased from high to normal mean value (138 +/- 27 and 115 +/- 6 ml/min, p < 0.001), RPF followed the same trend, and the DTPA diffusion volume did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Hormones; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Renal Circulation; Vasopressins

Atrial natriuretic peptide (ANP) levels in cardiocytes and plasma were examined by using immunohistochemistry, electron microscopy, and radioimmunoassay in non-obese diabetic mice (NOD). Cardiocyte ANP mRNA expression was measured by the polymerase chain reaction method. ANP immunoreactivity in the auricular cardiocytes was more prominent in hyperglycemic mice (NOD-h) than in normoglycemic mice (NOD-n). Ultrastructural examination showed that auricular cardiocytes of the NOD-h group contained more cytoplasmic granules than cells of the NOD-n group. Ultrastructural morphometry indicated that the number of granules per auricular cardiocyte was significantly larger in the NOD-h group than in the NOD-n group (P less than 0.01), whereas the granule diameter was significantly smaller in the NOD-h group (P less than 0.01). Radioimmunoassay showed that ANP levels in the NOD-h auricular cardiocytes were significantly higher than those in the NOD-n cardiocytes (P less than 0.01); the opposite was true in plasma. Cardiocyte ANP mRNA expression was lower in the NOD-h group than in the NOD-n group.

Topics: Animals; Atrial Natriuretic Factor; Cytoplasmic Granules; Diabetes Mellitus, Type 1; Feedback; Female; Gene Expression Regulation; Heart Atria; Hyperglycemia; Mice; Mice, Inbred NOD; Myocardium; RNA, Messenger

The relative contribution of atrial natriuretic peptide (ANP) and vasodilatory prostaglandins to hyperfiltration in Wistar rats with experimental diabetes was studied 6-8 wk after streptozocin injection. Plasma levels of immunoreactive ANP were significantly higher (P less than 0.01) in hyperglycemic diabetic (72.9 +/- 11.7 pg/ml) than in normoglycemic diabetic (44.8 +/- 8.6 pg/ml) or nondiabetic (40.0 +/- 6.8 pg/ml) rats. Blocking endogenous ANP by specific ANP-antiserum infusion reduced significantly (P less than 0.01) glomerular filtration rate (GFR) and renal plasma flow (RPF) of hyperglycemic rats compared with preinfusion values (1.23 +/- 0.06-1.02 +/- 0.04; 2.87 +/- 0.25-2.40 +/- 0.10 ml.min-1.100 g-1, respectively). However, correction of hyperfiltration and hyperperfusion was only partial (nondiabetic rats GFR 0.85 +/- 0.07; RPF 2.27 +/- 0.13 ml.min-1.100 g-1). Because diabetic rats with hyperglycemia also had an increased urinary excretion of prostacyclin metabolite 6-keto-prostaglandin F1 alpha (220.6 +/- 62.8 ng/24 h) compared with nondiabetic rats (51.2 +/- 2.7 ng/24 h), we wondered whether excessive prostacyclin formation contributed to hyperfiltration and hyperperfusion in this setting. Indomethacin infusion partially reduced GFR (1.25 +/- 0.07 to 1.06 +/- 0.07 ml.min-1.100 g-1, P less than 0.05) and RPF (2.85 +/- 0.11 to 2.46 +/- 0.12 ml.min-1.100 g-1, P less than 0.01) in diabetic rats. The combined infusion of ANP antiserum and indomethacin normalized GFR and RPF in diabetic rats with hyperglycemia (1.27 +/- 0.05 to 0.88 +/- 0.05 and 2.84 +/- 0.10 to 2.22 +/- 0.06 ml.min-1.100 g-1, respectively; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Diabetes Mellitus, Experimental; Drug Synergism; Epoprostenol; Glomerular Filtration Rate; Hyperglycemia; Indomethacin; Infusions, Intravenous; Injections, Intravenous; Kidney; Male; Radioimmunoassay; Rats; Rats, Inbred Strains; Regional Blood Flow; Streptozocin

In normoalbuminuric patients with insulin-dependent diabetes mellitus, plasma atrial natriuretic factor (ANF), cyclic GMP and active renin and the renal clearances of [99Tcm]-diethylenetriaminepentaacetic acid (DTPA) lithium and sodium were studied on a hyperglycaemia day and a euglycaemia day. Baseline euglycaemia was achieved by an overnight variable insulin infusion, which during study days was fixed at the rate necessary to maintain euglycaemia in the morning. After a baseline euglycaemic clearance period of 90 min, measurements were repeated in a new 90-min period beginning 150 min later. On the hyperglycaemia day i.v. infusion of 20% glucose was started at the end of the euglycaemic baseline period, increasing blood glucose (5.3 +/- 1.3 vs 12.1 +/- 1.2 mmol l-1, p less than 0.01). On the euglycaemia day blood glucose declined (5.1 +/- 1.0 vs 4.2 +/- 1.0 mmol l-1, p less than 0.02). Glomerular filtration rate (GFR) was unchanged by acute hyperglycaemia (127 +/- 16 vs 129 +/- 24 ml min-1, NS), but nearly normalized during maintained euglycaemia on the euglycaemia day (124 +/- 17 vs 105 +/- 16 ml min-1, p less than 0.01). When comparing the hyperglycaemic study period with the similarly timed period on the euglycaemia day, GFR was elevated by hyperglycaemia (129 +/- 24 vs 105 +/- 16 ml min-1, p less than 0.01), while the renal clearances of lithium and sodium were similar. Consequently, the calculated absolute proximal reabsorption rate of sodium and water was elevated during hyperglycaemia. Hyperglycaemia reduced the slight decline in plasma concentrations of ANF and cyclic GMP observed on the euglycaemia day. Active renin, glucagon and plasma osmolality were unchanged. In conclusion, marked changes in glomerular filtration rate are induced by changes in blood glucose concentration, but the effect is delayed and thus not directly related to renal tubular transport of glucose. Hyperglycaemia does not affect renal clearances of lithium and sodium, while proximal tubular reabsorption is markedly stimulated. These changes are not related to changes in ANF, renin, glucagon or plasma osmolality.

Topics: Adult; Atrial Natriuretic Factor; Blood; Blood Glucose; Cyclic GMP; Diabetes Mellitus, Type 1; Glomerular Filtration Rate; Humans; Hyperglycemia; Insulin; Kidney; Lithium; Osmolar Concentration; Potassium; Renin; Sodium