B-type natriuretic peptide in reversible myocardial ischaemia.

BACKGROUND: Coronary heart disease is associated with increased B-type natriuretic peptides (BNPs), and, although controversial, may cause exaggerated exercise-induced BNP secretion. We investigated BNP in relation to reversible myocardial ischaemia. MATERIALS AND METHODS: Serum N-terminal proBNP (NT-proBNP) was measured before and after an exercise electrocardiogram test (ETT) in 14 patients with and 45 patients without exercise-induced myocardial ischaemia. Statistical analysis was carried out on logarithmically transformed data. Results, however, are pre-transformed data. RESULTS: NT-proBNP increased with exercise both in ETT-positive patients (mean (SD) 71.4 (41.2) v 76.8 (44.0) ng/l; p<0.001) and ETT-negative patients (54.0 (61.2) v 60.1 (69.0) ng/l; p<0.001). Pre-exercise and post-exercise NT-proBNP were higher (p<0.05) in ETT-positive than in ETT-negative patients. Incremental NT-proBNP was similar in ETT-positive (4.7 (4.2) ng/l) and ETT-negative (6.2 (8.6) ng/l) patients. CONCLUSION: Serum NT-proBNP concentrations are higher in patients with exercise-induced myocardial ischaemia than in those without. Exercise-induced electrocardiographic myocardial ischaemia, however, is not associated with exaggerated BNP secretion.

The thiazolidinedione insulin sensitiser, BRL 49653, increases the expression of PPAR-gamma and aP2 in adipose tissue of high-fat-fed rats.

The effects of the thiazolidinedione insulin sensitiser BRL 49653 on plasma leptin concentrations and on epididymal fat OB, PPAR-gamma and aP2 mRNA expression were examined in high-fat-fed and high-carbohydrate-fed adult Wistar rats. Diets were given for 4 weeks, with BRL 49653 (10 micromol/kg/day) administered by oral gavage for the last 4 days. Treatment with BRL 49653 reduced plasma leptin concentrations in high-fat-fed rats from 2.34 +/- 0.19 (n=9) to 1.42 +/- 0.09 (n=9) ng/ml (p<0.001). Plasma leptin was unaffected by BRL 49653 in the high-carbohydrate-fed rats. There was no difference in OB mRNA expression between high-fat-fed and high-carbohydrate-fed rats, with or without treatment. PPAR-gamma and aP2 mRNA expression were significantly increased in the high-fat-fed rats treated with BRL 49653 (p < 0.01 and p < 0.001 respectively), but not in carbohydrate-fed rats.

Beta-cell tropin- and glucose-induced hypersecretion of insulin and amylin from perfused fatty rat pancreas.

The neurointermediate pituitary peptide beta-cell tropin (BCT) has potent insulin-releasing and lipogenic properties and is elevated in obesity and type-2 diabetes. The effects of BCT and glucose on the release of insulin and amylin from the perfused pancreas of obese 'fatty' (fa/fa) rats and lean (Fa/?) controls were measured. Pancreata were perfused, sequentially, with buffer containing: 5.6 mmol glucose/l (basal); basal glucose +/- 0.5 nmol BCT/l; 16.7 mmol glucose/l (high). Insulin and amylin release during basal glucose treatment was eight to nine times greater from pancreata from fatty than from lean rats. BCT induced a fivefold greater monophasic insulin and amylin release from fatty compared with lean pancreata. When not preceded by BCT there was a twofold greater high glucose-induced amylin release from fatty pancreata but no difference in insulin secretion. When preceded by BCT stimulation, high glucose induced twofold greater insulin and fourfold larger amylin release from fatty compared with lean pancreata. Molar secretion ratios of insulin:amylin varied between 30:1 and 50:1. In view of the elevated levels of BCT found in the fatty rat and in the light of the above findings, it is concluded that the peptide may have a role in the development of hyperinsulinaemia, hyperamylinaemia and insulin resistance in this animal model of obesity and diabetes.

The effects of insulin and the pituitary peptide beta-cell tropin on the incorporation of D-3-3H-glucose into lipid in brown adipocytes from lactating and non-lactating rats.

Lactating and non-lactating rat brown adipocytes were used to study the dose-dependent stimulation of lipogenesis by Beta-cell tropin (BCT) and insulin. In non-lactating animals BCT increased lipogenesis approximately 2-fold compared to a 3-fold stimulation with insulin; however BCT was effective at a substantially lower molar concentration than insulin. In lactating animals resistance was observed to both BCT and insulin action.

Plasma B-cell tropin (ACTH22-39) concentration in lean and obese (ob/ob) mice and lean and obese (fa/fa) Zucker rats.

A method has been developed for the measurement of plasma concentrations of Beta-cell tropin (BCT), which is a potent insulinotropic and lipogenic peptide secreted by the pituitary. The method was employed to compare plasma Beta-cell tropin concentrations between lean and genetically obese (ob/ob) mice and between lean and genetically obese (fa/fa) Zucker rats. The plasma concentration in lean mice was 0.17 +/- 0.02 (5)nmole/l (mean +/- SEM, n = 5), while that in obese (ob/ob) mice was significantly higher, being 2.88 +/- 1.13 (5)nmole/l. The plasma BCT concentration in Zucker rats was 0.14 +/- 0.02 (15)nmole/l, while that in obese Zucker (fa/fa) rats was significantly higher, being 1.69 +/- 0.72 (16)nmole/l. These results explain previously observed differences in the Beta-cell tropin-like biological activity in plasma from lean and obese animals, and support the hypothesis that the peptide has a role in the development of hyperinsulinaemia and obesity.

The effects of structural modifications on the insulin-releasing activity of beta-cell-tropin.

The minimal effective concentration of the pituitary insulin secretagogue beta-cell-tropin (beta-CT) on the in vitro perfused pancreas was established and the effects of various modifications of the peptide on its potency were tested: iodination with 127I and acetylation reduced the insulin-releasing activity of beta-cell-tropin, and the C-terminal fragments beta-CT-(2-18), beta-CT-(3-18) and beta-CT-(6-18) were all less potent than the intact molecule; beta-CT-(1-6) was not active and did not inhibit beta-CT-induced insulin release.

Studies on insulin secretion and the pituitary insulin secretagogue beta-cell-tropin in the sand-rat (Psammomys obesus).

The sand-rat (Psammomys obesus) is an animal model for the study of human maturity onset diabetes which appears to be controlled by caloric intake. In the present investigations, these animals have been studied in relation to the influence of low- and high-energy diets on body weight, plasma insulin and blood glucose levels, and on insulin secretion from the perfused pancreas and the secretion of corticotropin-like intermediate lobe peptide (CLIP, ACTH18-39) and the insulin secretagogue beta-cell-tropin (beta-CT, ACTH22-39) from the pituitary neurointermediate lobe. The sand-rats maintained on the high-energy diet all became obese. Insulin secretion from the perfused pancreas of the obese sand-rat in the presence of 5.6 mM glucose was significantly higher than in the lean controls maintained on low-energy diets. Increasing the glucose concentration to 16.7 mM only produced a small stimulation of insulin secretion in the obese animals, and the difference between the two groups was not significant. Stimulation of insulin secretion by beta-CT was variable, but the obese animals appeared to be more responsive. Pituitary neurointermediate lobes were incubated for 4 h to measure the secretion of the ACTH related peptide. These were separated by gel filtration and the concentrations measured by radioimmunoassay with a CLIP antiserum and a CLIP standard. In all experiments beta-CT was 4-6 per cent of the total CLIP immunoreactive material. In these experiments the obese animals maintained on a high-energy diet were divided into two groups, those with plasma insulin levels less than 500 mu u/ml and those with insulin levels greater than 500 mu u/ml. The latter group had a significantly higher blood glucose level, presumably due to the insulin resistance resulting from the severe hyperinsulinaemia. It was also observed that CLIP-IRM and beta-CT secretion was lower in this group than in the animals maintained on low-energy diets or those on high-energy diets with moderate hyperinsulinaemia. This suggests a possible feedback inhibition by insulin on the secretion of beta-CT.

Evidence for the presence of the pituitary insulin secretagogue beta-cell trophin in human plasma.

It has been demonstrated that the insulin secretagogue beta-cell-trophin, ACTH(22-39), is present in human plasma. The hormone, separated from plasma by affinity chromatography on a corticotrophin-like intermediate-lobe peptide antibody column, behaves similarly to synthetic beta-cell-trophin on a gel filtration column and on reverse-phase high-performance liquid chromatography. Sufficient amounts of the hormone were isolated from the plasma of two patients with Nelson's syndrome to demonstrate its biological activity on the perfused rat pancreas.

Beta-cell tropin: synthesis and biological activity.

The structure of beta-cell tropin, an insulin secretagogue released by the neuro-intermediate lobe of the obese (ob/ob) mouse, has recently been determined as the 22-39 moiety of ACTH. A method for the preparation of this octadecapeptide using mild solid-phase procedures followed by preparative high pressure liquid chromatography is described. The molecular weight of the synthetic peptide has been confirmed by Fast Atom Bombardment mass spectrometry. Synthetic beta-cell tropin is indistinguishable in its chromatographic, antigenic and biological properties from natural beta-cell tropin.