Factors affecting the development of atrial fibrillation and atrial flutter (AF/AFL) following autologous hematopoietic SCT (auto-HSCT).

The use of autologous hematopoietic SCT (auto-HSCT) has expanded to include older patients. Increasing age is a well-appreciated risk factor for the development of atrial fibrillation and/or atrial flutter (AF/AFL) in the general population. As more elderly patients undergo auto-HSCT, the risk of developing AF/AFL post transplant may also increase. However, few data evaluating other risk factors for the development of AF/AFL following auto-HSCT exist. Therefore, we performed a retrospective study to determine the incidence of AF/AFL following auto-HSCT and to determine the risk factors associated with the development of AF/AFL. Patients who developed AF/AFL were compared with a group of patients who received auto-HSCT within the same time period (April 1999 to May 2005) and were within 5 years of age. Of the 516 patients who underwent auto-HSCT at the University of Nebraska Medical Center 44 (8.5%) developed AF/AFL at a median time of 4 days (range, days 1-9) following auto-HSCT. In multivariate analysis, risk factors for developing AF/AFL were older age, odds ratio and 95% CI of 1.14 (1.07-1.21), elevated serum creatinine level, 2.69 (1.00-7.22), history of previous arrhythmia, 9.33 (3.01-28.99), and history of previous mediastinal irradiation, 11.12 (1.33-92.96).

Potent bombesin receptor antagonists distinguish receptor subtypes.

To determine whether newly described bombesin (BN) receptor antagonists distinguish subtypes of BN receptors, we investigated their abilities to interact with BN receptors on esophageal muscle or pancreatic acinar tissue. For inhibition of binding of 125I-[Tyr4]BN to rat pancreatic tissue, the relative potencies were [D-Phe6]BN-(6-13)ethyl ester (5 nM) greater than Ac-gastrin-releasing peptide (GRP)-(20-26)ethyl ester (17 nM) greater than [D-Phe6,Cpa,14, psi 13-14]BN-(6-14) (40 nM) greater than [Leu14, psi 13-14]BN (0.43 microM) greater than [Tyr4,D-Phe12]BN = [D-Pro4, D-Trp7,9,10]substance P (SP)-4-11 (13 microM) greater than [Leu14, psi 9,10]BN (32 microM) greater than [D-Arg1,D-Trp7,9,Leu11]SP (70 microM). Each antagonist also inhibited binding of 125I-[Tyr4]BN or 125I-Bolton-Hunter-neuromedin B to rat esophageal tissue, and the potency of each antagonist for each tracer was similar. In comparison to rat pancreas, [D-Phe6]BN-(6-13)ethyl ester, Ac-GRP-(20-26)ethyl ester, [D-Phe6,Cpa14, psi 13-14]BN-(6-14), [Leu14, psi 13-14]BN, and [Leu14, psi 9,10]BN had a 10,000-, 2,940-, 1,425-, 122-, and 4-fold, respectively, weaker affinity for BN receptors. In contrast [Tyr4,D-Phe12]BN, [D-Pro4,D-Trp7,9,10]SP-4-11, and [D-Arg1,D-Trp7,9,Leu11]SP had a 4-, 4-, and 9-fold, respectively, higher affinity compared with pancreatic tissue. Comparison of the activity of each peptide at inhibiting the ability of equipotent concentrations of BN or neuromedin B to stimulate contraction of rat esophageal muscle demonstrated that each peptide had the same relative potencies as for inhibiting binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreastatin inhibits insulin secretion as induced by glucagon, vasoactive intestinal peptide, gastric inhibitory peptide, and 8-cholecystokinin in the perfused rat pancreas.

Pancreastatin is a 49-amino acid straight chain molecule isolated from porcine pancreatic extracts. In the perfused rat pancreas, this peptide has been shown to inhibit unstimulated insulin release and the insulin responses to glucose, arginine, and tolbutamide. To further explore the influence of pancreastatin on islet cell secretion, the effect of synthetic porcine pancreastatin (a 2-micrograms priming dose, followed by constant infusion at a concentration of 15.7 nmol/L) was studied on the insulin, glucagon, and somatostatin responses to 1 nmol/L vasoactive intestinal peptide (VIP), 1 nmol/L gastric inhibitory peptide (GIP), and 1 nmol/L 26 to 33 octapeptide form of cholecystokinin (8-CCK). The effect of pancreastatin on the insulin and somatostatin secretion elicited by glucagon (20 nmol/L) was also examined. Pancreastatin infusion consistently reduced the insulin responses to VIP, GIP, and 8-CCK without modifying glucagon or somatostatin release. It also inhibited the insulin release but not the somatostatin output induced by glucagon. These observations broaden the spectrum of pancreastatin as an inhibitor of insulin release. The finding that pancreastatin does not alter glucagon or somatostatin secretion supports the concept that it influences the B cell directly, and not through an A cell or D cell paracrine effect.

Effects of galanin on islet cell secretory responses to VIP, GIP, 8-CCK, and glucagon by the perfused rat pancreas.

Exogenous galanin has been shown to suppress insulin secretion as elicited by a number of secretagogues such as glucose, arginine, tolbutamide, carbachol, and oral nutrients. To achieve further insight into the influence of galanin on the endocrine pancreas, we have investigated the effect of synthetic porcine galanin (a 200 ng bolus followed by constant infusion at a concentration of 16.8 ng/mL for 16 to 24 minutes) on unstimulated insulin, glucagon, and somatostatin release, as well as on the responses of these hormones to 1 nmol/L vasoactive intestinal peptide (VIP), 1 nmol/L gastric inhibitory peptide (GIP), 1 nmol/L 26 to 33 octapeptide form of cholecystokinin (8-CCK) or 10 nmol/L glucagon in the perfused rat pancreas. Galanin infusion reduced unstimulated insulin secretion by 60% without modifying glucagon and somatostatin output. Galanin also blocked insulin release elicited by VIP, GIP, and 8-CCK, it did not affect the glucagon responses to VIP and GIP, or the somatostatin responses to VIP, GIP, and 8-CCK. Finally, galanin inhibited the insulin output, but not the somatostatin release induced by glucagon. In conclusion, in the perfused rat pancreas, galanin appears to behave as a general inhibitor of insulin secretion. Since this neuropeptide does not modify glucagon or somatostatin release, a direct effect of galanin on the B-cell seems plausible.

In vitro effects of BAY K 8644, a dihydropyridine derivative with hypoglycaemic properties, on hepatic glucose production and pancreatic hormone secretion.

In rats, oral administration of BAY K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate), a dihydropyridine derivative, Ca2+-channel activator, lowers fasting glycaemia and improves glucose tolerance to carbohydrate loading without elevating peripheral plasma insulin. To study the hypoglycaemic mechanism of this compound, we have examined its effects on glucose production by isolated rat hepatocytes and on hormone secretion by the perfused rat pancreas. Incorporation of BAY K 8644 (0.2-10 microM) into the hepatocyte incubation medium failed to significantly modify glycogenolysis, gluconeogenesis or L-lactate production. Hepatocyte glycogen phosphorylase a (EC 2.4.1.1) activity and fructose 2,6-bisphosphate levels were also unaffected by BAY K 8644. In the perfused rat pancreas, BAY K 8644 markedly stimulated insulin release without modifying glucagon or somatostatin output. Thus, the possibility that this compound exerts its hypoglycaemic effect by provoking insulin secretion should be further investigated.

Effects of pancreastatin on insulin, glucagon and somatostatin secretion by the perfused rat pancreas.

Pancreastatin is a novel peptide, isolated from porcine pancreatic extracts, which has been shown to inhibit glucose-induced insulin release "in vitro". To achieve further insight into the influence of pancreastatin on pancreatic hormone secretion, we have studied the effects of this peptide on unstimulated insulin, glucagon and somatostatin output, as well as on the responses of these hormones to glucose and to tolbutamide in the perfused rat pancreas. Pancreastatin strongly inhibited unstimulated insulin release as well as the insulin responses to glucose and to tolbutamide. It did not significantly affect glucagon or somatostatin output under any of the above-mentioned conditions. These findings suggest that pancreastatin inhibits B-cell secretory activity directly, and not through an A-cell or D-cell paracrine effect.

Characterization of gastrin receptors on guinea pig pancreatic acini.

Recent studies have demonstrated gastrin receptors in some pancreatic tumors and that gastrin is a potent stimulant of pancreatic Na+-H+ exchange. In the present study we used 125I-labeled gastrin (125I-gastrin) to characterize gastrin receptors on guinea pig pancreatic acini. Binding of 125I-gastrin was temperature dependent, saturable, and specific for gastrin-related peptides. Analysis demonstrated a single class of receptors with high affinity for gastrin (Kd = 1.5 nM) and a binding capacity of 1 fmol/mg protein. Binding of 125I-gastrin was inhibited with the following relative potencies (Kd): cholecystokinin octapeptide (CCK-8) (0.35 nM) greater than gastrin-17-I = gastrin-34-I (1.5 nM) greater than pentagastrin (7 nM) greater than desulfated [des(SO3)]CCK-8 (28 nM) greater than CCK-4 (508 nM) and by the receptor antagonists CBZ-CCK-27-32-NH2 (3.5 microM) greater than proglumide analogue 10 (30 microM) greater than asperlicin (265 microM) greater than Bt2-guanosine 3',5'-cyclic monophosphate (828 micron). In contrast, for both stimulation of enzyme secretion and inhibition of binding of 125I-CCK-8 the relative potencies were CCK-8 much greater than des(SO3)CCK-8 greater than gastrin-17-I = gastrin-34-I greater than pentagastrin greater than CCK-4. For each receptor antagonist the dose-inhibition curve for gastrin-stimulated amylase release was superimpossible with that for CCK-8-stimulated amylase release. Gastrin-17-I at concentrations less than 0.1 microM did not potentiate carbachol or vasoactive intestinal peptide-stimulated amylase secretion and did not affect basal or stimulated adenosine 3',5'-cyclic monophosphate or 45Ca outflux.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of galanin on hormone secretion from the in situ perfused rat pancreas and on glucose production in rat hepatocytes in vitro.

UNLABELLED: Galanin is a novel peptide, widely distributed throughout the central and peripheral nervous system, including nerve endings surrounding the pancreatic islets. In dogs, galanin infusion has been reported to induce hyperglycemia along with a reduction of circulating insulin. In this work, we have studied the effect of galanin (a 200 ng bolus followed by constant infusion at a concentration of 16.8 ng/ml for 22-24 min) on insulin, glucagon, and somatostatin secretion in the perfused rat pancreas. In addition, we have investigated the effect of galanin (10 and 100 nM) on glycogenolysis and gluconeogenesis in isolated rat hepatocytes. In the rat pancreas, galanin infusion marked inhibited unstimulated insulin release as well as the insulin responses to glucose (11 mM), tolbutamide (100 mg/liter) and arginine (5 mM). Galanin failed to alter the glucagon and somatostatin responses to glucose, tolbutamide, and arginine. In isolated rat hepatocytes, galanin did not influence glycogenolysis or glucagon phosphorylase a activity. Gluconeogenesis and the hepatocyte concentration of fructose 2,6-bisphosphate were also unaffected by galanin. IN CONCLUSION: in the perfused rat pancreas, galanin inhibited insulin secretion without modifying glucagon and somatostatin output, thus pointing to a direct effect of galanin on the B cell; and in rat hepatocytes, galanin did not affect glycogenolysis or gluconeogenesis; hence, the reported hyperglycemia induced by exogenous galanin does not seem to be accounted for by a direct effect of this peptide on hepatic glucose production.

Inhibitory effect of galanin on pancreatic polypeptide release by the perfused rat pancreas.

We have investigated the effect of galanin infusion on unstimulated pancreatic polypeptide (PP) release as well as on the PP response to arginine by the perfused rat pancreas. Galanin significantly reduced unstimulated PP output. Addition of arginine to the perfusate evoked a biphasic pattern of PP release; the second phase of this PP response was delayed when galanin was simultaneously infused. These findings point to a regulatory role of galanin in the control of PP secretion.

Mechanism of action of calcitonin gene-related peptide in stimulating pancreatic enzyme secretion.

In guinea pig pancreatic acini rat calcitonin gene-related peptide (CGRP) caused an eightfold increase in amylase release with various phosphodiesterase inhibitors present. Rat CGRP and rat [Tyro]CGRP caused half-maximal effect at 2 nM, and were threefold more potent than human CGRP. CGRP-stimulated amylase release was not inhibited by VIP-(10-28) or secretin-(5-27). CGRP stimulated cAMP and was augmented by phosphodiesterase inhibitors with the order of sensitivity being Ro-20-1724 greater than isobutylmethylxanthine greater than theophylline. CGRP did not increase 45Ca outflux or effect of 125I-VIP binding. CGRP specifically inhibited 125I-CGRP binding. The dose-response curves were broad and each peptide accelerated dissociation of bound 125I-CGRP. Computer analysis demonstrated two classes of CGRP-binding sites. Occupation of a high-affinity class (Kd 20 nM) correlated with stimulation of enzyme secretion and cAMP, and occupation of the low-affinity class (Kd 1 microM) correlated with accelerated dissociation. These studies demonstrate that CGRP interacts with specific pancreatic receptors, CGRP-stimulated cAMP is in a different compartment from that stimulated by other secretagogues, and CGRP differs from other agents that increase cAMP and amylase release in the relationship among receptor occupation, cAMP generation, and enzyme secretion.

Somatostatin, insulin and glucagon secretion by the perfused pancreas from the cysteamine-treated rat.

In rats, administration of a single dose of cysteamine (300 mg/kg, intragastrically) induces a depletion of pancreatic somatostatin content (approximately 60%) without modifying pancreatic insulin or glucagon content. In perfused pancreases from cysteamine-treated rats, there was a lack of somatostatin response to glucose, arginine or tolbutamide. In the absence of stimulated somatostatin release, the secretory responses of insulin and glucagon to glucose, to arginine, and to tolbutamide were not significantly different from those observed in pancreases from control rats. Our data do not support the concept that pancreatic somatostatin plays a major role in the control of insulin and glucagon release.

Selective modification of the ability of cholecystokinin to cause residual stimulation of pancreatic enzyme secretion.

In the C-terminal heptapeptide of cholecystokinin (-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2), replacing the aspartic acid residue by beta-aspartic acid did not alter the ability of the peptide to cause stimulation, desensitization, or residual stimulation of enzyme secretion from dispersed pancreatic acini. Replacing the tyrosine sulfate residue by hydroxynorleucine sulfate did not alter the ability of the heptapeptide to cause stimulation or desensitization, but caused a 50-fold decrease in the potency with which the peptide caused residual stimulation of enzyme secretion. These findings suggest that a modification of the N-terminal region of cholecystokinin heptapeptide, which does not alter the ability of the peptide to bind to its receptor on pancreatic acini and by so doing cause stimulation and desensitization of enzyme secretion, can increase the rate at which the bound peptide dissociates when the acini are washed and reincubated. This increased dissociation is reflected by a reduction in the potency with which the peptide causes residual stimulation of enzyme secretion.

Structural requirements for action of cholecystokinin on enzyme secretion from pancreatic acini.

Using dispersed acini prepared from guinea pig pancreas, we found that the structural requirements for cholecystokinin-induced stimulation of amylase secretion are the same as those for cholecystokinin-induced desensitization of amylase secretion. 1) The relative potencies with which various C-terminal fragments of cholecystokinin cause stimulation are the same as their relative potencies for causing desensitization. 2) With each fragment tested, desensitization occurs with peptide concentrations that are supramaximal for causing stimulation of amylase secretion. 3) Fragments of cholecystokinin less efficacious in causing supramaximal inhibition of amylase secretion are also less efficacious in causing desensitization of amylase secretion. In contrast, there is no obvious fixed relation between the ability of a cholecystokinin fragment to cause stimulation of enzyme secretion and its ability to cause residual stimulation of enzyme secretion. Cholecystokinin and its C-terminal hexadecapeptide are 25-40% more efficacious than the C-terminal decapeptide, octapeptide, and heptapeptide in causing residual stimulation, and the C-terminal pentapeptide and tetrapeptide caused no detectable residual stimulation. The C-terminal tetrapeptide, however, can prevent as well as reverse the residual stimulation caused by other cholecystokinin fragments, and the ability of the tetrapeptide to prevent cholecystokinin-induced residual stimulation is itself fully reversible.

Characterization of the pancreatic polypeptide response to hypoglycemia in man.

The human pancreatic polypeptide (hPP) responses to insulin injection (0.05-0.1 U/kg, i.v.) and to endogenous insulin release as provoked by i.v. tolbutamide (1 g) and oral glucose administration (1.75 g/kg) have been examined. The injection of insulin or tolbutamide was followed by a marked elevation of circulating hPP which was abolished by preventing the hypoglycemic effect of these substances by intravenous glucose infusion. Atropine pre-treatment (1 mg, i.v.) also blocked the hPP responses to insulin- or tolbutamide-induced hypoglycemia. Approximately three hours after glucose ingestion, coinciding with the hypoglycemic phase of the test, there was a clear-cut increase in circulating hPP. This hPP response was blunted by impeding the blood sugar fall to sub-baseline values-by means of a glucose infusion-as well as by prior atropinization. It is concluded that: 1) The hPP secretagogue activity of both, insulin and tolbutamide is mediated by their hypoglycemic effect. 2) The elevation of circulating hPP, which occurs during the late hypoglycemic phase of an oral glucose test, is also dependent upon the blood sugar decline to sub-baseline values. 3) Under the above conditions, the hPP response to hypoglycemia can be blocked by atropine, thus indicating that it is due to activation of the cholinergic system and not to the direct effect of glucose lack at the level of the hPP-cell.

Human pancreatic polypeptide secretion in conditions of exogenous and endogenous hyperglycaemia.

The effects of exogenous and endogenous hyperglycaemia on human pancreatic polypeptide secretion have been studied. In normal subjects elevation of plasma glucose concentration by glucose infusion both depressed the basal levels of circulating human pancreatic polypeptide (by 40-50%) and consistently reduced the human pancreatic polypeptide response to the ingestion of a portion-rich meal (areas above pre-meal value: 19.5 +/- 4.1 (mean +/- SEM) vs. 9.6 +/- 2.1, p < 0.01) as well as to caerulein infusion (areas above pre-caerulein value: 8.8 +/- 2.2 vs. 4.6 +/- 1.4, P < 0.01). In diabetic subjects treated with sulphonylureas or diet (fasting plasma glucose: 166 +/- 11 mg/dl, n = 24), human pancreatic polypeptide secretion evoked by food was similar to that of 24 healthy individuals (areas above basal value: 46.6 +/- 9.9 and 33.6 +/- 3.6, respectively). In insulin dependent diabetics (fasting plasma glucose: 231 +/- 19 mg/dl, n = 21) the human pancreatic polypeptide response to the meal (area above basal value: 78.2 +/- 13.7) was significantly greater than that of the controls as well as that of the noninsulin-dependent group (P < 0.05). Since the administration of pancreatic polypeptide to man has been shown to decrease pancreatic exocrine output, postprandial human pancreatic polypeptide hypersection may contribute to the decreased exocrin function of the pancreas often found in insulin-dependent diabetics.