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Biomedical subjects

B L Furman

Publications and source records attributed to B L Furman.

At least 55 records · Page 3Linked to original sources
PubMed1988

Augmentation of glucose induced insulin secretion by pertussis vaccine, phentolamine and benextramine: involvement of mechanisms additional to prevention of the inhibitory actions of catecholamines in rats.

Pertussis vaccine, pertussis toxin, and the alpha-adrenoceptor blocking drug phentolamine augment glucose-induced insulin secretion. The present study was carried out to determine the relationship between this action and the ability of these agents to prevent the inhibitory actions of adrenaline. Pertussis vaccine augmented glucose-induced insulin secretion in rat islets ex vivo and prevented the inhibitory actions of adrenaline and clonidine. Incubation of islets with phentolamine or the irreversible alpha-adrenoceptor blocking agent benextramine also augmented glucose-induced insulin secretion. However, the alpha-adrenoceptor blocking drugs idazoxan, yohimbine or phenoxybenzamine, in concentrations that prevented the inhibitory effects of adrenaline and/or clonidine, did not modify glucose-induced insulin release in vitro. Benextramine (1 X 10(-5) mol/l) blocked the inhibitory effect of clonidine, whilst having no significant effect on the response to adrenaline. It is concluded that stimulation of insulin secretion by certain alpha-adrenoceptor blocking drugs can be dissociated from their alpha-adrenoceptor properties. The ability of pertussis vaccine, phentolamine or benextramine to augment glucose-induced insulin release in vitro is unlikely to be due to the prevention of the inhibitory action of endogenous catecholamines.

Adrenergic alpha-Antagonists↗
PubMed1988

Role of the adrenal medulla in stress-induced hyperinsulinaemia in normal mice and in mice infected with Bordetella pertussis or treated with pertussis toxin.

Intranasal infection of mice with a sublethal dose of Bordetella pertussis or the intravenous administration of purified pertussis toxin resulted in a marked increase in the serum immunoreactive insulin concentration following ether stress. This stress-induced hyperinsulinaemia was not modified significantly by blockade of alpha 2-adrenoceptors with idazoxan, beta-adrenoceptors with propranolol, autonomic ganglia with hexamethonium, opioid receptors with naloxone, muscarinic cholinoceptors with atropine or by adrenal demedullation. The effect of pertussis in promoting stress-induced hyperinsulinaemia was mimicked qualitatively by alpha 2-adrenoceptor blockade, adrenal demedullation or ganglionic blockade. However, the serum immunoreactive insulin response to ether stress was smaller in animals subjected to these procedures compared with the response seen in mice infected with B. pertussis or treated with pertussis toxin. Thus, in the mouse, acute stress produces hyperinsulinaemia under conditions in which the release of adrenal medullary catecholamines is prevented, or the inhibitory action on insulin secretion is blocked by alpha 2-adrenoceptor antagonists or by pertussis toxin.

Adrenal Medulla↗
PubMed1987

Hypoglycaemia and acute stress-induced hyperinsulinaemia in mice infected with Bordetella pertussis or treated with pertussis toxin.

Intranasal infection of mice with a sublethal dose of Bordetella pertussis produced hypoglycaemia and hyperinsulinaemia. Exposure to ether vapour did not modify serum insulin concentrations in control mice, but produced a marked transient hyperinsulinaemia in mice infected with B. pertussis. A similar hyperinsulinaemia in infected, but not control, mice was also seen after a brief (10-15 s) period of anoxia (produced by exposure to an atmosphere of 100% N2 or 100% CO2), or following the injection of histamine or 2-deoxyglucose. Exposure to cold (2-4 degrees C) or hypoxia (8% O2 in 92% N2), however, did not alter serum concentrations of insulin in control or infected mice. The hyperinsulinaemic response to ether stress observed in mice infected with B. pertussis was abolished by pretreatment with alloxan. The hyperglycaemic effects of histamine and 2-deoxyglucose were attenuated or abolished in mice infected with B. pertussis. However, none of the stimuli which produced hyperinsulinaemia in the infected mice resulted in any further lowering of the blood glucose concentration. Pretreatment of mice with pertussis toxin (150 ng/mouse, i.v.) produced hypoglycaemia similar in magnitude to that found in animals infected with B. pertussis. Moreover, exposure of mice treated with pertussis toxin to ether vapour produced marked hyperinsulinaemia. It is suggested that the metabolic alterations seen in animals infected with B. pertussis may be mediated by pertussis toxin.

Animals↗
PubMed1986

Role of insulin in the hypoglycaemic effect of sublethal Bordetella pertussis infection in mice.

Mice were infected intranasally with a sub-lethal dose of Bordetella pertussis organisms (1.2 x 10(5) colony forming units per mouse), control animals receiving the vehicle intranasally. The experiments were performed 14 days later. Serum glucose and insulin concentrations were studied across a 24 h period in freely fed animals and the changes in serum glucose and insulin concentrations in response to feeding were examined in mice fasted for 18 h. The responsiveness of mice to injected insulin (0.5 and 5.0 units/kg i.v.) was also examined. Pertussis-infected mice developed hypoglycaemia and hyperinsulinaemia relative to the controls. These changes were present across a 24 h period although the magnitude of the differences between values seen in control and infected animals varied and the hyperinsulinaemia was not seen at all times. Infected mice showed a markedly diminished hyperglycaemia and an exaggerated hyperinsulinaemia following food ingestion, relative to normal controls. Pertussis-induced hypoglycaemia was abolished following destruction of the pancreatic islet B cells with alloxan (80 mg/kg i.v.). The serum glucose response to a low dose of insulin was significantly attenuated by B. pertussis infection although the hypoglycaemia produced by a high dose was prolonged. It was concluded that B. pertussis infection-induced hypoglycaemia was secondary to hyperinsulinaemia, possibly caused by an exaggerated insulin secretory response to food intake.

Animals↗
PubMed1986

Modification by oxygen free radical scavengers of the metabolic and cardiovascular effects of endotoxin infusion in conscious rats.

Since oxygen free radicals may have a role in the pathophysiology of endotoxin shock, we have studied the effects of a wide range of compounds (alpha-tocopherol, reduced glutathione, allopurinol, superoxide dismutase (alone or in combination with catalase) and phenyl butylnitrone) that can act either to remove free radicals as they are generated or to prevent their generation. The effects of these substances on the metabolic and cardiovascular responses to endotoxin were examined in conscious rats. The intravenous infusion of endotoxin (10 mg/kg i.v. given over 4 h) resulted in systemic hypotension, transient tachycardia, an increase in plasma lactate, and an initial hyperglycemia followed, in those rats that died before 24 h, by hypoglycemia. The hypotension and tachycardia produced by endotoxin were not significantly modified by alpha-tocopherol, allopurinol, or superoxide dismutase, alone or in combination with catalase. The tachycardia was attenuated by reduced glutathione and phenyl butylnitrone. alpha-Tocopherol attenuated the initial hyperglycemia produced by endotoxin whilst alpha-tocopherol, allopurinol, and phenyl butylnitrone all significantly attenuated the endotoxin-induced increase in plasma lactate. Among the free radical scavenging systems studied, only alpha-tocopherol and phenyl butylnitrone improved survival. These results suggest a contribution from oxygen-free radicals to the pathophysiology of endotoxemia.

Allopurinol↗
PubMed1985

Lack of effect of BW755c on glucose-induced insulin secretion in the rat in-vivo.

Glucose-induced elevations in plasma immunoreactive insulin (IRI) were examined in anaesthetized rats pretreated with BW755c, sodium meclofenamate or vehicle. Neither drug influenced the glucose-induced hyperinsulinaemia or the glucose disappearance rate. The results do not support a physiological role for arachidonic acid metabolites in the regulation of glucose-induced insulin secretion.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1985

Plasma catecholamines during endotoxin infusion in conscious unrestrained rats: effects of adrenal demedullation and/or guanethidine treatment.

We have examined the effect of E coli endotoxin infusion (41 micrograms kg-1 min-1 iv for 4 h) on plasma concentrations of epinephrine (E), norepinephrine (NE), and dopamine (DA) in the conscious unrestrained rat. Saline infusion did not change catecholamine concentrations from the preinfusion values of 230.8 +/- 32.9 pg ml-1 (E), 456.8 +/- 104.9 pg ml-1 (NE), and 49.0 +/- 19.9 pg ml-1 (DA). Endotoxin produced marked elevations in all three catecholamines. At 1 h, the plasma concentrations were 3,279 +/- 494.6 pg ml-1 (E), 1,670 +/- 137.0 pg ml-1 (NE), and 191.5 +/- 13.7 pg ml-1 (DA). Thereafter, concentrations of E decreased whereas concentrations of NE and DA increased. These increases were prevented by a combination of adrenal demedullation (28 days previously) and treatment with guanethidine (25 mg kg-1 iv, -24 h) ("sympathectomy"). Guanethidine alone markedly reduced the peak NE concentrations without affecting the E concentrations or the 1-h NE concentrations. Demedullation alone prevented the increase in E and reduced the 1-h NE concentrations. Survival in such "sympathectomized" animals was markedly reduced (survival at 4 h in rats receiving endotoxin alone, 100%: in "sympathectomized" animals receiving endotoxin, 12.5%). The tachycardia produced by endotoxin was attenuated in "sympathectomized" rats and mean arterial blood pressure fell rapidly. Endotoxin-induced hyperglycemia was prevented by "sympathectomy" and hypoglycemia was evident as early as 1 h after commencing the infusion. Endotoxin produced hypoinsulinemia in normal rats but did not change plasma insulin values in "sympathectomized" animals, although these animals showed a pre-endotoxin fasting hyperinsulinemia. An important protective role for catecholamines is suggested, especially in the early stages of shock.

Adrenal Medulla↗
PubMed1985

Metabolic and cardiovascular effects of endotoxin infusion in conscious unrestrained rats: effects of methylprednisolone and BW755C.

Infusion of Escherichia coli endotoxin (41.7 micrograms kg-1 min-1 i.v. for 4 h; 10 mg kg-1 total) in conscious unrestrained rats produced an increase in heart rate and a gradual decrease in arterial blood pressure. Initially plasma glucose was transiently elevated but fell to hypoglycaemic values in the 1-2 h before death. There was a marked elevation in the plasma concentrations of lactate, thromboxane B2, and 6-keto prostaglandin F1 alpha, (PGF1 alpha). Methylprednisolone treatment (two doses of 30 mg kg-1) significantly reduced mortality, provided the first dose was given before commencing the endotoxin infusion; there was no effect on mortality if it was given 2 h after starting the endotoxin infusion. Methylprednisolone pretreatment maintained arterial blood pressure and plasma glucose and prevented the increase in plasma lactate in rats given endotoxin. Methylprednisolone treatment did not modify the increase in plasma thromboxane B2 but attenuated the increase in plasma 6-keto PGF1 alpha concentrations. Pretreatment with BW755C, an inhibitor of both cyclooxygenase and lipoxygenase enzymes, completely prevented the increase in plasma prostanoid concentrations but did not improve survival or significantly modify any other detrimental effects of endotoxin. It is suggested that the beneficial effects of methylprednisolone in this model of endotoxin shock are not related to a reduction in the formation of pharmacologically active arachidonic acid metabolites.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Failure of drugs that selectively inhibit thromboxane synthesis to modify endotoxin shock in conscious rats.

The effects of two thromboxane synthetase inhibitors ( dazoxiben and UK 38485) were investigated on the cardiovascular and metabolic effects of Escherichia coli endotoxin infusion in the conscious, unrestrained rat. Infusion of E. coli endotoxin (41.7 ng kg-1 min-1) for 4 h produced a fall in mean arterial pressure, an increase in heart rate, a transient hyperglycaemia (at 1 h) followed by hypoglycaemia (evident at 6 h), an elevation in plasma lactate and a profound thrombocytopenia. The above changes were accompanied by a marked elevation in plasma thromboxane B2 concentrations (e.g. endotoxin-treated 935 +/- 150 pg ml-1 at 1 h compared with pre-endotoxin values of 125 +/- 30 pg ml-1). The administration of either dazoxiben (30 mg kg-1 i.v., given 30 min before starting the endotoxin infusion) or UK 38485 (15 mg kg-1 given 30 min before, and again 4 h after, starting the endotoxin infusion) prevented the rise in plasma thromboxane B2 concentrations. Neither dazoxiben nor UK 38485 prevented the metabolic, cardiovascular or thrombocytopenic effects of endotoxin and did not modify mortality. These results suggest that, although large amounts of thromboxane are generated in response to endotoxin, they do not play an important role in the major pathophysiological consequences of acute endotoxaemia.

Animals↗
PubMed1983

Evaluation of combined adrenal demedullation and chronic guanethidine treatment as a sympathectomy procedure for metabolic studies.

The usefulness of a combination of adrenal demedullation and treatment with guanethidine (25 mg kg-1 day-1, i.p. for 14 days) as a sympathectomy procedure for metabolic studies was investigated in the rat. The procedure reduced markedly or abolished pressor and positive chronotropic responses to tyramine, nicotine or electrical stimulation of the sympathetic spinal outflow. Hyperglycaemic responses to nicotine or spinal sympathetic stimulation were abolished. Nicotine infusion in intact animals reduced glucose-induced hyperinsulinaemia. On the other hand nicotine infusion in sympathectomized animals produced a marked elevation in glucose-induced hyperinsulinaemia relative to that seen in intact animals. The early hyperinsulinaemic response to glucose infusion during sympathetic stimulation was markedly greater in sympathectomized rats compared with that seen in intact rats. The sympathectomy procedure did not modify the glycaemic responses to adrenaline or insulin or glucose-induced hyperinsulinaemia.

Adrenal Medulla↗
PubMed1982

Effects of inhibitors of 5-hydroxytryptamine uptake on plasma glucose and their interaction with 5-hydroxytryptophan in producing hypoglycaemia in mice.

The effects of various inhibitors of 5-HT uptake on plasma glucose have been studied in normal and monoamine oxidase inhibitor pretreated mice. Additionally their interaction with 5-hydroxytryptophan (5-HTP) in producing hypoglycaemia was studied. Clomipramine, fenfluramine, fluoxetine, ORG 6582 (dl-8-chloro-11-anti-amino-benzo-(b)-bicyclo[3.3.1]nona-3, 6 alpha(10 alpha)-diene hydrochloride), ORG 6997 (dl-4-exo-amino-8-chloro-benzo-(b)-bicyclo[3.3.1]nona-2-6 alpha(10 alpha)-diene hydrochloride), MK 212 and mazindol did not modify the plasma glucose in normal mice but produced hypoglycaemia in mice pretreated with either nialamide or pargyline. Dexamphetamine did not influence plasma glucose in either normal or monoamine oxidase inhibitor pretreated mice. Each of the above drugs except ORG 6997 but including dexamphetamine augmented the hypoglycaemic effect of 5-HTP in normal mice. These responses did not appear to be mediated by insulin since none of the drugs increased the plasma immunoreactive insulin concentration or augmented the hyperinsulinaemic effect of 5-HTP. Moreover, fenfluramine, fluoxetine and ORG 6582 did not augment the hypoglycaemic action of injected insulin although such an augmentation was produced by mazindol.

5-Hydroxytryptophan↗
PubMed1982

Dopaminergic suppression of pancreatic somatostatin secretion.

To characterize dopaminergic influences on pancreatic islet D cell function and its potential interaction with islet A and B cell function, the effect of dopamine (0.5-100 micro M) on immunoreactive somatostatin (IRS), insulin (IRI), and glucagon (IRG) release from rat islets incubated in vitro was studied. Dopamine significantly suppressed the release of IRS (P less than 0.001) and IRI (P less than 0.001) and augmented IRG release (P less than 0.001). Maximum suppression of IRS and IRI release was evident at 20 micro M dopamine with half-maximal suppression occurring at 0.5-1 micro M. Maximal stimulation of IRG release was observed at 100 micro M dopamine with a half-maximal response occurring at 5-10 micro M. Suppression of IRS secretion by dopamine (20 micro M) was completely reversed by the dopaminergic antagonists haloperidol (5 micro M) and pimozide (5 micro M) but was only partially reversed by the alpha adrenergic antagonist phentolamine (2 micro M), and was further suppressed by the beta adrenergic antagonist phentolamine (2 micro M). Suppression of IRI release by dopamine was completely reversed by propranolol, but was unaffected by haloperidol, pimozide, and phentolamine. There results indicate that dopamine directly affects pancreatic islet D cell function, and that islet B and D cells appear to be more sensitive to dopamine than are A cells. Dopamine suppresses IRS secretion predominantly through activation of dopaminergic receptors, whereas it suppresses IRI release through an alpha adrenergic mechanism and stimulates IRG release through a beta adrenergic mechanism.

Adrenergic alpha-Antagonists↗
PubMed1981

Exdotoxin-induced metabolic changes in the conscious, unrestrained rat: hypoglycemia and elevated blood lactate concentrations without hyperinsulinemia.

The effects of E coli endotoxin on the plasma concentrations of glucose, lactate, and immunoreactive insulin (IRI) were studied in conscious unrestrained rats. Additionally the effects of endotoxin on glucose-induced elevations in the plasma IRI concentration and on the rate of disappearance of an intravenous glucose load were examined. After a transient and small hyperglycemia endotoxin administration resulted in a progressive, dose-dependent decrease in the plasma glucose concentration and a marked elevation of plasma lactate. The initial hyperglycemia was accompanied by a small, transient increase in the plasma IRI concentration. There was no increase in the plasma IRI concentration during the development of hypoglycemia. The hypoglycemic effect of endotoxin was fully manifest in streptozotocin diabetic rats which displayed low insulin concentrations initially and throughout the experiment. Endotoxin injection produced a significant reduction in the plasma IRI response to glucose administration and a decrease in the rate of disappearance of a glucose load. It is suggested that the metabolic effects of endotoxin in the rat are not mediated by an increase in insulin secretion.

Animals↗
PubMed1981

Bordetella pertussis-induced hyperinsulinaemia without marked hypoglycaemia: a paradox explained.

B. pertussis vaccine or pulmonary infection produced marked hyperinsulinaemia in mice relative to controls (e.g. control 32 mU/1; B. pertussis infected 113 mU/1). This was associated with a modest relative hypoglycaemia (15-25%). The hyperinsulinaemia was observed only when blood was collected from mice anaesthetized with ether, pentobarbitone, or trichloroethylene but not from unanaesthetized animals. Ether-induced hyperinsulinaemia in B. pertussis was transient. Adrenaline produced marked hyperinsulinaemia in B. pertussis-infected mice whereas it tended to produce hypoinsulinaemia in control animals. The hyperinsulinaemic effect of ether anaesthesia in B. pertussis-infected mice was significantly reduced by beta-adrenoceptor blockade using propranolol. It is suggested (a) that pertussis-infected or vaccinated mice are not chronically hyperinsulinaemic but show elevated insulin concentrations only when subjected to an additional stimulus; (b) that hyperinsulinaemia produced by anaesthesia in pertussis-treated mice is secondary to an altered responsiveness of the insulin-secreting cells to this stimulus; (c) that part of this stimulus may be due to catecholamines released during anaesthesia.

Anesthesia, General↗
PubMed1981

Some factors modifying the insulinotropic and cardiovascular effects of isoprenaline in the rat.

The effects of L-isoprenaline on plasma immunoreactive insulin (IRI) and glucose concentrations were examined in pentobarbitone anaesthetized rats. When given by bolus injection hyperinsulinaemia was produced only by very large doses of isoprenaline (100-200 micrograms/kg). Infusion of isoprenaline allowed the demonstration of hyperinsulinaemia at low dose rates (0.07-0.7 microgram kg-1 min-1). Pretreatment with phentolamine or production of a functional sympathectomy by bilateral adrenal demedullation and chronic guanethidine treatment augmented the hyperinsulinaemic effect of isoprenaline. Isoprenaline-induced hyperglycaemia was attenuated by sympathectomy and by phentolamine pretreatment, this attenuation being attributed to the augmented hyperinsulinaemic effect of isoprenaline under these conditions. The increase in heart rate and reduction in blood pressure produced by isoprenaline were also augmented in sympathectomized rats.

Animals↗
PubMed1980

Further studies on the effects of 5-hydroxytryptophan on plasma glucose and insulin in the mouse.

The effects of 5-hydroxytryptophan on plasma concentrations of glucose and immunoreactive insulin were examined in conscious mice. Blood samples were obtained after anaesthetizing the mice lightly with ether at the desired time. Large doses of L-5-hydroxytryptophan (5HTP) (200-400 mg/kg IV) produced a dose-dependent hypoglycaemic response in fasted mice (e.g. control 5.7 +/- 0.2 mmol/l, 5HTP 400 mg/kg 2.6 +/- 0.3 mmol/l). This response was preceded by a significant elevation in the plasma immunoreactive insulin concentration (e.g. control 6 +/- 2 mU/l; 5HTP 400 mg/kg 53 +/- 7 mU/l). Induction of diabetes with alloxan (80 mg/kg IV 72 h previously) prevented the hypoglycaemic effect of 5HTP. Alloxan diabetes abolished the hyperinsulinaemic response to 100 mg/kg of 5HTP and reduced by 66% the response to 400 mg/kg of 5HTP. In alloxan diabetic mice 5HTP produced a marked hyperglycaemic response (control 17.9 +/- 2.0 mmol/l; 5HTP 100 mg/kg 36.1 +/- 2.3 mmol/l). In normal mice pre-treated with nialamide, a monoamine oxidase inhibitor, much lower doses of 5 HTP (5-10 mg/kg) were required to produce hypoglycaemia. There was no detectable elevation in the plasma insulin concentration accompanying the hypoglycaemic response to smaller doses of 5HTP in nialamide treated mice. The hyperinsulinaemic and hypoglycaemic actions of 5HTP in normal mice were prevented completely by pretreatment with benserazide, an inhibitor of aromatic amino acid decarboxylase. 5-hydroxytryptamine did not modify the plasma glucose concentration in either normal or nialamide-treated animals. It is concluded that the hypoglycaemic response to 5HTP in normal mice is mediated at least partly through an elevation in the plasma insulin concentration, although it is likely that additional mechanisms are involved.

5-Hydroxytryptophan↗