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Biomedical subjects

B L Furman

Publications and source records attributed to B L Furman.

At least 37 records · Page 2Linked to original sources
PubMed1994

Attenuation by dexamethasone of endotoxin protection against ischaemia-induced ventricular arrhythmias.

Ventricular arrhythmias from a 30 min occlusion of the left coronary artery were assessed in Langendorff perfused isolated hearts removed from rats administered either saline, or endotoxin derived from Escherichia coli (2.5 mg kg-1 i.p.) given either 2, 4, 8, 24 or 48 h previously. Arrhythmia severity was markedly reduced in those hearts removed from rats administered endotoxin with a maximum protection at 8h; there was a marked reduction in the incidence of ventricular fibrillation (from 54% to 4%) and in the number of ventricular premature beats during the occlusion period (e.g. from 1165 +/- 144 to 37 +/- 19; P < 0.01). Dexamethasone (3 mg kg-1, given 1 h prior to endotoxin or saline) markedly attenuated the protection afforded by endotoxin.

Animals↗
PubMed1994

Platelet activating factor impairs pressor responses to noradrenaline in the anaesthetized rat but does not mediate endotoxin-induced hyporeactivity.

A nonhypotensive dose of endotoxin (Escherichia coli lipopolysaccharide, 250 micrograms kg-1 h-1) impaired both the pressor responsiveness to noradrenaline and its effects in reducing renal and hindquarter blood flow, measured using ultrasound Doppler flow probes. Platelet activating factor (PAF, 50 ng kg-1 h-1) similarly impaired pressor responsiveness to noradrenaline, although this effect was accompanied by marked hypotension. These actions of PAF were prevented by pretreatment with the PAF antagonists WEB 2086 (20 mg kg-1) or BN 50739 (10 mg kg-1) 15 min before commencing the infusion. However, neither antagonist modified the effect of endotoxin in impairing vascular responsiveness to noradrenaline. Thus, these results do not support a role for PAF in mediating endotoxin-induced vascular hyporeactivity, at least in the early stages of endotoxaemia.

Anesthesia↗
PubMed1993

Endothelium-dependent vasodilator responses of the isolated mesenteric bed are preserved in long-term streptozotocin diabetic rats.

Endothelium-dependent and endothelium-independent responses to exogenous vasoactive substances were compared in isolated, perfused mesenteric beds from control rats and in rats subjected to prolonged (15-17 weeks) streptozotocin induced diabetes. The main aim of the study was to determine whether the prolonged period of diabetes altered vascular endothelial function, and thereby modified vascular responsiveness to vasoconstrictors or vasodilators. Noradrenaline induced vasoconstriction was not significantly altered in preparations from diabetic rats compared to control. Vasodilator responses to acetylcholine (ACh) and ATP were endothelium-dependent, since they were greatly reduced or abolished after endothelium removal by perfusion with 0.1% Triton-X 100. The vasodilator action of these agents was fully preserved in the diabetic animals. Sodium nitroprusside produced a vasodilation which was endothelium-independent, this vasodilation was also preserved in the diabetic animal. We conclude that prolonged streptozotocin-induced diabetes does not reduce the ability of the mesenteric vascular endothelium to release vasodilator substances, nor does it alter the responsiveness of the bed to exogenous endothelium-independent vasodilator sodium nitroprusside or vasoconstrictor noradrenaline.

Acetylcholine↗
PubMed1992

Modification of alpha-adrenoceptor-mediated pressor responses by NG-nitro-L-arginine methyl ester and vasopressin in endotoxin-treated pithed rats.

Pithed rats were used to compare the abilities of vasopressin and NG-nitro-L-arginine methyl ester (L-NAME) to prevent the early (1 h after starting an endotoxin infusion) E. coli endotoxin-induced impairment of pressor responsiveness to noradrenaline, cirazoline, BHT 933 and to sympathetic stimulation (T8). L-NAME increased arterial blood pressure and augmented pressor responses to noradrenaline and to sympathetic nerve stimulation to a similar degree in control and endotoxin-treated rats. The response to the alpha 1-adrenoceptor agonist cirazoline was augmented by L-NAME in endotoxin-treated rats only, whereas the response to the alpha 2-adrenoceptor agonist BHT 933 was unaffected. Vasopressin (0.64 I.U. kg-1 h-1) prevented the hypotension that resulted from endotoxin administration and produced a similar increase in blood pressure to that produced by L-NAME. This dose of vasopressin also augmented pressor responses to noradrenaline and sympathetic nerve stimulation similarly in both control and endotoxin-treated rats. Sodium nitroprusside, in a dose that mimicked the degree of hypotension caused by endotoxin, also impaired pressor responsiveness to cirazoline; this impairment was prevented by co-infusion of vasopressin. Thus the effects of L-NAME in preventing the early phase of endotoxin-induced impairment of vascular responsiveness may be related to its hypertensive properties, due to inhibition of the constitutive form of nitric oxide synthase, rather than inhibition of endotoxin-induced nitric oxide synthase. These data suggest that early endotoxin-induced impairment of vascular reactivity probably involves factors other than nitric oxide. The well documented effect of endotoxin in inducing nitric oxide synthase probably explains the later, more sustained loss of vascular responsiveness.

Adrenergic alpha-Agonists↗
PubMed1992

The effects of Indian red scorpion Buthus tamulus venom in vivo and in vitro.

The Indian red scorpion Buthus tamulus (or Mesobuthus tamulus) can cause fatal envenoming, but its mechanism of action is unclear. Venom was tested in vivo in anaesthetized rats and in vitro on isolated cardiac and skeletal muscle preparations. In vivo, the venom caused marked rhythmical fluctuations in blood pressure preceding cardiovascular collapse and death. On sheep Purkinje fibres, venom could induce spontaneous action potentials and cause prolongation of action potential duration. In chick biventer cervicis and mouse triangularis sterni preparations, venom enhanced the release of acetylcholine and induced repetitive firing of nerve action potentials in response to single shock stimulation. High concentrations caused stimulation then block of neuromuscular transmission. The main effects of Buthus tamulus venom are likely to be due to toxins that affect the opening of Na+ channels in nerves and muscles. This will cause an increase in the release of neurotransmitters in the peripheral nervous system, which may produce cardiovascular abnormalities and respiratory paralysis.

Action Potentials↗
PubMed1992

The calcium channel blocker LAS 30538, unlike nifedipine, verapamil, diltiazem or flunarizine, potently inhibits insulin secretion in-vivo in rats and dogs.

The effects of a novel calcium channel blocker, LAS 30538 (1-[2-(2,6-dimethylphenoxy)ethyl]-alpha,alpha-bis-(p-fluorophenyl)-4- piperidine methanol), were studied on glucose tolerance and insulin secretion in rats and dogs in-vitro and in-vivo. Some comparisons were made with nifedipine, verapamil, diltiazem, flunarizine, diazoxide, cromakalim and minoxidil. LAS 30538, like a number of calcium channel blockers, was found to inhibit insulin secretion in-vitro, but was 1000-fold more potent than verapamil or diltiazem in this respect. LAS 30538 differed from the other calcium channel blockers studied in that it also potently inhibited insulin secretion and impaired glucose tolerance in-vivo. The evidence that LAS 30538 is more potent than diazoxide as a hyperglycaemic agent in-vivo suggests that this could be a useful drug for the treatment of hyperinsulinaemia in man.

Administration, Oral↗
PubMed1991

Endotoxin-induced impairment of vasodepressor responses in the pithed rat.

The effects of Eschericia coli endotoxin on vascular responsiveness were compared with those of sodium nitroprusside in pithed rats. Infusion of endotoxin (250 micrograms kg-1 h-1) produced a fall in mean arterial blood pressure (11 mmHg) and impaired vasodepressor responses to endothelin, 5-hydroxytryptamine, acetylcholine, bradykinin, sodium nitroprusside and salbutamol. Prevention of endotoxin-induced hypotension with vasopressin infusion (0.64 i.u. kg-1 h-1 i.v.) restored responsiveness to bradykinin, tended to restore responsiveness to endothelin and sodium nitroprusside but failed to restore responsiveness to acetylcholine, 5-HT or salbutamol. Infusion of sodium nitroprusside at a rate (400 micrograms kg-1 h-1) producing a similar fall in blood pressure to that produced by endotoxin markedly impaired vasodepressor responsiveness to 5-HT. However, this was fully restored when the hypotension was prevented by vasopressin infusion. Vasodepressor responsiveness to either acetylcholine or salbutamol was not impaired by sodium nitroprusside in vasopressin-infused rats. The impairment of vasodepressor responsiveness by endotoxin is not due to endotoxin-induced hypotension and does not fit clearly with an endotoxin-mediated impairment of endothelial function.

Acetylcholine↗
PubMed1991

Endotoxin impairs the response of rat anococcygeus muscle to electrical field stimulation.

Rat anococcygeus muscles were isolated 4 h after treatment with either E. coli endotoxin (20 mg kg-1 i.p.) or saline. The contractile responses of the muscle to electrical field stimulation, and to the alpha 1-adrenoceptor agonist cirazoline were impaired by endotoxin treatment. Inhibition of the L-arginine pathway with L-NG-nitro arginine methylester (3 x 10(-5) M) failed to restore responsiveness to either electrical field stimulation or to cirazoline. Endotoxin impaired inhibitory responses to electrical field stimulation in preparations precontracted with cirazoline. Responsiveness to sodium nitroprusside was also impaired by endotoxin under these conditions. These results show an impairment by endotoxin of both contractile and inhibitory responses of the rat anococcygeus muscle to electrical field stimulation. The impairment appears to be post-junctional. In contrast to the findings in vascular smooth muscle, the endotoxin-induced impairment of contractile responses does not appear to involve the L-arginine pathway.

Adrenergic alpha-Agonists↗
PubMed1990

Chronic chloroquine treatment enhances insulin release in rats.

The effects of chronic chloroquine treatment on intravenous glucose tolerance, and the plasma insulin response to intravenous glucose were studied in rats. Plasma glucose disappearance constants (Kg) were significantly greater (6.2 +/- 0.5% min-1) than in corresponding controls (3.7 +/- 0.4% min-1, p less than 0.001). This improved glucose tolerance was associated with significantly higher plasma immunoreactive insulin levels in response to glucose injection. Islets isolated from rats treated with chloroquine showed significantly enhanced (P less than 0.05) insulin release when incubated with 16.7 mM glucose but not with lower glucose concentrations (3 and 8 mM). Pre-incubation of islets with streptozotocin (0.05-1.5 mg/ml) produced a dose-dependent reduction in glucose-stimulated insulin secretion which was not modified in islets from chloroquine-treated rats. The concentration of chloroquine in the pancreas increased rapidly during administration and reached a value of 20.2 +/- 0.7 micrograms/g (fresh weight) after 20 weeks of treatment. It is concluded that chronic chloroquine treatment results in an improved glucose tolerance associated with an enhanced glucose-induced insulin secretion. Although earlier work showed chloroquine to reduce the severity of diabetes induced subsequently with streptozotocin, the present study shows that such an amelioration was not due to a protective effect against the beta-cell cytotoxic action of streptozotocin.

Animals↗
PubMed1990

Investigation of the selectivity of alpha, beta-methylene ATP in inhibiting vascular responses of the rat in vivo and in vitro.

1. The proposal that alpha,beta-methylene adenosine 5'-triphosphate (mATP) inhibits pressor responses in the pithed rat by selective desensitization of P2x-purinoceptors was examined by comparing the selectivity of its inhibitory effect on vascular responses in vitro and in vivo. 2. In isolated ring preparations of rat femoral and tail artery, which had been denuded of endothelium, mATP markedly reduced the contractile response to exogenous ATP but had no effect on the response of the arteries to exogenous noradrenaline (NA). 3. In the pithed rat a substantial proportion of the pressor response to sympathetic nerve stimulation was resistant to alpha-adrenoceptor blockade, suggesting a non-adrenergic component to the sympathetic vasoconstriction. 4. In the pithed rat, repeated administration of desensitizing doses of mATP attenuated the pressor response to sympathetic nerve stimulation by approximately 80%, suggesting that a component of the sympathetic vasoconstriction is mediated by ATP acting on vascular P2x-purinoceptors. However, the same mATP treatment also attenuated, to a similar degree, the pressor responses to intravenous NA, angiotensin II and vasopressin, indicating that the desensitization procedure was non-selective. 5. These results demonstrate that while mATP can be used to desensitize selectively P2x-purinoceptors in vitro, its attenuation of the sympathetic nerve-mediated pressor response in vivo is non-selective.

Adenosine Triphosphate↗
PubMed1990

Endotoxin-induced impairment of vasopressor and vasodepressor responses in the pithed rat.

1. Effects of E. coli endotoxin on vascular responsiveness to a variety of agents were compared with those of the calcium channel blocking drug nicardipine in pithed rats. 2. Infusion of endotoxin (250 micrograms kg-1 h-1) produced a fall in mean arterial blood pressure (8 mmHg). A similar fall (11 mmHg) was seen in rats receiving nicardipine (1.0 mg kg-1). 3. Endotoxin impaired responsiveness to vasopressin, phenylephrine and cirazoline, producing a shift to the right in the dose-response curves without any change in the maximum response. Responsiveness to 5-hydroxytryptamine (5-HT) and to the alpha 2-adrenoceptor agonists clonidine and BHT 933, was also impaired with a marked reduction in their maximum responses. The dose-response curve to the pressor effects of endothelin was not significantly modified. 4. Nicardipine produced a similar pattern of impairment of responsiveness to these agents to that produced by endotoxin. However, nicardipine also shifted the pressor dose-response curve to endothelin to the right with no significant alteration in its maximum response. 5. The pressor responses to endothelin and to 5-HT were, respectively, preceded and followed by dose-dependent depressor responses, which were markedly reduced by endotoxin and nicardipine. 6. The concomitant infusion of arginine vasopressin (0.64 iu kg-1 h-1) prevented endotoxin-induced hypotension and also prevented the impairment in responsiveness to cirazoline and to BHT 933. 7. The similarity of the pattern of impaired pressor responsiveness (except in relation to endothelin) and depressor responsiveness produced by endotoxin and nicardipine may be consistent with a common mechanism of action.

Animals↗
PubMed1990

Endotoxin-induced impairment of vascular reactivity in the pithed rat: role of arachidonic acid metabolites.

The effect of endotoxin on vascular reactivity was studied in pithed rats. Endotoxin infusion (1 mg kg-1 h-1) impaired pressor responses to noradrenaline, angiotensin II, BAY K 8644, and stimulation of the spinal sympathetic outflow. The loss of reactivity was prevented by pretreatment with the cyclooxygenase inhibitor flurbiprofen or the dual cyclooxygenase/lipoxygenase inhibitor BW755C. The effect of endotoxin in impairing vascular reactivity to noradrenaline was mimicked by prostaglandin E2 and platelet-activating factor but not by the prostacyclin analogue iloprost. Platelet-activating factor also impaired responsiveness to sympathetic stimulation. These results suggest a role for cyclooxygenase products and, possibly, platelet-activating factor in endotoxin-induced impairment of vascular reactivity.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Effect of hyperreactivity to endotoxin on the toxicity of pertussis vaccine and pertussis toxin in mice.

In mice, greatly enhanced susceptibility to the lethal toxicity of whole-cell pertussis vaccine (PV) was produced by agents known to induce hypersusceptibility to endotoxin (LPS). The decreases in LD50 were 100-fold, 125-fold and 16-fold with galactosamine (GalN), actinomycin D (AcD) and lead acetate (PbAc) respectively and the animals died within 1-2 days. However, these decreases were less than those observed with extracted E. coli LPS, the LD50 of which was reduced approximately 500-fold, 800-fold and 50-fold respectively by these agents. In control mice, without drugs, the main lethal factor in the PV used here seemed to be pertussis toxin (PT), since deaths occurred at 3-5 days after injection, and heating the vaccine at 80 degrees C for 30 min raised the LD50 from 4 to greater than 6 single human doses (SHD) per mouse. In GalN and PbAc-treated mice, the toxicity of PV can be explained by its LPS content in view of the failure of heating at 80 degrees C to reduce toxicity. However, in AcD-treated mice, the 80 degrees C heated vaccine was threefold less toxic than the unheated material, suggesting a contribution of PT to vaccine toxicity in these animals. Indeed the toxicity of PT was increased by AcD. The possible bearing of these observations on children who appear to show serious adverse reactions to PV is discussed. Two acellular vaccines were devoid of lethal toxicity in either normal mice or in mice treated with any of the three drugs.

Animals↗
PubMed1989

Attenuation of streptozotocin-induced diabetes in rats by pretreatment with chloroquine.

1. The effect of chronic administration of chloroquine on glucose homoeostasis was investigated in normal and diabetic rats by determining fasting plasma glucose, glycated plasma protein, plasma immunoreactive insulin, plasma protein and glycated haemoglobin. Animal weights, as well as the survival of the diabetic animals without insulin therapy, were also observed. 2. Apart from an elevation in the plasma immunoreactive insulin levels (4.1 +/- 0.6 vs 2.1 +/- 0.4 micrograms/l, P less than 0.025), there were no significant differences among the other parameters compared with age-matched controls up to week 12 for the normal rats on chloroquine treatment. After 20 weeks of treatment, however, plasma glucose (7.2 +/- 0.1 vs 8.4 +/- 0.2 mmol/l, P less than 0.005) and glycated haemoglobin (2.9 +/- 0.1 vs 3.3 +/- 0.1%, P less than 0.01) levels were lower in the treated animals. Diabetic rats treated with chloroquine for 12 weeks before the onset of diabetes showed significantly higher plasma insulin and protein levels than control diabetic animals, while plasma glucose (17.7 +/- 2.5 vs 29.4 +/- 1.7 mmol/l, P less than 0.005), glycated plasma protein and glycated haemoglobin (6.6 +/- 0.4 vs 7.8 +/- 0.4%, P less than 0.05) levels were lower. 3. It is concluded that after a prolonged administration of chloroquine there is a hypoglycaemic effect in normal animals, and pretreatment with the drug ameliorates diabetes induced subsequently.

Animals↗
PubMed1988

Slight hyperinsulinaemia but no hypoglycaemia in pertussis patients.

Because of the central rôle postulated for Pertussis Toxin in the pathogenesis of whooping cough, and the well-established ability of this toxin to alter insulin and glucose levels in animal blood, a study of insulin and glucose levels in hospitalised pertussis patients and in controls was made. With blood specimens collected in heparin-fluoride anticoagulant, the geometric mean plasma-insulin level (13.3 microU/ml) in a series of 24 pertussis patients was slightly, but statistically significantly, higher than that (8.9 microU/ml) in a series of 27 non-pertussis controls with other infectious diseases (p less than 0.02). Portions of the same blood specimens collected in lithium-heparin anticoagulant yielded higher mean plasma-insulin values of 15.5 and 11.4 microU/ml respectively, with no significant difference between them (p less than 0.05). Mean plasma glucose concentrations were not significantly different between the two groups, and hypoglycaemia was not detected in any pertussis patient. There were no statistically significant differences between pertussis and control children in the mean levels of plasma calcium, magnesium or phosphate.

Blood Glucose↗
PubMed1988

Inhibition of glucose-induced insulin secretion by calcium channel blocking drugs in-vitro but not in-vivo in the rat.

The organic calcium channel blocking drugs darodipine, nicardipine, diltiazem and verapamil inhibited glucose-induced (8.3 mmol L-1) insulin secretion by rat isolated islets in a concentration-dependent manner. The IC50 values (mumol L-1) for nicardipine, diltiazem and verapamil were 0.0025, 1.94 and 3.6, respectively. There were no significant differences between the potencies of any one drug when compared at two different glucose concentrations (27.8 and 8.3 mmol L-1). Isolated islets were also responsive to the calcium channel activating drugs BAY K 8644 and CGP 28392, which enhanced glucose-induced insulin secretion and prevented the inhibitory effect of verapamil. BAY K 8644 was more potent than CGP 28392. In the anaesthetized rat, neither verapamil (1 mg kg-1 i.v. 10 min before glucose) nor nicardipine (0.2 mg kg-1 i.v.) modified the glucose or insulin response to intravenous glucose whilst producing marked cardiovascular effects. The plasma concentrations of nicardipine (3.9 X 10(-8) M at 10 min post injection) were similar to those producing effects in-vitro whereas the plasma concentrations of verapamil (5 X 10(-7) M) were lower. It thus appears that the islet B cell calcium channel is less sensitive to calcium channel blocking drugs in-vivo than in-vitro. Moreover, in-vivo, the cardiovascular system is more sensitive to these drugs than are the islet B cells, although the potencies of the calcium channel blocking drug in isolated islets are similar to those reported for cardiac muscle and vascular smooth muscle in-vitro.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗