Biomedical subjects

B L Furman

Publications and source records attributed to B L Furman.

At least 19 recordsLinked to original sources

PubMed2005

The effect of NCX4016 [2-acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl ester] on the consequences of ischemia and reperfusion in the streptozotocin diabetic rat.

The aim of this study was to assess the effect of chronic administration of NCX4016 [2 acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl ester], a nitric oxide-releasing aspirin derivative on the consequences of coronary artery occlusion in streptozotocin-diabetic rats. Rats were made diabetic by injection of streptozotocin (60 mg kg(-1)) and received insulin (2.5 U kg(-1) s.c.) daily for 4 weeks. Animals received vehicle (1 ml kg(-1) polyethylene glycol), aspirin (65.2 mg kg(-1)), NCX4016 (60 mg kg(-1)), or (iv) NCX4016 (120 mg kg(-1)) orally, once daily for the last 5 days before coronary artery occlusion (CAO). One hour after the last dose, pentobarbital-anesthetized rats were subjected to CAO for 30 min followed by 120-min reperfusion. Neither drug significantly modified initial hemodynamics or plasma glucose levels compared with vehicle treatment in either nondiabetic or diabetic rats. Neither drug modified the total ventricular premature beat (VPB) count in normal animals, although NCX4016, but not aspirin, reduced the total VPB count and the incidence of ventricular tachycardia in diabetic rats. In nondiabetic animals, both aspirin and NCX4016 reduced infarct size. However, in diabetic rats, infarct size was reduced only by the larger dose of NCX4016 (120 mg kg(-1)) but not by aspirin or the lower dose of NCX4016. These results demonstrate that the cardioprotective effects of NCX4016 are reduced in the presence of diabetes compared with the effects seen in nondiabetic animals. In summary, the present study confirms the protective effect of NCX4016 against ischemia-reperfusion injury in the normal rat heart and demonstrates for the first time its protective effect in the heart of streptozotocin-diabetic rats.

Animals↗

PubMed2003

Cyclic nucleotide phosphodiesterases in pancreatic islets.

Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5' derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2000

The effects of lignocaine on actions of the venom from the yellow scorpion "Leiurus quinquestriatus" in vivo and in vitro.

Many toxins from scorpion venoms activate sodium channels, thereby enhancing neurotransmitter release. The aim of the present work was to determine if the in vivo and in vitro effects of Leiurus quinquestriatus venom (LQQ) could be ameliorated by lignocaine, a sodium channel blocker. In urethane anaesthetised rabbits, LQQ venom (0.5 mg kg(-1), i.v.) caused initial hypotension and bradycardia followed by hypertension, pulmonary oedema, electrocardiographic changes indicating conduction defects, ischaemia, infarction, and then hypotension and death. Lignocaine (1 mg kg(-1) i.v. bolus initially, followed by i.v. infusion of 50 microg kg(-1) min(-1)) significantly attenuated the majority of the venom-evoked effects and reduced mortality. Addition of LQQ venom (1, 3 and 10 microg ml(-1)) to chick biventer cervicis, guinea pig ileum, and rat vas deferens preparations, increased the height of electrically-induced twitches, elevated resting tension, and caused autorhythmic oscillations. Lignocaine (3 x 10(-4)-1.2 x 10(-3) M) greatly attenuated these venom-evoked actions in the three preparations. Antagonists of appropriate neurotransmitters were also tested to determine the contribution of released transmitters to LQQ effects. Atropine significantly decreased the venom-elicited effects on guinea pig ileum preparations, while prazosin and guanethidine significantly reduced the venom's actions on rat vas deferens. In chick biventer cervicis preparations, tubocurarine and hexamethonium significantly attenuated the venom-induced effects. This study supports the hypothesis that many effects of LQQ venom involve the release of neurotransmitters and may be ameliorated by treatment with lignocaine.

Animals↗

PubMed2000

The role of the cyclic GMP-inhibited cyclic AMP-specific phosphodiesterase (PDE3) in regulating clonal BRIN-BD11 insulin secreting cell survival.

We report here that the cyclic GMP-inhibited cyclic AMP specific phosphodiesterase (PDE3B) is expressed as a membrane-bound protein in clonal insulin-secreting BRIN-BD11 cells. This was shown using SKF94836 (PDE3 inhibitor) which maximally inhibited membrane-bound cyclic AMP PDE activity by approximately 25-30% and by RT-PCR. We also demonstrated that insulin growth factor-1 (IGF-1) activates PDE3B in BRIN-BD11 cells. We therefore evaluated the role of phosphoinositide 3-kinase (PI3K) and p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) pathways in regulating this enzyme. We report here that the PI3K inhibitor, wortmannin, prevented the IGF-1-dependent stimulation of PDE3B activity. In contrast, the inhibitor of MEK-1 activation, PD098059 (which reduced IGF-1-stimulated p42/p44 MAPK phosphorylation), had no effect on PDE3B activation. Furthermore, IGF-1-dependent stimulation of p42/p44 MAPK and PDE3B was abolished in serum-deprived cells and this was associated with apoptosis. We propose that the deregulation of the PI3K/PDE3B pathway might result in increased intracellular cyclic AMP accumulation, which promotes apoptosis. This was supported by the finding that the adenylyl cyclase activator, forskolin, also induced apoptosis. Finally, we found that orthovanadate (a phosphotyrosine phosphatase inhibitor) fully restored the activation of p42/p44 MAPK in serum-deprived cells, but had only a small effect on PDE activity. This confirmed that p42/p44 MAPK is on a separate pathway to PDE3B. Therefore, IGF-1-dependent regulation of PDE3B may be linked to cell survival through PI3K and not p42/p44 MAPK.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2000

Effect of type-selective inhibitors on cyclic nucleotide phosphodiesterase activity and insulin secretion in the clonal insulin secreting cell line BRIN-BD11.

1. The cyclic nucleotide phosphodiesterases (PDEs) present in an insulin secreting cell line, BRIN - BD11, were characterized using calcium/calmodulin, IGF-1, isoenzyme-selective PDE inhibitors and RT - PCR. 2. Calmodulin activated cyclic AMP or cyclic GMP PDE activity in pellet and was 3 fold (P=0.002) more potent in activating cyclic nucleotide hydrolysis in pellet compared with supernatant fractions. 3. The PDE1/PDE5 inhibitor zaprinast inhibited both cyclic AMP and cyclic GMP PDE activity in both pellet and supernatant fractions of cell homogenates by a maximum of around 25% (IC(50) 1 - 5 microM), while rolipram (PDE4 selective) inhibited only cyclic AMP hydrolysis. 4. The PDE3-selective inhibitors Org 9935 (0.02 - 10 microM) and siguazodan (0.1 - 10 microM) inhibited cyclic AMP PDE activity in the pellet but not the supernatant fractions of cell homogenates, with a maximum inhibition of about 30%. IGF-1 (2 - 7.5 ng ml(-1)) potently augmented this PDE activity. 5. RT - PCR using specific primers for PDE3B, but not for PDE3A, amplified, from BRIN - BD11 cell total RNA, a 351 base pair product that was >97% homologous with rat adipose tissue PDE3B. 6. IBMX, Org 9935, siguazodan and rolipram (1 - 50 microM), but not zaprinast, each augmented glucose-induced insulin secretion in the presence of 16.7 mM but not 1 mM glucose. 7. These findings, in a clonal insulin secreting cell line, are consistent with an important role for PDE3B in regulating the pool of cyclic AMP relevant to the modulation of glucose-induced insulin secretion.

1-Methyl-3-isobutylxanthine↗

PubMed1999

The in vivo interaction between gliclazide and glibenclamide and insulin on glucose disposal in the rat.

Many reports suggest that extrapancreatic actions contribute to the antidiabetic effect of sulphonylurea drugs (SUs). In this work, the ability of two SUs, namely, gliclazide and glibenclamide, to augment insulin action was studied in vivo. Both drugs elevated the plasma concentration of immunoreactive insulin (IRI) and lowered the plasma concentrations of glucose and non-esterified fatty acids (NEFA) in normal intact rats. These changes were not reproduced in alloxan-diabetic or eviscerated rats. The actions of insulin on plasma glucose and NEFA were not augmented by gliclazide in alloxan-diabetic rats. Neither gliclazide nor glibenclamide (given acutely and for 30 days) augmented the actions of exogenously administered insulin in reducing plasma glucose or NEFA concentrations in intact or eviscerated animals. It was concluded that these SUs do not produce their acute or chronic effects on blood glucose by augmenting the actions of insulin.

Animals↗

PubMed1999

Novel weight-reducing activity of Galega officinalis in mice.

Galega officinalis (galega, Goat's Rue, French Lilac) is well known for its hypoglycaemic action and has been used as part of a plant mixture in the treatment of diabetes mellitus. During pharmacological investigations of an ethanolic extract of a powdered mixture of equal proportions of G. officinalis, Cressa cretica, Mangifera indica and Syzygium jambolanum, a weight reducing effect of galega was discovered. In this study we have investigated the novel weight reducing effect of galega in mice. Galega herb (10% w/w in the diet) caused a significant reduction in body weight in both normal and genetically obese (ob/ob) animals treated for 28 days when compared with respective controls (P < 0.01). In normal mice, the weight loss was reversible and initially associated with a transient reduction in food intake but was then maintained even in the presence of increased eating above the control level. Pair-fed normal mice receiving galega for seven days also showed significant weight loss (P < 0.01, compared with the control) in the presence of increasing food intake. In sharp contrast, weight loss in galega-treated ob/ob mice was accompanied by a persistent reduction in food intake over the 28-day treatment period. Post-mortem examinations of all galega-treated mice revealed a striking absence of body fat. Serum glucose was significantly reduced in both strains of mice receiving galega for 28 days (P < 0.01), whereas serum insulin was significantly reduced only in obese mice (P < 0.01). In summary, together with its established hypoglycaemic effects, galega has a novel weight reducing action that, in normal mice, is largely independent of a reduction in food intake. The mechanism of the weight reducing action of galega is unclear but involves loss of body fat.

Animals↗

PubMed1998

Monophosphoryl lipid A reduces both arrhythmia severity and infarct size in a rat model of ischaemia.

A non-toxic derivative of the active lipid A component of the endotoxin molecule (monophosphoryl lipid A) when given to rats in a dose of 5 mg kg(-1) by intraperitoneal injection 24 h prior to anaesthesia and coronary artery occlusion, markedly decreased the severity of ischaemia-reduced ventricular arrhythmias (ventricular fibrillation reduced from 60 to 21%; P < 0.05) and reduced myocardial infarct size (from 35.8 +/- 1.6% of the area at risk to 22.7 +/- 2.0%; P < 0.05). It did not modify blood pressure or heart rate either before or during the period of ischaemia.

Adjuvants, Immunologic↗

PubMed1998

Coronary endothelial dysfunction increases the severity of ischaemia-induced ventricular arrhythmias in rat isolated perfused hearts.

In order to determine the role of coronary vascular endothelial cells in generating cardioprotective substances during myocardial ischaemia, rat isolated hearts, perfused at constant flow by the Langendorff technique, were subjected to treatment with the detergent Triton X100 and the responses of these hearts to a 30 or 60 min period of coronary artery occlusion was determined. Endothelial damage or denudation was shown both by histological examination and by the altered vasodilator response to the endothelium-dependent vasodilator bradykinin (100 nM), which was reversed to vasoconstriction in hearts treated with Triton X-100. In contrast, the responses to sodium nitroprusside (100 microM) were unimpaired in these hearts and were not different from control responses. Ventricular ectopic activity was much more pronounced in hearts with endothelial dysfunction (e.g., 3329 +/- 361 ventricular premature beats over a 30 min occlusion period compared to 243 +/- 34 in controls; P < 0.01), and the duration of ventricular tachycardia was greatly increased (1162 +/- 391 s v 9 +/- 12 s in the controls; P < 0.01). Ventricular ectopic activity was still marked when the occlusion was prolonged to 1 h and was still apparent at the end of this 1 h occlusion period. Reperfusion arrhythmias (ventricular tachycardia and ventricular fibrillation) were marked in endothelium-damaged hearts (50%); whereas there were no such arrhythmias after a 30 or 60 min occlusion period in control hearts. Hearts were also preconditioned by a 3 min coronary artery occlusion period 10 min prior to a 30 min coronary artery occlusion. This reduced ventricular ectopic activity in both control and endothelium-damaged hearts to about the same extent (between 80 and 90% suppression). The results suggest that under normal conditions substances generated from endothelial cells protect the myocardium against ventricular arrhythmias both during ischaemia and reperfusion. However, in this species, preconditioning is still possible in hearts from which the coronary vascular endothelium has been removed. If these results can be extrapolated to the clinical situation, it suggests that in patients with endothelial dysfunction ventricular arrhythmias may be more pronounced following a period of ischaemia and especially of reperfusion.

Animals↗

PubMed1998

The involvement of plasma kinins in the cardiovascular effects of Leiurus quinquestriatus scorpion venom in anaesthetised rabbits.

The present study was undertaken to investigate the involvement of kinins in the cardiovascular- and respiratory effects of LQQ venom. Blood pressure, heart rate, electrocardiogram (ECG) and respiration were studied in anaesthetised rabbits, in the presence and absence of aprotinin and icatibant, a B2 bradykinin antagonist. Plasma bradykinin concentrations were also measured following venom injection. LQQ venom caused a triphasic effect on blood pressure comprising an immediate fall, a pronounced rise and a progressive decline until death. Bradycardia, myocardial damage, arrhythmias, respiratory distress and pulmonary oedema were also exhibited. Pretreatment with aprotinin attenuated the venom-induced hypotension, bradycardia, ECG and respiratory changes and prolonged survival. Pretreatment of atropinized animals with icatibant gave similar protection. In animals treated with LQQ venom, plasma bradykinin was significantly higher than controls, although there was considerable inter-animal variation in plasma kinin concentrations and the elevation was seen relatively late after venom administration. The data provides some support for the hypothesis that kinins are involved in the cardiovascular and lethal effects of LQQ venom in rabbits.

Adrenergic beta-Antagonists↗

PubMed1997

The effect of selective phosphodiesterase inhibitors on plasma insulin concentrations and insulin secretion in vitro in the rat.

We have examined in rats the effects of Org 9935 (4,5-dihydro-6-(5,6-dimethoxy-benzo[b]-thien-2-yl)-methyl-1-(2H)-p yridazinone), a selective inhibitor of type 3 phosphodiesterase (phosphodiesterase 3) and Org 30029 (N-hydroxy-5,6-dimethoxy-benzo[b]-thiophene-2-carboximidamide HCl), an inhibitor of phosphodiesterase 3/4 on rat plasma insulin and glucose concentrations in pentobarbitone-anaesthetised rats and on insulin secretion by rat isolated islets. We have also compared their effects on islet phosphodiesterase activity. Org 9935 (0.1 and 1.0 mg kg(-1) i.v. 15 min previously) dose dependently elevated fasting and post-glucose (0.25 g kg(-1) i.v.) plasma insulin concentrations. Org 30029 in a dose of 10 mg kg(-1), but not 1 mg kg(-1), also increased plasma insulin concentrations. Neither drug modified either fasting or post-glucose plasma glucose concentrations. Each drug augmented glucose-induced insulin release by rat isolated islets in a static incubation system, with approximate EC50 values of 1.5 microM for Org 9935 and 20 microM for Org 30029. Phosphodiesterase activity, in both supernatant and pellet fractions of islet homogenates, was inhibited concentration dependently by each drug. Although the shape of the concentration-inhibition curve for Org 30029 precluded estimation of an IC50 value, this drug was clearly much less potent than Org 9935 (IC50 about 50 nM) in inhibiting islet phosphodiesterase activity. We conclude that the increase in plasma insulin produced by each drug is a consequence of augmented insulin secretion, probably secondary to inhibition of phosphodiesterase 3 in the islet beta cell, with a resultant elevation in cAMP. The failure of the drugs to modify plasma glucose may be due to concomitant inhibition of cAMP phosphodiesterase in liver and adipose tissue.

Animals↗

PubMed1996

Endotoxin-induced inhibition of mesenteric vasodilator responses to acetylcholine, bradykinin, and post-occlusion hyperemia in anesthetized rats.

The effects of endotoxin (20 mg kg-1 i.p.) on the mesenteric vascular responses to acetylcholine, bradykinin, sodium nitroprusside, and to transient occlusion of the superior mesenteric artery were examined in rats anesthetized with pentobarbitone. Mesenteric vasodilator responses to close arterial injections of acetylcholine and bradykinin were reduced at 1.5 h after endotoxin and almost abolished by 4 h; responses to sodium nitroprusside were unaffected. Occlusion of the superior mesenteric artery for 30, 60, or 120 s produced, on release of the occlusion, a time-dependent vasodilator response in the mesenteric circulation (post-occlusion hyperemia). This hyperemia was markedly reduced by nitro-L-arginine methyl ester (L-NAME); L-NAME did not modify acetylcholine-induced vasodilation. Endotoxin-pretreatment did not modify mesenteric post-occlusion hyperemia 1.5 h after administration but markedly reduced the response by 2.5 h. The administration of L-NAME to endotoxin-treated rats did not further attenuate the hyperemic responses. Mesenteric vasoconstrictor responses to phenylephrine were not modified by endotoxin, although systemic pressor responses to this agent were impaired. We concluded that endotoxin impairs endothelium and nitric oxide-dependent vasodilator responses in the mesenteric circulation.

Acetylcholine↗

PubMed1996

Influence of indomethacin on the haemodynamic effects of lipopolysaccharide in rats.

This study was undertaken to evaluate the influence of the cyclooxygenase inhibitor indomethacin on the time course of the haemodynamic effects of lipopolysaccharide (LPS) intravenous infusion (10 mg.kg-1.h-1) in anaesthetized rats. LPS infusion produced a rapid (within 10 min) and prolonged (over the 90 min observation period) fall in mean arterial blood pressure (MABP) and a decrease in the pressor responses to noradrenaline (NA, 0.1, 0.3 and 1 microgram.kg-1, intravenously [i.v.]) elicited 60 and 90 min after the onset of LPS infusion. Indomethacin (7 mg.kg-1 i.v. 30 min prior to the onset of saline or LPS infusion), which by itself did not affect basal MABP nor reactivity to NA in control rats, significantly attenuated the fall in MABP observed within 20 min after the onset of LPS infusion (but did not significantly modify the hypotension observed between 30 and 90 min). Indomethacin also completely prevented the hyporeactivity to NA observed 60 min after the onset of LPS infusion, but it did so only partially at 90 min. Aortic rings removed from LPS or LPS + indomethacin-treated rats showed an identical profile of contractile reactivity (hyporesponsiveness to NA, relaxation to L-arginine, and restoration of the contractile response by methylene blue). These results suggest that in this model, cyclooxygenase products are involved in the early haemodynamic effects of LPS. However, they do not seem to play an obligatory role in the onset of longer term haemodynamic changes.

Analysis of Variance↗

PubMed1996

Delayed protection against ischaemia-induced ventricular arrhythmias and infarct size limitation by the prior administration of Escherichia coli endotoxin.

1. Bacterial endotoxin (lipopolysaccharide derived from Escherichia coli) was injected intraperitoneally in conscious rats in doses ranging from 0.5 to 2.5 mg kg-1. At various times afterwards the animals were anaesthetized and subjected to a 30 min period of left coronary artery occlusion. 2. Under these conditions the severity of ventricular arrhythmias was markedly suppressed, in comparison with saline-injected controls, but this was particularly marked with the higher doses (1.5 and 2.5 mg kg-1); the number of ventricular premature beats was reduced from 1687 +/- 227 over the 0.5 h coronary artery occlusion period to 190 +/- 46 in those rats administered 2.5 mg kg-1 endotoxin 8 h previously (P < 0.05). The duration of ventricular tachycardia was also significantly reduced (138 +/- 26 s to 8.9 +/- 4.2 s; P < 0.01) and there was a reduction in the incidence of ventricular fibrillation (from 56% to 10%). 3. The time course of this protection was studied following the administration of a single dose of 2.5 mg kg-1 of endotoxin by anaesthetizing rats 4, 8 or 24 h later. Protection was apparent at each time but was particularly marked at 8 h. 4. No rat given the highest dose of endotoxin (32 in all) died as a result of ventricular fibrillation, or from any other cause, during an occlusion, in contrast to a 26% mortality in the controls (P < 0.01). 5. Infarct size, measured following a 30 min period of coronary artery occlusion followed by a 3 h reperfusion period, was reduced both 8 and 24 h after the administration of 2.5 mg kg-1 endotoxin (reductions of 24.3 and 23.1% respectively; P < 0.05). Endotoxin had no significant effect on the area at risk. 6. The beneficial effects of endotoxin on infarct size and on ventricular arrhythmias were markedly attenuated by the prior administration of dexamethasone, 3 mg kg-1 given 1 h prior to endotoxin administration. Dexamethasone itself reduced infarct size (P < 0.05) but had no direct effect on arrhythmia severity following coronary artery occlusion. 7. The mechanisms of this "cross-tolerance' induced by bacterial endotoxin against ischaemia-reperfusion injury remain to be elucidated but the most likely mechanisms appear to be the induction of protective enzymes or proteins (e.g. nitric oxide synthase, cyclo-oxygenase (COX) 2) probably mediated by cytokine release.

Animals↗

PubMed1996

Effects of L-canavanine, an inhibitor of inducible nitric oxide synthase, on endotoxin mediated shock in rats.

The effects of L-canavanine, an inhibitor of nitric oxide synthase, on endotoxin-induced shock was investigated in the pentobarbitone anesthetized rat. Endotoxin infusion (2.5 mg kg-1 h-1 over 6 h) produced progressive and marked hypotension and hypoglycemia. Electron microscopy showed marked changes in the kidney, comprising severe endothelial cell disruption and the accumulation of platelets in the blood vessels. In the lung, there was marked accumulation of polymorphonuclear leukocytes in small blood vessels and endothelial disruption. Treatment with L-canavanine (10 mg kg-1 by bolus injection each hour starting 70 min after endotoxin or saline infusion) significantly reduced endotoxin-induced hypotension, without any effect on the hypoglycemia. This treatment markedly reduced the endotoxin-induced electron microscopical changes in the kidneys and lungs. Although L-canavanine, like L-NAME, inhibited both cerebellar constitute and splenic inducible nitric oxide synthase in vitro, in contrast to L-NAME it did not modify either arterial blood pressure or carotid artery blood flow in control rats. The data are consistent with L-canavanine being a selective inhibitor of inducible nitric oxide synthase, at least in vivo, and suggest that inhibitors of this enzyme may be beneficial in endotoxin-induced shock.

Animals↗

PubMed1995

The effect of endotoxin on sympathetic responses in the rat isolated perfused mesenteric bed; involvement of nitric oxide and cyclo-oxygenase products.

1. The effects of endotoxin on the vasoconstrictor responses to sympathetic nerve stimulation (SNS) were investigated in the rat isolated perfused mesenteric bed. 2. Rats received either saline (0.1 ml h-1) or endotoxin (2.5 mg kg-1 h-1) intravenously for 4 h; the mesenteric beds were then isolated, perfused with Krebs and prepared for SNS (50 V, 3 ms, 7-40 Hz). 3. SNS caused a frequency-dependent vasoconstrictor response which was abolished by either tetrodotoxin (10(-7) M), prazosin (2.4 x 10(-7) M) or guanethidine (2.4 x 10(-7) M). 4. In mesenteric vascular beds removed from rats infused with endotoxin, there were markedly impaired vasoconstrictor responses to SNS, although responses to noradrenaline were not modified. 5. Removal of the endothelium with distilled water prevented endotoxin-induced impairment of vasoconstrictor responses to SNS, without modifying these responses in preparations from control rats. 6. Pretreatment with dexamethasone (3 mg kg-1 i.p. 1h before commencing endotoxin or saline infusions) did not modify responses to SNS in control rats but prevented the effects of endotoxin. 7. Both L-NAME (10(-3) M) and indomethacin (10(-5) M) restored responses to SNS in preparations from endotoxin-treated rats without modifying these responses in control preparations. However, co-administration of L-NAME and indomethacin markedly augmented responses in both control and endotoxin-treated preparations. 8. The effects of L-NAME were reversed by addition of L-arginine (10(-3) M). 9. The data suggest that endotoxin impairs the release of noradrenaline and that this effect is secondary to increased production of nitric oxide and prostanoids, possibly by the endothelium.

Animals↗

PubMed1995

Effects of type-selective phosphodiesterase inhibitors on glucose-induced insulin secretion and islet phosphodiesterase activity.

1. We examined various type-selective phosphodiesterase (PDE) inhibitors on glucose-induced insulin secretion from rat isolated islets, on islet PDE activity and on islet cyclic AMP accumulation in order to assess the relationship between type-selective PDE inhibition and modification of insulin release. 2. The non-selective PDE inhibitor, 3-isobutyl-1-methylxanthine (IBMX, 10(-5)-10(-3) M), as well as the type III selective PDE inhibitors SK&F 94836 (10(-5)-10(-3) M), Org 9935 (10(-7)-10(-4) M), SK&F 94120 (10(-5)-10(-4) M) and ICI 118233 (10(-6)-10(-4) M) each caused concentration-dependent augmentation (up to 40% increase) of insulin release in the presence of a stimulatory glucose concentration (10 mM), but not in the presence of 3 mM glucose. 3. Neither the type IV PDE inhibitor rolipram (10(-4) M) nor the type I and type V PDE inhibitor, zaprinast (10(-4)-10(-3) M) modified glucose-induced insulin release when incubated with islets, although a higher concentration of rolipram (10(-3) M) inhibited secretion by 55%. However, when islets were preincubated with these drugs followed by incubation in their continued presence, zaprinast (10(-6)-10(-4) M) produced a concentration-dependent inhibition (up to 45% at 10(-4) M). Under these conditions, rolipram inhibited insulin secretion at a lower concentration (10(-4) M) than when simply incubated with islets. 4. A combination of SK&F 94836 (10(-5) M) and forskolin (5 x 10(-8) M) significantly augmented glucose-induced insulin secretion (30% increase), although neither drug alone, in these concentrations, produced any significant effect. 5. Islet cyclic AMP levels, which were not modified by forskolin (10-6 M), SK&F 94836 (10-4 M) or Org 9935 (10-5 M) were significantly elevated (approximately 3.7 fold increase) by forskolin inc ombination with either SK&F 94836 or Org 9935.6 Homogenates of rat islets showed a low Km (1.7 microM) and high Km (13 microM) cyclic AMP PDE in the supernatant fractions (from 48,000 g centrifugation), whereas the particulate fraction showed only a low Km (1.4 microM) cyclic AMP PDE activity.7. The PDE activity of both supernatant and pellet fractions were consistently inhibited by SK&F94836 or Org 9935, the concentrations required to reduce particulate PDE activity by 50% being 5.5 and 0.05 microM respectively.8 Rolipram (10-5 10-4 M) did not consistently inhibit PDE activity in homogenates of rat islets and zaprinast (10-4 M) consistently inhibited activity by 30% in the supernatant fraction, but not consistently in the pellet.9 These data are consistent with the presence of a type III PDE in rat islets of Langerhans.

1-Methyl-3-isobutylxanthine↗

PubMed1994

Acute stress-induced hyperinsulinemia in the pertussis toxin-treated rat: possible role of humoral beta-cell-tropic factors.

The present study was undertaken to determine if acute stress induced by exposure to ether resulted in the presence of beta-cell-tropic factors in rat plasma and if this insulinotropic activity was increased by pertussis toxin. Rats pretreated with pertussis toxin (5 micrograms/kg, 5 days previously) showed marked hyperinsulinemia, but only after exposure to ether before blood sampling. This hyperinsulinemia was not modified by adrenal demedullation. Effects on insulin secretion were assessed by incubation of plasma (diluted with Krebs buffer) with collagenase-isolated rat pancreatic islets. When blood was collected by decapitation from normal rats, the subsequently prepared plasma (12.5% to 50%) profoundly inhibited insulin release from rat isolated islets. This inhibition was probably mediated by catecholamines, since it was not seen with plasma from adrenal-demedullated rats and was prevented by alpha 2-adrenoceptor-blocking drugs. Plasma from adrenal-demedullated, pertussis toxin-treated rats stimulated insulin secretion (by 60%) when the donor rats had been exposed to ether before blood sampling. It is suggested that stress may result in the presence of circulating beta-cell-tropic factors, which may contribute to the acute stress-induced hyperinsulinemia seen in pertussis toxin-treated animals.

Acute Disease↗