Comparative effects of quinine and quinidine on glucose metabolism in healthy volunteers.

1. To investigate the relative effects of quinine and quinidine on glucose metabolism, 11 healthy males aged 17-32 years were given three separate 1 h intravenous infusions; normal saline alone, quinine dihydrochloride 10 mg base kg-1 body weight (BW) in normal saline, and quinidine dihydrochloride 10 mg base kg-1 BW in normal saline. A constant infusion of 5 mg glucose kg-1 ideal BW min-1 was given for 1 h before and during each study. 2. Assessment of pancreatic beta cell function and tissue insulin sensitivity from plasma glucose and insulin concentrations at the end of the first hour using the Continuous Infusion of Glucose with Model Assessment (CIGMA) technique confirmed normal glucose tolerance for each subject on each test day. 3. Plasma glucose concentrations at 1 h were similar to those at 2 h. There was no significant difference between the plasma glucose profiles during the three infusion regimes (P greater than 0.05). Plasma insulin rose significantly during the second hour (P less than 0.0001); increments after quinine (geometric mean [-1 s.d- +1 s.d.]; 47.0 [27.8-79.4] mu l-1) were significantly greater than those after quinidine (19.8 [6.1-65.2] mu l-1) and saline (7.5 [0-21.5] mu l-1; P less than 0.05). Plasma quinine concentrations at the end of the infusion (6.5 +/- 4.4 mg l-1) correlated with insulin increments during the second hour (r = 0.662, P = 0.028) and were significantly greater than those of quinidine (3.0 +/- 0.8 mg l-1; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of intra-arterial endothelin on resting blood flow and sympathetically mediated vasoconstriction in the forearm of man.

1. The hypothesis that endothelin (ET) influences sympathetically mediated vasoconstriction was investigated in 13 healthy, male subjects. 2. ET (1 pmol min-1) was infused for 60 min into the left brachial arteries of seven healthy male subjects. Resting forearm blood flow, and sympathetic vasoconstriction produced by lower body negative pressure (LBNP; 15 mm Hg), was measured in both arms by strain gauge plethysmography. In a further six subjects, noradrenaline (NA) was infused intra-arterially at doses of 150-600 pmol min-1, with and without co-infusion of ET (1 pmol min-1), with blood flow measured in both forearms. 3. ET produced a small but significant reduction of blood flow in the infused forearm from 3.9 +/- 0.6 ml 100 ml-1 min-1 during infusion of saline, to 3.3 +/- 0.7 ml 100 ml-1 min-1 during infusion of ET at 60 min (P less than 0.05). Blood flow in the non-infused forearm was not altered by ET infusion. 4. NA produced a significant and dose-dependent reduction of blood flow in the infused forearm from 3.13 +/- 0.5 ml 100 ml-1 min-1 during saline infusion, to 1.49 +/- 0.2 ml 100 ml-1 min-1 with NA at 600 pmol min-1 (P less than 0.001). During co-infusion of ET, blood flow was reduced similarly in the infused arm from 3.15 +/- 0.7 ml 100 ml-1 min-1 during saline infusion to 1.55 +/- 0.2 ml 100 ml-1 min-1 with NA at 600 pmol min-1. Blood flow in the non-infused arm was not altered by ET and NA infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium antagonists and blood glucose in normal rabbits

The effects of the calcium antagonists verapamil and nifedipine on blood glucose levels, glucose tolerance, insulin secretion during glucose tolerance and hypoglycaemic effect of tolbutamide were studied in normal nondiabetic rabbits. Daily dosage of 40 mg/kg verapamil and 5 mg/kg nifedipine given orally up to 7 days did not affect blood glucose level, glucose tolerance, insulin secretion during glucose tolerance and hypoglycaemic activity of tolbutamide 250 mg/kg p.o.     

Effects of intravenous infusion of doxorubicin on blood chemistry, blood pressure and heart rate in rabbits

The effects of a 1 h continuous infusion of doxorubicin (12.5 mg kg-1, 200 mg M-2) on blood chemistry was examined in rabbits over a 6-h period. Plasma glucose levels remained unchanged while insulin levels were significantly decreased to 39, 45 and 61% of the zero time value (12.8 +/- 2.9 ng ml-1) at 30, 60 and 120 min, respectively, after starting the drug infusion. Plasma cortisol levels were increased to 141, 140 and 131% of the initial zero time value (12.3 +/- 2.2 ng ml-1) at 120, 240 and 360 min, respectively. Doxorubicin had no effect on plasma electrolytes, osmolality and urea nitrogen but significantly increased plasma creatinine over the corresponding control value (2.2 +/- 0.8 micrograms ml-1 to 4.9 +/- 0.7 micrograms ml-1) at 120 min and the level remained elevated for the remaining period of the study. Systolic and diastolic pressure, and heart rate were also depressed at 240 and 360 min. The data collected in the present study indicate that the doxorubicin infusion might have a direct effect on beta cells in the pancreas as well as muscle tissue. Changes in cortisol, blood pressure and heart rate appear to be secondary to other effects produced by doxorubicin.     

Quantification of heparin-induced TFPI release: a maximum release at low heparin dose

AIMS: Heparin releases tissue factor pathway inhibitor (TFPI) from the endothelium and this release may decrease after repeated high dose heparin administration. The primary aim was to investigate and quantify this phenomenon during a short low dose heparin infusion. Also, the effects of heparin on tissue plasminogen activator (t-PA) were studied. METHODS: Nine healthy, nonsmoking, male volunteers (range 19-23 years) received a continuous heparin infusion (2000 IU) over 40 min. The endothelial TFPI release rate was estimated from the total TFPI concentration profile using a pharmacokinetic model. RESULTS : Mean +/- s.d. total and free TFPI increased from 62.9 +/- 9.4/8.3 +/- 2.1 ng ml-1 at baseline to 237.2 +/- 40.9/111.0 +/- 19.9 ng ml-1 after 40 min infusion. The relationship between heparin concentration (anti-IIa activity) and TFPI concentration followed a maximum effect model and a clockwise loop (proteresis) was observed. The TFPI release rate rapidly increased to maximum of 200 +/- 45 micro g min-1 after 17.5 min heparin infusion but did not increase further although heparin concentrations further doubled. In contrast to TFPI, t-PA antigen decreased from 5.6 +/- 1.0 at baseline to 4.5 +/- 1.0 ng ml-1 at the end of infusion (t = 40 min) (difference of 1.1 ng ml-1 (95% confidence interval; 0.9, 1.3). CONCLUSIONS: Our application of concentration-effect models and pharmacokinetic principles to these haemostatic variables showed that endothelial TFPI release has a maximum that is already reached at low heparin dose, corresponding with an anti-IIa activity of 0.08 IU ml-1. The relationship between anti-IIa activity and TFPI release rate showed signs of acute tolerance (clockwise loop) indicating exhaustion of endothelial TFPI pools. These findings may be of importance for the heparin dose used in conditions such as unstable angina, in which the favourable effects of heparin have been ascribed to its ability to release TFPI.     

Desensitization of islet cells to bombesin involves both receptor down-modulation and inhibition of receptor function

The neuropeptide bombesin has a powerful but transient stimulatory effect on insulin secretion in the pancreatic islet cell line HIT-T15. We have previously shown that pretreatment of HIT-T15 cells with a saturating concentration of bombesin (100 nM) for 1.5-2 hr abolishes their secretory response to a second challenge with peptide and decreases [125I-Tyr4]bombesin binding by over 90%. In this study we examined the mechanisms involved in desensitization to bombesin. To determine whether receptor modulation was responsible, we compared the effect of bombesin pretreatment on [125I-Tyr4]bombesin binding and on the ability of bombesin to stimulate insulin release. Both effects occurred very rapidly and were maximal by 10 min. Although pretreatment of cells for 90 min with a subsaturating concentration of bombesin did not affect either the ED50 for bombesin-stimulated secretion or the apparent Kd for bombesin binding, it decreased both the maximum secretory response to a subsequent challenge with the peptide and bombesin receptor number. However, the extent of desensitization was greater than the extent of receptor down-regulation at all times examined during pretreatment and recovery. Furthermore, bombesin was 3 times more potent at inducing desensitization (ED50 = 0.35 +/- 0.08 nM) than down-regulation (ED50 = 1.1 +/- 0.4 nM). These results suggest that desensitization was not due solely to a reduction in receptor number. Because bombesin stimulates diacylglycerol production in HIT-T15 cells, we used the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to determine whether protein kinase C also played a role in desensitization to the peptide. Pretreatment of cells with TPA did not affect either [125I-Tyr4]bombesin binding or the dose dependence for bombesin-stimulated hormone release. However, TPA pretreatment did decrease the maximum secretory response to bombesin by 40% and caused a 50% reduction in bombesin-induced accumulation of inositol triphosphates and elevation of intracellular free calcium. Conversely, bombesin pretreatment reduced the secretory response to TPA by 40%. These studies indicate that the mechanism for desensitization to bombesin is a complex process that involves down-regulation of the bombesin receptor, inhibition of intracellular second messenger production, and reduction of protein kinase C-stimulated secretion.     

The metabolic actions of intravenous salbutamol and aminophylline singly and in combination.

1 The following four treatments were administered by constant intravenous infusion of four healthy volunteers in a balanced randomized study: 1) saline (30 min), salbutamol (0.15 micrograms kg-1 min-1 for 30 min) (sS), 2) saline, aminophylline (0.2 mg kg-1 min-1 for 30 min) (sA), 3) salbutamol, salbutamol (SS) and 4) aminophylline, salbutamol (AS). 2 Heart rate was recorded and venous blood taken for estimation of insulin, glucose, potassium and theophylline before and during the infusions (10, 20, 30, 40, 50 and 60 min). 3 The mean, peak heart rate increases from control, baseline values were 23.0 (sS), 3.5 (sA), 28.5 (SS) and 28.0 (AS) beats/min, the mean, peak insulin increases, 34.0 (sS), 0.5 (sA), 39.0 (SS) and 57.5 (AS) microU ml-1, the mean, peak glucose increases, 1.4 (sS), 0.1 (sA), 2.6 (SS) and 2.0 (AS) mmol 1(-1) and the mean, peak potassium changes, -0.45 (sS), 0.58 (sA), -0.78 (SS) and -0.68 (AS) mmol 1(-1). 4 The mean, peak serum theophylline levels were 48.1 mumol 1(-1) at 60 min in sA and 52.6 mumol 1(-1) at 50 min in AS (39.1 mumol 1(-1) at 30 min). 5 Salbutamol stimulated significant insulin release and produced hypokalaemia and glycogenolysis, whereas aminophylline induced no metabolic effect. 6 A comparison of sS and AS indicated a trend for aminophylline to potentiate the metabolic effects of salbutamol.     

The relationships between dose and concentration of tolbutamide and insulin and glucose responses in patients with non-insulin-dependent diabetes

Summary It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The interrelationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group).In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration.In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response.In the subset with a fasting blood glucose concentration of less than 8 mmol·l^–1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.     

Effect of loxiglumide (CR-1505) on bombesin- and meal-stimulated plasma cholecystokinin in man

Summary Cholecystokinin (CCK)-receptor antagonists have been reported to inhibit the effects of the hormone on the gastrointestinal tract. Their effect on plasma CCK levels in man has not been described.The present study in 5 normal subjects demonstrated that i.v. infusion of the potent, specific CCK-receptor antagonist loxiglumide (CR 1505) significantly augmented plasma CCK levels during infusion of bombesin (402 pM per 30 min) and after administration of a meal (1390 pM per 300 min) when compared to the bombesin- (192 pM per 30 min) and meal- (886 pM per 300 min) stimulated CCK responses during infusion of saline. The basal plasma CCK during saline infusion (0.1 pM per 40 min) was not significantly influenced by CR 1505 (–1.8 pM per 40 min).Thus, both enteral (meal) and parenteral (bombesin) stimulation of CCK secretion are augmented by CCK-receptor blockade.     

Effect of glucagon on gastric emptying and on postprandial gastrin and insulin release in man

In a double-blind placebo-controlled study the effect of glucagon on gastric emptying, as well as on serum concentrations of gastrin, insulin, glucose, calcium, and phosphorus after ingestion of a mixed solid-liquid meal was examined in nine normal males. An i.v. bolus of 0.5 mg of crystalline glucagon was followed by 1.5 mg infused at a constant rate over 90 minutes. The gastric emptying of a radiolabelled meal was measured with the use of a gamma camera. Glucagon evoked a marked delay in gastric emptying in all patients studied--the emptying index, Ix: 2.065 +/- 0.211 min-1 after placebo vs 0.358 +/- 0.090 min-1 after glucagon, p less than 0.01. The postprandial gastrin release was suppressed during the first 60 minutes of glucagon infusion and occurrence of the postprandial increment in the serum gastrin concentration was delayed. The integrated gastrin response did not, however, significantly change: the area under the gastrin curve, AUC0-90, 8733 +/- 1502 min.ng.l-1 after placebo vs 7434 +/- 1372 min.ng.l-1 after glucagon. A promotion of insulin release by glucagon was reflected by a significant increase in the area under the insulin curve, AUC0-90: 1842 +/- 153 min.mU.l-1 after placebo vs 3388 +/- 567 min.mU.l-1 after glucagon, p less than 0.02. Moreover, a sooner and significantly higher increase of the serum glucose level was observed during glucagon infusion when compared to the placebo situation. Glucagon did not significantly change the serum calcium level, whereas the serum phosphorus concentration was markedly lowered throughout glucagon infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction between tolbutamide and ketoconazole in healthy subjects.

A possible interaction between tolbutamide and ketoconazole was studied in seven healthy volunteers. Treatment for 1 week with 200 mg oral ketoconazole increased the elimination half-life (from mean +/- s.d. 3.7 +/- 0.4 to 12.3 +/- 1.9 h) and AUC(0.12 h) of tolbutamide (from 309 +/- 27 to 546 +/- 20 micrograms ml-1 h) by 25 +/- 64 and 66 +/- 15%, respectively. The percentage blood glucose reduction was also increased when tolbutamide and ketoconazole were coadministered.     

Arguments for an inhibiting role of prostaglandin E1 on insulin secretion in man.

This study aimed at investigating the effect of exogenous prostaglandin E1 (PGE1) administration on both basal and glucose-stimulated insulin secretion in normal man. For this purpose, six normal subjects were submitted to an infusion of PGE1 (0.2 microgram/kg/min) over a period of 75 min. Plasma glucose exhibited a progressive increase whereas insulin did not show any significant change. In order to exclude the participation of endogenously released catecholamines in these responses to PGE1, six additional subjects received PGE1 60 min after the start of the infusion of the alpha-adrenergic blocking agent phentolamine. Hyperglycemia developed during the combined infusion of phentolamine plus PGE1, but plasma insulin remained essentially unchanged. In other six normal volunteers, PGE1 (0.5 microgram/kg/min) significantly reduced both insulin response to intravenous glucose and glucose tolerance. These results seen to indicate that an intraislet synthesis of prostaglandins is involved in the beta-cell regulation of insulin release.     

Acute troglitazone action in isolated perfused rat liver

1. The thiazolidinedione compound, troglitazone, enhances insulin action and reduces plasma glucose concentrations when administered chronically to type 2 diabetic patients. 2. To analyse to what extent thiazolidinediones interfere with liver function, we examined the acute actions of troglitazone (0.61 and 3.15 microM) on hepatic glucose and lactate fluxes, bile secretion, and portal pressure under basal, insulin- and/or glucagon-stimulated conditions in isolated perfused rat livers. 3. During BSA-free perfusion, high dose troglitazone increased basal (P < 0.01), but inhibited glucagon-stimulated incremental glucose production by approximately 75% (10.0 +/- 2.5 vs control: 40.0 +/- 7.2 micromol g liver(-1), P < 0.01). In parallel, incremental lactate release rose approximately 6 fold (13.1 +/- 5.9 vs control: 2.2 +/- 0.8 mmol g liver(-1), P < 0.05), while bile secretion declined by approximately 67% [0.23 +/- 0.02 vs control: 0.70 +/- 0.05 mg g liver(-1) min(-1)), P < 0.001]. Low dose troglitazone infusion did not enhance the inhibitory effect of insulin on glucagon-stimulated glucose production, but rapidly increased lactate release (P < 0.0005) and portal venous pressure (+0.17 +/- 0.07 vs +0.54 +/- 0.07 cm buffer height, P < 0.0001). 4. These results indicate that troglitazone exerts both insulin-like and non-insulin-like hepatic effects, which are blunted by addition of albumin, possibly due to troglitazone binding.     

Metabolic effects of lacidipine: a placebo-controlled study using the euglycaemic hyperinsulinaemic clamp.

1. Twelve healthy male volunteers received lacidipine 4 mg and matching placebo, each for 2 weeks, in a randomised, double-blind crossover study, and attended on 4 study days to evaluate the effects of single and multiple dosing using the euglycaemic hyperinsulinaemic 'clamp'. 2. On each study day, a primed constant-rate infusion of soluble insulin (1.5 mu kg-1 min-1) was administered for 180 min with a variable-rate infusion of 20% dextrose to maintain euglycaemia (5.2 mmol l-1). Whole-body insulin sensitivity was calculated during the past 40 min of the 'clamp'. At frequent intervals, measurements of BP and HR were recorded and venous blood samples collected for serum insulin, C-peptide, potassium, triglyceride (TG) and plasma noradrenaline concentrations. 3. Lacidipine was generally well tolerated and there were no adverse biochemical events. Mean values for insulin sensitivity +/- s.d. were 8.9 +/- 1.6 and 9.1 +/- 2.0 mg kg-1 min-1 after single doses of lacidipine and placebo respectively (95% CI, -1.0, 1.3), and correspondingly 9.6 +/- 2.1 and 9.7 +/- 1.5 mg kg-1 min-1 after 2 weeks (95% CI, -1.0, 1.3). 4. There was a significant reduction in fasting serum TG concentrations after 2 weeks of lacidipine: 0.7 +/- 0.3 mmol l-1 vs 0.9 +/- 0.6 (P < 0.001). However, changes in serum TG and potassium concentrations during the 'clamp' were not significantly different between the 4 study days. 5. Thus, in 'insulin sensitive' volunteers, lacidipine reduces fasting serum TG concentrations but has no effect on insulin-stimulated uptake of glucose, potassium and TG under euglycaemic hyperinsulinaemic conditions.     

Effect of somatostatin-14 on gastric emptying and on gastrin and insulin release after ingestion of a mixed solid-liquid meal in man

The effect of somatostatin-14 on gastric emptying, as well as on serum concentrations of gastrin, insulin, glucose, calcium, and phosphorus after ingestion of a mixed solid-liquid meal was examined in seven healthy men in a double-blind placebo-controlled study. An i.v. bolus injection of 61 nmol somatostatin was followed by 244 nmol infused at a constant rate over 90 minutes. Gastric emptying of a radiolabelled meal was surveyed with the use of a gamma camera. A weak delaying effect of somatostatin on gastric emptying of a solid meal did not prove to be statistically significant. Somatostatin decreased significantly the postprandial gastrin release: the area under the gastrin curve, AUC0-90, 9954 +/- 2287 ng.l-1 min (placebo) vs 5327 +/- 718 ng.l-1 min (somatostatin), p less than 0.05. At the same time suppression of the postprandial insulin release by somatostatin was observed--area under the insulin curve, AUC0-90, 1450 +/- 161 mU.l-1 min (placebo) vs 501 +/- 60 mU.l-1 min (somatostatin), p less than 0.002. The postprandial increase in serum glucose concentration was initially attenuated, and shifted towards the end of somatostatin infusion, when referred to the placebo situation. Somatostatin did not change significantly the serum calcium or phosphorus concentrations. The results obtained indicate that somatostatin's effect on gastric evacuation is less pronounced in contrast to the significant inhibitory influence of somatostatin on release of gastrointestinal hormones.     

C-peptide has no effect on forearm blood flow during local hyperinsulinaemia in healthy humans

BACKGROUND: C-peptide increases forearm blood flow (FBF) in patients with Type 1 diabetes, probably by interaction with insulin, but not in healthy subjects. It is unclear if the vasodilating effect is sealed at normal fasting insulin concentrations. METHODS: The effects of C-peptide alone and during local hyperinsulinaemia were studied in healthy young men. Subjects received intra-arterial insulin at 6 pmol min-1 (low dose) or placebo for 60 min with subsequent coinfusion of C-peptide at increasing doses of 2-60 pmol min-1 in a double-blind crossover study (n = 8). In control experiments insulin at 30 pmol min-1 (high dose) was coinfused with C-peptide (n = 3). FBF was measured by strain-gauge plethysmography. RESULTS: Placebo had no effect on FBF (mean percentage change from baseline at 50 min -3.1%, 95% confidence interval [CI]-14.9, + 8.7). Insulin infusion slightly enhanced FBF by + 10.2% (95% CI -6.8, + 27.2; low dose) and + 17.6% (95% CI -38.8, + 74.0; high dose), respectively. The mean individual difference of the change in FBF between low-dose insulin and placebo was + 13.3% (95% CI -6.0, + 32.7; P = NS). Infusion of C-peptide increased local C-peptide concentrations from 1.8 +/- 0.1 ng ml-1 to 6.1 +/- 2.8 ng ml-1, but had no effect on FBF during placebo or hyperinsulinaemia (mean difference vs low dose insulin -16.0%, 95% CI -38.9, + 6.9). CONCLUSION: The vasodilating effect of C-peptide seen in Type 1 diabetes is not detectable during fasting or hyperinsulinaemia in the forearm vasculature of healthy subjects. This suggests saturation of its vasodilating potency at insulin concentrations within the normal or in the supraphysiological range.     

The effect of 443C81, a mu opioid receptor agonist, on the response to inhaled capsaicin in healthy volunteers.

Activation of mu opioid receptors on sensory nerves in the lung represents an attractive mechanism for reducing cough and reflex bronchoconstriction. We have examined the effect of the peptide 443C81, a peripherally acting mu opioid agonist, on the cough and reflex increase in respiratory resistance (Rrs) produced by capsaicin in nine healthy male volunteers. Using a randomised, double-blind crossover design, each subject inhaled either saline, 1 mg ml-1 443C81 or 4 mg ml-1 443C81 for 10 min from an ultrasonic nebuliser. The cough response to a range of doses of inhaled capsaicin and the increase in Rrs caused by inhalation of a single subtussive dose of capsaicin were measured before and after each treatment. There was no evidence of an effect of either 1 or 4 mg ml-1 443C81 on cough or increase in Rrs produced by capsaicin when compared with the saline placebo. It is concluded that inhalation of this mu opioid receptor agonist had no effect on capsaicin-induced cough or reflex bronchoconstriction in healthy volunteers.     

Lack of effect of the specific cholecystokinin receptor antagonist loxiglumide on cholecystokinin clearance from plasma in man.

Saline or loxiglumide (2.5 mg kg-1 in 10 min, followed by 5 mg kg-1 h-1 for 200 min) was administered intravenously in random order to six healthy subjects. After 60 min cholecystokinin (CCK-33) was infused (0.5 i.d.u. kg-1 h-1 for 1 h then 1.0 i.d.u. kg-1 h-1 for 1 h). Loxiglumide did not change basal levels of CCK and did not augment plasma CCK-immunoreactivity during CCK-33 infusion. After cessation of the CCK-infusion, plasma CCK concentrations decreased rapidly to basal values within 12 min, and the elimination half-life during loxiglumide infusion (4.8 +/- 0.8 min) was not significantly different from that during saline infusion (4.2 +/- 1.0 min). These results suggest that loxiglumide does not interfere with the distribution and metabolism of CCK.     

Effects of drugs on glucose and tolbutamide-stimulated insulin release from isolated rat islets of Langerhans

The effects of acetylsalicylic acid, sulphadimidine, phenylbutazone and chlorpromazine on glucose- and tolbutamide-stimulated insulin release by isolated rat islets of Langerhans have been investigated. Acetylsalicylic acid did not influence glucose-stimulated insulin secretion; although at 2.5 mM it potentiated the effect of tolbutamide. Sulphadimidine potentiated the effects of glucose and tolbutamide on insulin secretion, whereas phenylbutazone was found to augment glucose-stimulated insulin release and to antagonize the tolbutamide effect. The effects of glucose and tolbutamide on insulin secretion were inhibited by low concentrations of chlorpromazine (0.005 mM–0.01 mM) and were stimulated by high concentrations (0.5 mM–1 mM). These results are discussed in relation to the possibilities that certain drugs may affect tolbutamide-stimulated insulin release either by altering the binding of tolbutamide to the B-cell or to other proteins, or by affecting the cyclic AMP system of the B-cell.     

Cyclo-oxygenase inhibitors antagonize indirectly evoked contractions of the guinea-pig isolated ileum by inhibiting acetylcholine release

The effects of indomethacin, sodium meclofenamate and ketoprofen on the contractile responses of the guinea-pig isolated ileum to directly and indirectly evoked stimuli were investigated. The effects of the cyclo-oxygenase inhibitors on acetylcholine (ACh) release from plexus containing longitudinal muscle strips were also studied. The cyclo-oxygenase inhibitors reduced contractile responses to transmural stimulation (TMS) and nicotine at concentrations which had no effect on ACh-induced contractions. In whole ileum preparations (WIP) indomethacin and ketoprofen (40 micrograms ml-1) reduced TMS responses by 17 +/- 1.8% and 12 +/- 1.8% (n = 6), respectively (30 min incubation). In longitudinal muscle strips (LMS) in which Auerbach's plexus is exposed, indomethacin and ketoprofen (1 microgram ml-1) reduced TMS responses by 28 +/- 2.3% and 34 +/- 2.7% (n = 6), respectively (10 min incubation). Thus the cyclo-oxygenase inhibitors were up to 80 times more effective in LMS than in WIP. The drugs were similarly more effective in blocking nicotine contractions in LMS than in WIP. The cyclo-oxygenase inhibitors reduced basal and stimulated ACh release from LMS. For example, indomethacin (1 microgram ml-1) reduced stimulated ACh release by 35% after 10 min incubation. The percentage inhibition increased to 79% after 40 min incubation (n = 6). Prostaglandin E2 (PGE2) (0.1-2.5 ng ml-1) restored the contractile responses and ACh release depressed by the cyclo-oxygenase inhibitors but not the contractile responses depressed by atropine. PGF2 alpha had no effect on mechanical responses or ACh release depressed by the cyclo-oxygenase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)