A hypothesis to explain the presynaptic effects of adrenoceptor antagonists.

The hypothesis of negative feedback regulation of transmitter release was examined in a range of tissues obtained from three species. Tissues were transmurally stimulated with 100 pulses at 2 Hz with pulse durations from 50 microseconds to 5,000 microseconds, and the efflux of [3H]-noradrenaline determined. The stimulation-induced efflux of tritium increased with increasing pulse duration, but yohimbine, a prototypal alpha 2-antagonist had an effect which was consistently contrary to expectations for a negative feedback system. Enhancement of efflux by the antagonist, supposedly correlated directly with the extent of ongoing auto-inhibition, became smaller rather than larger as the stimulation-induced efflux rose with increases in pulse duration, with all other parameters of stimulation maintained constant. Similar findings were obtained in rat spleen with the haloalkylamine antagonist, phenoxybenzamine. It is concluded that the presynaptic effects of adrenoceptor antagonists do not involve a negative feedback function nor do they relate, in any detectable way, to the extracellular concentration of transmitter. The effects on stimulation-induced tritium efflux of yohimbine, phenoxybenzamine and enlargment of the pulse duration, in a variety of tissues, support the previously described hypothesis of a common action to enhance efflux. The antagonists increased efflux to approximately the same value between 50 and 1,000 microseconds pulse durations and that value was equivalent to that obtained in each given tissue with pulses of 1,000-2,000 microseconds in the absence of the antagonist. Tetraethylammonium, an inhibitor of stimulation-induced potassium efflux from nerves had an effect on transmitter efflux in rat spleen essentially like that of the adrenoceptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of nicotine-induced attentional enhancement in rats by adrenoceptor antagonists

Rationale Understanding the neuropharmacological mechanisms mediating attentional enhancement by nicotine would help a targeted search for nicotinic compounds with retained therapeutic but reduced unwanted side-effects. Previous studies suggested that the dopamine-releasing effects of nicotine may not be of primary importance for its attention-enhancing properties.Objectives The present study examined the role of noradrenergic neurotransmission for the effects of nicotine on different response indices of an attentional paradigm.Methods The effects of systemic injections of the ₁-adrenoceptor antagonist prazosin that also displays significant affinity at _2B and _2C-adrenoceptors and the -adrenoceptor antagonist propranolol were tested in both the presence and absence of nicotine in rats trained in a version of the five-choice serial reaction time task.Results Nicotine generally enhanced the accuracy of signal detection, reduced omission errors and shortened response latencies. At the largest doses tested, both prazosin (1 mg/kg) and propranolol (10 mg/kg) impaired performance. For propranolol, these effects depended on the rate of target signal presentation. The two compounds differentially modulated the effects of nicotine. Propranolol (6 mg/kg and 10 mg/kg) but not prazosin reduced its effects on omission errors and accuracy. By contrast, prazosin (0.5 mg/kg) reversed the nicotine-induced reductions in response latency.Conclusions The data provide the first evidence that -adrenoceptors are involved in mediating the effects of nicotine on signal detection, while activation of -adrenoceptors may contribute to its effects on response speed. This is a further indication that, from among nicotines wide range of neuropharmacological effects, specific facets can be dissociated that are responsible for its attention-enhancing properties.     

Plasma insulin levels andβ-adrenoceptor antagonists. Relevance of the steric configuration ofβ-adrenoceptor antagonists to their effect on glucose tolerance

The relevance of the steric configuration to the effects of two non-selective beta-adrenoceptor antagonists without intrinsic sympathomimetic activity (+)- and (--)-bupranolol (10 and 50 micrograms/kg i.v.) and (4)- and (--)-propranolol (100 and 500 micrograms/kg i.v.) on the i.v. glucose tolerance test (IVGTT) were investigated in conscious, normoglycemic dogs. The effects of the beta-adrenoceptor antagonists on plasma glucose, and insulin levels and insulin-glucagon ratio following IVGTT were evaluated by calculating the respective areas under the curve (AUC). The AUC values for plasma glucose were significantly increased by the (--)-configuration of both beta-adrenoceptor increased by the (--)-configuration of both beta-adrenoceptor antagonists. In the (+)-configuration only propranolol (500 micrograms/kg i.v.) increased the AUC value for plasma glucose significantly. The AUC values for plasma insulin and also for the plasma insulin-glucagon ratio were significantly increased by (--)-propranolol (500 micrograms/kg i.v.) and by (--)-bupranolol (10 and 50 micrograms/kg i.v.). Thus the impairment of glucose tolerance, due to suppression of the plasma insulin level, depends mainly on the beta-adrenoceptor antagonistic activity of the (--)-configuration.     

Strain-dependent effects of post-training GABA receptor agonists and antagonists on memory storage in mice

Post-training administration of the GABA-A and GABA-B receptor agonists muscimol and baclofen dose-dependently impaired retention of an inhibitory avoidance response in C57 mice, while improving memory consolidation in the DBA strain. By contrast, picrotoxin (blocker of GABA-activated ionophores), bicuculline (GABA-A antagonist) and CGP 35348 (GABA-B antagonist) dose-dependently improved retention in C57 mice and impaired it in DBA mice. These effects cannot be ascribed to non-specific actions of the drugs on retention performance, as the latencies during the retention test of those mice that had not received footshock during the training were not lengthened by the post-training drug administration. The effects on retention performance induced by GABA agonists and antagonists are probably due to an effect on memory consolidation, since they are observed when the drugs are given at short, but not at long, intervals after training. These results are discussed in terms of possible interaction of GABA systems with endogenous opioid and dopamine systems, whose activation has been shown to produce strain-dependent effects on memory processes. The possible utilization of these results for a genetic behavioral approach with recombinant inbred (RI) mice is also considered.     

Fuels for memory: the role of oxygen and glucose in memory enhancement

Recent studies indicate that some aspects of memory can be enhanced by the administration of oxygen or glucose. Considering the dependency of glucose metabolism upon oxygen supply, the present study predicted that administering a combination of 100% oxygen with glucose would have greater memory-enhancing effects than when either substance was administered alone. In a placebo-controlled study, 104 healthy adults were given a glucose or placebo drink, and inhaled 100% oxygen or air for 1 min, before carrying out a number of everyday memory tasks designed to measure short-term and long-term memory. Results showed support for the enhancing effects of oxygen (but not for glucose) on delayed recall. These findings are discussed in relation to the possible cholinergic properties of oxygen and glucose and the implications for their clinical use. Received: 19 June 1997/Final version: 15 October 1997     

The effect of adrenoceptor antagonists on the ileal brake mechanism in the rat.

1. The whole-cell patch-clamp technique has been used to examine Ca channel currents carried by Ba (IBa) in rat hippocampal neurones. 2. Quinacrine selectivity decreased the high-threshold current activated by membrane depolarization from a holding potential of -70 mV. Neither the low-threshold Ca channel current nor the fast tetrodotoxin (TTX)-sensitive sodium current were affected by quinacrine. 3. Bath application of quinacrine caused a dose-dependent reduction of the peak amplitude of IBa. This effect was fast, voltage-independent, reversible and had a Kd of 30 +/- 5 microM. 4. The quinacrine-induced block did not change the time-course and the voltage dependence of IBa activation and deactivation. The inhibition revealed no use-dependence, ruling out an open channel block by quinacrine. 5. p-Bromophenacyl bromide had no effect on IBa suggesting the lack of involvement of phospholipase A2 in the action of quinacrine. In addition, the quinacrine-induced block was not related to the calmodulin pathway and internal quinacrine did not affect the peak amplitude of IBa. 6. The effect of quinacrine on the amplitude of IBa was dependent of the external pH, and suggested that only the single-protonated form of the drug can bind to the channel receptor with a Kd of 3 microM. Quinacrine and other substituted acridines can thus be useful for pharmacological and structure-activity studies of Ca channels.     

The effects of adrenoceptor agonists and antagonists on plasma potassium concentration in anaesthetized guinea-pigs, rabbits and rats.

An intravenous K+-sensitive electrode has been used to monitor plasma [K+] changes induced by alpha- and beta-adrenoceptor agonists in anaesthetized guinea-pigs, rabbits and rats. The effects of phentolamine and propranolol on these responses were studied. In the guinea-pig both alpha- and beta-adrenoceptor agonists produced a biphasic response consisting of an initial rapid increase in [K+] which was followed, within 1 min, by a fall below baseline. The antagonist studies indicated that in this species both phases of the response could be elicited by either alpha- or beta-adrenoceptor activation. In the rabbit the responses were both slower and smaller than those seen in the guinea-pig and required larger agonist doses. In addition it was found that the increase in plasma [K+] was alpha-adrenoceptor-mediated while the subsequent fall was seen only with beta-adrenoceptor activation. In the rat triphasic changes in plasma [K+] were seen consisting of an initial decrease which was alpha-adrenoceptor-mediated, followed by an increase and then a second fall which was elicited by beta-adrenoceptor stimulation. The increase in plasma [K+] was only slightly reduced by either alpha- or beta-adrenoceptor antagonists. Apamin, a toxin from bee venom which blocks Ca2+-activated K+-channels, was found to block the hyperkalaemic phase of the response in the guinea-pig and rabbit but had no effect in the rat. It is concluded that there are marked species differences in the effects of adrenoceptor agonists on plasma [K+] in vivo.     

Effects of adrenoceptor agonists and antagonists on cardiovascular functional parameters in rats.

The effects of intravenous administration of adrenoceptor agonists and antagonists on electrocardiographic or blood pressure (BP) functional parameters were assessed in urethane-anesthetized rats. The responses of cardiovascular functional parameters produced by these drugs included: (1) isoproterenol decreased the duration of a whole BP cycle (Wd), duration of the diastolic wave (Dd), peak amplitude of the systolic wave (SYa), amplitude of the diastolic notch (DNa), amplitude of the diastolic wave (DWa), pulse pressure (dp) and mean arterial pressure (mp) but increased the heart rate (HR) accompanied by prolonged R-R (RR) or P-P interval (PP) (2) propranolol decreased SYa, DNa, dp, mp, HR, the amplitude of the P wave (Pa) and amplitude of the S wave (Sa) but increased the duration of the QRS wave, P-R interval, duration of the R wave (Rd) and duration of the P wave (Pd); (3) adrenaline decreased HR (accompanied by prolonged RR and PP), Rd, Pa and amplitude of the T wave (Ta) but increased Pd, Wd, Dd, DNA, the time interval between aortic valve opening and closure (Dw), dp, mp, amplitude of the Q wave and amplitude of the R wave (Ra); (4) noradrenaline decreased HR (accompanied by prolonged RR and PP) and Pa but increased Wd, Pd, SYa, DNa, Dw, dp, mp, Ra and Ta; (5) phenylephrine decreased HR (accompanied by prolonged RR and PP) and Pa but increased Wd, Dd, DNa, mp and Ra; (6) phentolamine decreased SYa, DNa, DWa, Dw, dp and mp. This study illustrates the utility of the automated electrocardiogram (ECG) and BP analysis system for investigation of adrenoceptor agonists and antagonists. The use of this methodology not only reproduced most of cardiovascular functional parameter effects produced by these drugs using the conventional methodology but also realizes some new information about the drug-induced ECG or BP waveform effects.     

The potential antidiabetic activity of some alpha-2 adrenoceptor antagonists.

The effect of alpha-2 adrenoceptor antagonists, yohimbine and efaroxan, on the plasma glucose and insulin levels was studied in non-diabetic control, type-I (insulin-dependent) and type-II (non-insulin-dependent) diabetic rats. Pretreatment with either yohimbine or efaroxan potentiated glucose-induced insulin release in non-diabetic control rats and produced an improvement of the oral glucose tolerance and potentiated glucose-induced insulin release in type-II but not in type-I diabetic rats. Treatment with either yohimbine or efaroxan reduced the plasma glucose level and increased the plasma insulin level of non-diabetic control and type-II diabetic rats but not of type-I diabetic rats. Effects of efaroxan were more marked. Pretreatment of non-diabetic control and type-II diabetic rats with either yohimbine or efaroxan inhibited clonidine-induced hyperglycaemia and suppressed or reversed clonidine-induced hypoinsulinaemia. Also, pretreatment of these animals with either yohimbine or efaroxan enhanced the hypoglycaemic and insulinotropic effects of glibenclamide. The combination of glibenclamide and efaroxan led to a synergistic increase in insulin secretion, while that of glibenclamide and yohimbine led to an additive increase. The hyperglycaemic effect of diazoxide in non-diabetic control and type-II diabetic rats was inhibited by pretreatment with either yohimbine or efaroxan. The hypoinsulinaemic effect of diazoxide in these animals was antagonized and reversed by pretreatment with yohimbine and efaroxan, respectively. In type-I diabetic rats, there was no change in the plasma glucose and insulin levels induced by the treatment of animals with each of clonidine or diazoxide alone or in combination with either yohimbine or efaroxan. Glibenclamide produced a slight decrease in the plasma glucose level of type-I diabetic rats, at the end of the 120 min period of investigation but there was no change in the plasma insulin level. Pretreatment of these animals with either yohimbine or efaroxan produced no change in glibenclamide effects. Additionally, bath application of efaroxan or glibenclamide inhibited the relaxant effects of different concentrations of diazoxide on the isolated norepinephrine-contracted aortic strips, while the application of yohimbine produced insignificant changes. The combination of glibenclamide and efaroxan led to complete inhibition of the relaxant effects of different concentrations of diazoxide, while that of glibenclamide and yohimbine did not produce such an effect. It is concluded that yohimbine, via blockade of postsynaptic alpha-2 adrenoceptors, and efaroxan, via blockade of postsynaptic alpha-2 adrenoceptors and adenosine triphosphate-sensitive potassium channels in the pancreatic beta-cell membrane, produce insulinotropic and subsequent hypoglycaemic effects.     

Synthesis of two glucagon antagonists: receptor binding, adenylate cyclase, and effects on blood plasma glucose levels

In diabetes mellitus, hyperglycemia is often associated with elevated levels of glucagon in the blood. This suggests that glucagon is a contributing factor in the metabolic abnormalities of diabetes mellitus. A glucagon-receptor antagonist would provide direct evidence for glucagon's role in diabetes mellitus. On the basis of careful consideration of conformational, amphiphilic, and structural factors, we have synthesized two new glucagon analogues with antagonist biological activities by using solid-phase methodology. These two new analogues, [Asp3,D-Phe4,Ser5,Lys17,18,Glu21]glucagon (2) and [D-Phe4,Tyr5,3,5-I2-Tyr10,Arg12,Lys17,18,G lu21]glucagon (3) had IC50 values 5.4% and 50% those of glucagon, respectively, and showed no measurable adenylate cyclase activity. When tested in normal rats, 2 lowered plasma glucose levels and suppressed glucagon-mediated hyperglycemia 105 +/- 8%, back to basal levels. Analogue 3, which lowered the basal adenylate cyclase activity in rat liver plasma membranes, increased plasma glucose levels at very high concentration in vivo and inhibited glucagon-mediated hyperglycemia in normal rats by 50%. However, neither of the new glucagon antagonists lowered the plasma glucose levels of diabetic animals. The data would suggest these new glucagon-receptor antagonists may have two actions: (a) in normal rats they can act as standard glucagon-receptor inhibitors of glucagon-mediated glycogenolysis; (b) in diabetic rats, however, because of the low levels of glycogen in the liver, the antagonists apparently have little or no antagonist effect or enhancement on glucagon-mediated glucose production.     

Selective nicotinic receptor antagonists: effects on attention and nicotine-induced attentional enhancement

Rationale  

The question of the subtype(s) of the nicotinic acetylcholine receptor (nAChR) mediating the attention-enhancing effects of nicotine is still unsettled. While early studies pointed towards subtypes other than the homomeric α7 nAChR, pro-cognitive effects of α7 nAChR agonists have since been demonstrated.     

Effects of adrenoceptor agonists and antagonists on sulfobromophthalein disposition in mice

The effects of alpha 2-adrenoceptor agonists on sulfobromophthalein (BSP) disposition in mice were studied. It was found that agents with both central and peripheral activities (clonidine, guanabenz, B-HT 920 and methyldopa) as well as peripherally acting alpha 2-adrenoceptor agonists (para amino-clonidine and St 91) inhibited sulfobromophthalein disposition in the mouse, and also caused substantial hypothermia. The effects of these agonists were inhibited by yohimbine, a specific alpha 2-antagonist, except for those of para amino-clonidine where only partial reversal was achieved. The effects of clonidine on BSP disposition were also reversed by piperoxan but not by the alpha 1-adrenoceptor antagonists, prazosin and phenoxybenzamine, nor by the beta-blocker, propranolol. These results suggest that, in mice, peripheral alpha 2-adrenoceptors are involved in the effects of the alpha-agonists on BSP disposition.     

Glucose and memory: fractionation of enhancement effects?

Recent research findings indicate that glucose administration enhances some aspects of cognitive functioning. To date, those studies which have investigated the effects of glucose on memory in human participants have concentrated on its apparent ability to attenuate memory impairment. Relatively little research has been done in humans investigating the effects of glucose on memory performance in young healthy participants in whom no memory deficits exist. Moreover, the work which has been conducted in this population has produced somewhat equivocal findings. In this study, after overnight fasting the influence of a 25 g oral dosage of glucose on a range of measures of memory performance was investigated in healthy young female participants. Two control treatments (saccharin and water) were also administered. There was a significant glucose facilitation effect upon performance of long-term verbal free and cued recall tasks which did not vary with test delay. Performance on these free and cued verbal recall measures correlated significantly with blood glucose levels across all participants. No glucose-related facilitation was observed on either a test of short-term verbal memory (forwards/backwards digit recall) or a test of long-term non-verbal memory (complex figure reproduction). However, the significant glucose-related effects observed with long-term free and cued recall remained after controlling for participants’ differential baseline blood glucose levels and individual levels of immediate memory performance. Therefore, memory improvement after glucose ingestion was not merely a consequence of lower baseline blood glucose or lower immediate memory performance in the glucose treatment group. These findings indicate that there may be some fractionation in the memory facilitation effects of glucose: the memory enhancing effect of glucose administration in healthy young adults may be greatest on tests of long-term verbal recall. The results suggest that glucose may enhance retention in and/or retrieval from long-term verbal memory. Received: 11 July 1997/Final version: 27 October 1997     

Effects of adrenoceptor blockade on plasma catecholamine levels during adrenaline infusion.

1. The present experiments investigate the effects of phenoxybenzamine and propranolol, singly and in combination, on plasma catecholamine levels in sheep receiving a three-hour adrenaline infusion. 2. Five groups of five anaesthetized sheep were studied for a period of 3 h each. One group acted as a control and received only a saline (0.9% w/v NaCl solution) infusion. A second group received a constant infusion of adrenaline (2 mug kg body weight-1 min-1). A third group received a similar adrenaline infusion, having been premedicated with phenoxybenzamine (1 mg/kg body weight). A fourth group recieved a similar adrenaline infusion following premedication with (+/-)-propranolol hydrochloride (7 mug/kg body weight). The fifth group received the adrenaline infusion following premedication with both the alpha- and beta-blocker in the above doses. 3. Plasma catecholamines were measured on blood samples taken at seven intervals before during and following the infusion. 4. Control animals receiving only a saline infusion remained physiologically and biochemically stable throughout the experimental period. 5. Adrenaline infusion in animals not receiving adrenoceptor blocking drugs caused a rise in plasma adrenaline levels from a low basal value of 1 mug/litre to a maximum level of 19.8 mug/litre. Animals premedicated with phenoxybenzamine exhibited a similar response. 6. Animals premedicated with propranolol before the infusion of adrenaline did not demonstrate as marked a rise of plasma adrenaline levels as the two previous groups. The maximum mean plasma adrenaline level recorded in this group was 6.88 mug/litre. 7. Animals premedicated with phenoxybenzamine and propranolol before the infusion of adrenaline showed only a small rise in plasma adrenaline levels compared with animals receiving adrenaline infusion alone. The maximum mean plasma adrenaline level in the group was only 3.43 mug/litre. 8. The studies demonstrate that by an unknown mechanism beta-adrenoceptor blockade with (+/-)-propranolol, either alone or in combination with phenoxybenzamine, lowers the plasma adrenaline response evoked by adrenaline infusion.     

Can the actions of adrenoceptor agonists and antagonists on pentagastrin-induced gastric secretion be due to their effects on histamine formation?

1 The effects of some adrenoceptor agonists and antagonists which have been reported to affect histamine formation in leucocytes (Assem & Feigenbaum, 1972) have been investigated on gastric secretion in conscious dogs with Heidenhain pouches.2 Submaximal secretion in response to pentagastrin was enhanced by propranolol (0.1-1.0 mg/kg i.v.) and phenylephrine (1.0 mug kg(-1) min(-1) i.v. for 20 min), which increase histamine formation, and was decreased by phentolamine (2 mg/kg i.v.) and isoprenaline (0.05-0.2 mug kg(-1) min(-1) i.v. for 30 min), which decrease histamine formation. Practolol (2 mg/kg i.v.), which has no effect on histamine formation, had no effect on secretion.3 Acid secretion in response to histamine was either unaffected or affected in the opposite direction by these drugs.4 The effects of the drugs on pentagastrin-induced secretion were not secondary to changes in mucosal blood flow (radioactive aniline clearance).5 The results are consistent with the hypothesis that acid secretion in response to pentagastrin involves the formation of endogenous histamine.     

Spatial working memory in rats: effects of monoaminergic antagonists

To assess the possible involvement of the monoaminergic neurotransmitters norepinephrine, dopamine and serotonin in the maintenance of spatial working memory rats were treated with antagonists 0 or 2 hr after completing the first 4 choices in an 8 arm maze. Haloperidol (0.25-1 mg/kg), when administered 2 hr after Choice 4, produced a small but consistent impairment in performance on retention tests given 5 hr after the first 4 choices. This deficit closely resembled natural forgetting in terms of the type of errors committed. By contrast, haloperidol in the same doses given 0 hr after Choice 4 or 3 hr before the first 4 choices did not affect retention. Likewise treatment with propranolol (10-20 mg/kg), phentolamine (5-20 mg/kg) or methysergide (5-15 mg/kg) did not impair spatial memory, regardless of when these drugs were injected within the session. Evidently dopaminergic neuronal systems are important in the maintenance of normal spatial working memory.     

Effects of adrenoceptor agonists and antagonists on morphine-induced Straub tail in mice

Straub-tail behavior was induced by subcutaneous injection of different doses (10-60 mg/kg) of morphine to mice. The maximum response was obtained with 20-40 mg/kg of the drug. The response induced by morphine (40 mg/kg) was decreased by intraperitoneal administration of different doses of clonidine (0.05-0.1 mg/kg). Pretreatment of animals with yohimbine (1-4 mg/kg i.p.) reversed the inhibitory action of clonidine. Yohimbine did not elicit any response by itself. Administration of prazosin (0.25, 0.5, and 1 mg/kg) reduced the morphine response. The combination of prazosin with yohimbine (1 mg/kg), but not with clonidine (0.05 mg/kg), caused a potentiated inhibition of the morphine effect. Phenylephrine (2-6 mg/kg i.p.) did not elicit any effect by itself and also did not alter the response induced by morphine or morphine plus clonidine. Dobutamine (2.5-10 mg/kg i.p.), atenolol (2.5-10 mg/kg i.p.), salbutamol (2.5-10 mg/kg i.p.), and propranolol (2.5-10 mg/kg i.p.) did not alter morphine-induced Straub-tail behavior in mice. In conclusion, activation of alpha2-adrenergic pathways contributes to morphine-induced Straub tail, while alpha1- and beta2-adrenergic may not be involved in this phenomenon.     

Effects of some catecholamines on the cat cardiovascular system: interactions with adrenoceptor antagonists

The effects of intravenous infusions of norepinephrine, epinephrine, isoproterenol, N-t-butylnorepinephrine, oxymethyleneisoproterenol, and RO363 on heart rate, mean arterial blood pressure, cardiac output, total peripheral resistance, and stroke volume were evaluated in chloralose-anaesthetized cats before and after phentolamine, propranolol, atenolol, and butoxamine. Pressor responses to both norepinephrine and epinephrine largely resulted from alpha-receptor-mediated increases in total peripheral resistance. Vasomotor reversal was noted with both drugs in the presence of alpha-receptor blockade. Dilator responses to norepinephrine were abolished by the beta 1-receptor selective antagonist atenolol, as were those to the beta 1-receptor selective agonists oxymethyleneisoproterenol and RO363. Dilator responses to epinephrine were abolished by the beta 2-receptor selective antagonist butoxamine, as were those to N-t-butylnorepinephrine (beta 2-selective) and isoproterenol (nonselective). These results indicate that in addition to beta 2-receptors, beta 1-receptors subserving vasodilatation occur in the cat vasculature. Atenolol displayed agonist-dependent inhibition of the cardiac responses. Responses to noradrenaline, RO363, and oxymethyleneisoproterenol were blocked to a greater extent than were those to epinephrine, N-t-butylnorepinephrine, and isoproterenol. Butoxamine did not display any marked agonist-dependent inhibition of cardiac responses. Nevertheless, the results are in accord with previous suggestions that cardiostimulant beta 2-receptors exist in the cat heart. Interpretation of the actions of catecholamines may be complicated by mixed beta-adrenoceptor populations in the cat cardiovascular system.     

Plasma levels of glucose and lactate after intravenous cadministration in some insulin-dependent diabetics. Therapeutic effects of an associated glipizide-insulin treatment

Summary

A study was carried out to evaluate the effectiveness of glipizide in insulin-dependent diabetic patients. An intravenous glipizide (2?mg)test was carried out in 7 patients before and after a period of associated insulin-glipizide treatment (mean daily dose of 80.7 i.v. lente insulin and 14.3?mg glipizide for 9.1 months)to assess the capacity of the sulphonylurea to reduce acutely the plasma glucose and lactate levels. Glipizide did not produce glucose variations in either test but did result in a significant decrease, in the first test only, in mean plasma baseline levels of lactate, which were higher than normal in these patients. There was no reduction in daily insulin requirements after the period of associated glipizide-insulin treatment. It is concluded that, in the dosage used, intravenous glipizide probably has no hypoglycaemic effects in insulin-dependent diabetics. Moreover, it did not prove useful in combination with insulin. However, the reduction in plasma lactate may be related to an acute enhancement of the exogenously administered insulin. This improvement in the insulin effect may be an acute one among the so-called ‘extra-pancreatic’ actions which have been demonstrated for glipizide and other sulphonylureas.