Effects Of Adrenoceptor Antagonists Research Articles

Stereo-selective inhibition of spinal morphine tolerance and hyperalgesia by an ultra-low dose of the alpha-2-adrenoceptor antagonist efaroxan

Ultra-low doses of alpha-2 (α2)-adrenoceptor antagonists augment spinal morphine antinociception and inhibit tolerance, but the role of receptor specificity in these actions is unknown. We used the stereo-isomers of the α2 adrenoceptor antagonist, efaroxan to evaluate the effect of receptor specificity on the induction of spinal morphine tolerance and hyperalgesia. Tail flick and paw pressure tests were first used to evaluate high dose efaroxan (12.6μg) and its stereo-isomers on clonidine analgesia in intrathecally catheterized rats. Ultra-low doses of individual isomers (1.3ng) were then co-administered with morphine (15μg) to determine their effects on acute antinociceptive tolerance and hyperalgesia induced by low dose spinal morphine (0.05ng). Results demonstrate that high dose (+) efaroxan antagonized clonidine-induced antinociception, while (−) efaroxan had minimal effect. In addition, an ultra-low dose of (+) efaroxan (1.3ng), substantially lower than required for receptor blockade, inhibited the development of acute morphine tolerance, while (−) efaroxan was less effective. Racemic (±) efaroxan effects were similar to those of (+) efaroxan. Furthermore, low dose morphine (0.05ng) produced sustained hyperalgesia in the tail flick test and this was blocked by co-injection of (+) but not (−) efaroxan (1.3ng). Given the isomer-specific efaroxan effects and their different receptor potencies, we suggest that inhibition of opioid tolerance by ultra-low dose efaroxan involves a specific interaction with spinal α2-adrenoceptors in this model. Likewise, inhibitory effects of adrenoceptor antagonists on morphine tolerance may be due to blockade of opioid-induced hyperalgesia.

Effects of adrenoceptor antagonists on the cutaneous blood flow increase response to sympathetic nerve stimulation in rats with persistent inflammation.

There is some evidence that the sympathetic nervous system plays a role in the development and/or maintenance of painful states, and that sympathetic nervous function is altered in these conditions. Our previous experiments showed that electrical stimulation of the lumbar sympathetic trunk (sympathetic stimulation: SS), which normally induces a decrease in blood flow (BF) of plantar skin, induced its BF increase in about 50% of adjuvant-inflamed rats. To investigate the mechanism of this BF-increase response, we examined whether noradrenaline (NA) plays any role in this changed response to SS, and which receptor subtype is involved. We measured paw cutaneous BF response with a laser Doppler flowmeter in rats chronically inflamed with complete Freund's adjuvant. SS induced the BF-increase response in 50-67% of measured sites. Close-arterially injected NA induced the BF-increase response at dosages between 10-100 ng/kg only at the sites with the BF-increase response to SS. The BF-increase and -decrease responses to NA was significantly reduced after the close-arterial injection of either alpha1- or alpha2-adrenoceptor antagonists (p lt; 0.05, respectively). In contrast, although the BF-decrease responses to SS were significantly reduced by administration of alpha1- and alpha2-adrenoceptor antagonist, BF-increase response was reduced only by alpha1-adrenoceptor antagonist, and that only at a higher dose. In addition, the beta-adrenoceptor antagonist had no effects on both responses. These results suggest that the BF-increase response to SS involves, additionally to NA, a non-adrenergic mechanism.

Effects of adrenoceptor antagonists on neuroendocrine responses to conditioned fear stimuli in rats

Effects of adrenoceptor antagonists on neuroendocrine responses to conditioned fear stimuli in rats

2324 Effects of adrenoceptor antagonists on neuroendocrine responses to conditioned fear stimuli in rats

Since protective efficacy of the current typhoid vaccines—oral whole-cell Salmonella Typhi Ty21a and parenteral Vi-capsular polysaccharide preparation—is not optimal, and no vaccines are available against paratyphoid or non-typhoidal Salmonella (NTS) serotypes, new approaches deserve to be explored. The immunological mechanisms elicited by the two typhoid vaccines are mainly targeted against different structures. We studied whether these vaccines would enhance S. Typhi-specific immune response and cross-reactivity against other Salmonellae, if administered concomitantly.Volunteers were immunized simultaneously with Ty21a and Vi vaccines (Ty21a + Vi group) or with either of the two singly (Ty21a and Vi groups). All volunteers were investigated for circulating specific and cross-reactive plasmablasts, identified by ELISPOT as IgA, IgG or IgM antibody-secreting cells (ASC) reactive with S. Typhi, S. Paratyphi A/B/C, or selected NTS serotypes (S. Enteritidis, S. Typhimurium).In the Ty21a + Vi group, no specific or cross-reactive plasmablasts were detected before vaccination. After vaccination, the number of S. Typhi-specific plasmablasts (878 ASC/106 PBMC, 95%CI 554–1201) proved higher than in the Ty21a (339 ASC/106 PBMC; p < 0.001) and Vi (149 ASC/106 PBMC; p < 0.001) groups. Likewise, cross-reactive responses in the Ty21a + Vi group were higher than in the Ty21a and Vi groups (Ty21a + Vi vs Ty21a: ASC against S. Paratyphi A/B, S. Enteritidis and S. Typhimurium p < 0.05, against S. Paratyphi C p < 0.01; Ty21a + Vi vs Vi: against S. Paratyphi C not significant, others p < 0.0001). A gut-directed homing profile was seen among O antigen-specific and a systemic one among Vi antigen-specific plasmablasts.Concomitant administration of Ty21a and Vi vaccines is well tolerated and induces an additive immune response to the two vaccines. Thus it enhances the magnitude of both typhoid-specific plasmablast responses and those cross-reacting with paratyphoid and most important NTS serotypes. The data encourage concomitant use of Ty21 and Vi vaccines for those at risk.

Effects of imidazoline antagonists of α 2-adrenoceptors on endogenous adrenaline-induced inhibition of insulin release

We studied the effects of adrenoceptor antagonists and imidazoline derivatives on endogenous adrenaline-induced inhibition of insulin release in anesthetized rats. The intracerebroventricular injection of neostigmine increased plasma levels of catecholamines and glucose but not insulin. Pretreatment with an i.p. injection with phentolamine caused a dose-dependent increase in insulin secretion. When atropine was coadministered with phentolamine, the phentolamine-induced increase in insulin secretion was inhibited. Neither phentolamine nor atropine affected plasma levels of catecholamine. Yohimbine and idazoxan, which are α 2-adrenoceptor antagonists, and tolazoline, a non-selective α-adrenoceptor antagonist, also reversed adrenaline-induced inhibition of insulin secretion. Phenoxybenzamine, prazosin, propranolol, and antazoline, an imidazoline without α 2-adrenoceptor activity, did not affect insulin levels. When agents were preinjected i.p. in rats that were given saline into the third cerebral ventricle, phentolamine and antazoline, but not yohimbine and idazoxan, increased plasma levels of insulin. The results suggest that the inhibition of insulin release induced by adrenaline was reversed by antagonism of α 2-adrenoceptors. Phentolamine and antazoline, both of which are imidazoline derivatives, induced insulin secretion independently of the adrenoceptors only under the resting conditions.

Effects of adrenoceptor antagonists on the hyperthermia and hyperglycemia induced by prostaglandin F 2α in rats

We investigated the effects of intraperitoneal administration of adrenoceptor antagonists on the hyperthermia and hyperglycemia induced by prostaglandin F 2α (50 μg) injected into the third cerebral ventricle in anesthetized rats. Phentolamine inhibited the hyperthermia and hyperglycemia induced by prostaglandin F 2α. Prazosin inhibited the hyperthermia induced by prostaglandin F 2α, while enhancing the hyperglycemia. Yohimbine inhibited the prostaglandin F 2α-induced hyperglycemia without an effect on the hyperthermia. Propranolol had no effect on either prostaglandin F 2α-induced hyperglycemia or hyperthermia. These observations suggest that the hyperglycemia induced by prostaglandin F 2α is regulated by α 2-adrenoceptor systems while the hyperthermia is regulated by α 1-adrenoceptor systems in rats.

Plasma glucose levels predict the disrupting effects of adrenoceptor antagonists on enhancement of memory storage

Adrenoceptor antagonists block the enhancement of memory storage produced by epinephrine injection, but not that produced by glucose injection. The present experiment determined whether adrenoceptor antagonists modify resting blood glucose levels or the magnitude of epinephrine-, glucose-, and footshock-induced increases in circulating glucose levels in a manner related to these previously observed effects on memory. The α- and β-adrenoceptor antagonists, phenoxybenzamine and propranolol, respectively, were injected in rats 30 min prior to administration of epinephrine, glucose, or footshock. Plasma glucose levels were sampled during the next 30 min. Epinephrine-induced increases in plasma glucose levels were potentiated by phenoxybenzamine and were attenuated and delayed by propranolol. The adrenoceptor antagonists did not alter resting plasma glucose levels, or the increases in plasma glucose levels resulting from glucose injection or footshock. These findings suggest that phenoxybenzamine and propranolol alter blood glucose responses to epinephrine injection in a manner which may contribute to attenuation of epinephrine-induced enhancement of memory storage with peripheral injections of adrenoceptor antagonists.

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

1. Studies were carried out in the rat to investigate the effect of adrenoceptor antagonists on stomach to caecum transit time under control conditions and during ileal infusion of Intralipid. Stomach to caecum transit time (SCTT) of the head of the meal was measured by use of environmental hydrogen analysis and the distribution of the meal was assessed by a scintigraphic technique. 2. Four adrenoceptor antagonists were used in these studies, the alpha 1 antagonist prazosin, the alpha 2 antagonist, idazoxan, the beta 1 antagonist atenolol and the beta 2 antagonist ICI 118551. 3. None of the antagonists affected SCTT of the head of the meal during ileal infusion of saline. However, the alpha 1 and beta 1 antagonists significantly reversed (P less than 0.05) the delay in SCTT induced by ileal infusion of Intralipid whereas the alpha 2 antagonist, idazoxan, potentiated this delay (P less than 0.05). 4. Study of the distribution of the radiolabelled meal showed that the Intralipid delayed SCTT by slowing both gastric emptying (P less than 0.05) and small bowel transit (P less than 0.05). 5. Prazosin delayed gastric emptying under control conditions (P less than 0.001) but did not alter significantly the effect of ileal lipid on the distribution of the meal, 100 min or 200 min after gavage.6. The meal distribution was more compatible with the hydrogen analysis after administration of the ,beta-adrenoceptor antagonists. The reversal of the lipid-induced delay in SCTT caused by atenolol was associated with more radioactivity in the large intestine 200min after the gavage. ICI 118551 had no significant effects on either the distribution of the meal or the SCTT of the head of the meal.7. In conclusion, the data confirm that the sympathetic nervous system normally modulates or mediates the mechanisms that influence gastrointestinal transit in the rat and suggest that these mechanisms may be involved in the ileal brake effect. Nevertheless the data also suggest that simple measurement of the transit of the head of the meal by use of environmental hydrogen analysis may sometimes give a misleading impression of the action of drugs on gastrointestinal transit of the bulk of a test meal.

Synergistic inhibitory effects of adrenoceptor antagonists and prostacyclin, and umbilical artery-derived prostacyclin-like activity on platelet aggregation

Adrenoceptor antagonists are being used increasingly for the treatment of pregnancy-induced hypertension (PIH). Previous studies have shown that these drugs can inhibit platelet aggregation and thromboxane production. The aims of this study were to determine (i) whether adrenoceptor antagonists had any effect on vascular prostacyclin (PGI 2) production and (ii) whether these drugs acted synergistically with PGI 2 and the PGI 2-like activity derived from umbilical artery to inhibit platelet aggregation in vitro. The adrenoceptor antagonists labetalol, pindolol and propranolol were found to have no effect on PGI 2 production from the umbilical artery at low drug concentrations. These agents were also found to act synergistically with both pure PGI 2 and PGI 2-like activity derived from umbilical artery to inhibit platelet aggregation. This synergistic effect may be beneficial in the treatment of disorders which are associated with reduced PGI 2 production, such as PIH where such synergy may help compensate for PGI 2 deficiency.

Differential effects of nebivolol on adrenoceptors in the heart and in resistance arterioles in the rat. Quantitative intravital microscopic analysis

The effects of adrenoceptor antagonists on heart rate and on arteriolar reactions to epinephrine, terbutaline, vasopressin, angiotensin II or dopamine in the rat cremaster muscle were compared using ECG analysis and quantitative intravital microscopy. Phentolamine (0.5 mg/kg i.v.) significantly reduced the vasoconstriction of arterioles elicited by topically applied epinephrine (10 −8 to 3.3 × 10 −6 M) while propranolol (0.63 mg/kg i.v.) significantly attenuated the arteriolar vasodilatation elicited by topically applied terbutaline (10 −6 to 10 −4 M). Nebivolol (0.63 mg/kg i.v.) at a dose producing a reduction of resting heart rate equivalent to that caused by propranolol modified neither the epinephrine-induced constriction nor the terbutaline-induced vasodilatation of arterioles. The arteriolar vasoconstriction induced by topically applied vasopressin (9.3 × 10 −9 M), angiotensin II (9.4 × 10 −7 M) or dopamine (5.2 × 10 −5 M) was not modified by nebivolol either. While propranolol reduced the tachycardia and hypotension induced by isoprenaline (0.025, 0.1 μg/kg i.v.), nebivolol reduced the cardiac rhythm increase but not the blood pressure drop in response to the catecholamine (0.025, 0.1, 0.4 μg/kg i.v.). The present intravital microscopic study in the rat demonstrated that, at a dose exerting cardiac β 1-adrenoceptor blockade, nebivolol is devoid of significant activity on α 1-, α 2-, β- 2-adrenoceptors and on receptors for vasopressin, angiotensin II or dopamine in resistance arterioles.

A Comparative Study of the Effects of Adrenoceptor Antagonists on Platelet Aggregation and Thromboxane Generation

Platelet aggregation and thromboxane A2 have been implicated in the pathogenesis of several forms of vascular disease. The aim of this study was to determine the effect of a wide range of adrenoceptor antagonists on platelet aggregation, and thromboxane A2 production, from normal human platelet rich plasma in vitro. Labetalol, pindolol and propranolol inhibited platelet aggregation to collagen in a dose dependent manner. Increasing the concentration of collagen "shifted" the dose response curve to the right. These 3 drugs also significantly inhibited thromboxane A2 generation in response to collagen but not to arachidonic acid. This effect was independent of any inhibitory effect of these drugs on platelet aggregation, and occurred at a drug concentration close to that obtained in vivo. Atenolol, metoprolol, prazosin and timolol were similarly assessed but had no effect on either platelet aggregation or thromboxane A2 generation. This ability of labetalol, pindolol, and propranolol to inhibit platelet aggregation and thromboxane generation, may be of clinical benefit in view of the increasing evidence implicating thromboxane A2 in the pathogenesis of vascular disease.

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. These findings provide further support for an alternative to the hypothesis of negative feedback. Yohimbine and other presynaptic antagonists may prolong the period of potassium efflux from nerve varicosities, and by this means prolong depolarization and the associated period of transmitter release, rather than act by disrupting an ongoing system sensing and responding to fluctuations in extracellular transmitter levels.

Yohimbine and prolongation of stimulation pulse duration alter similarly 3H-transmitter efflux in heart: an alternative to the negative feedback hypothesis.

The hypothesis of negative feedback regulation of noradrenaline release was studied in guinea-pig left atrial halves mounted in vitro. Tissues were transmurally stimulated with 30, 100 or 300 pulses at 2 Hz with pulse durations ranging from 50 mus to 2,000 mus, and the efflux of 3H-transmitter determined. The efflux of tritium increased with increasing pulse duration as was anticipated, but the effects of supposed presynaptic antagonism by yohimbine were opposite to expectations for a negative feedback system. The magnification of efflux by yohimbine, compared to untreated controls was less rather than more as stimulation-induced transmitter efflux climbed with increases in pulse duration, and with all other parameters of stimulation held constant. It is concluded that the neuronal effect of yohimbine is not linked to negative feedback or to any other system sensing the perineuronal concentration of previously released transmitter. Analysis of the effects on tritium efflux of yohimbine and of prolongation of the stimulation pulse duration, reveals a similarity in the way that they promote transmitter release. Yohimbine increased efflux to approximately the same value at all pulse durations between 50 and 1,000 mus and the value reached was equivalent to that obtained in untreated atria during stimulation with very long pulses (2,000 mus duration). It is suggested that yohimbine prolongs the outward current attributable to the efflux of potassium from axon terminals, and by this means prolongs depolarization and the period of transmitter release. Tetraethylammonium (TEA), a quaternary ion known to plug potassium efflux channels, had an effect on transmitter efflux that was, in some ways, similar to that of yohimbine but of greater magnitude. The present findings provide, for the first time, an alternative to the hypothesis of negative feedback, that might explain the presynaptic effects of adrenoceptor antagonists and possibly other compounds.

Influence of sympathomimetic drugs (1-phenyl-2-amino-ethan-1-ol derivatives) on the biosynthesis of prostaglandins and thromboxane B2.

1--The influence of substituted 1-phenyl-2-amino-ethan-1-ols on prostaglandin and thromboxane biosynthesis was studied using ram seminal vesicle microsomes and homogenates of rat lung and of rat stomach fundus. 2--Clear structure-activity relationships were to be seen regarding the effects of sympathomimetic drugs on prostacyclin (PGI2) biosynthesis in the rat stomach fundus homogenates. 3'- and 4'-Monohydroxy-phenyl derivatives as well as 3',4'-dihydroxy-phenyl derivatives stimulated prostaglandin and thromboxane B2 (TXB2) biosynthesis. Contrary to this the 3',5'-dihydroxy-phenyl derivatives orciprenaline, terbutaline and fenoterol were inhibitors of the biosynthesis in rat organ homogenates. 3--All the sympathomimetic drugs tested stimulated cyclo-oxygenase. Orciprenaline suppressed the adrenaline-activated cyclo-oxygenase in a dose-dependent manner. 4--The effects of adrenoceptor antagonists were also studied. Phenoxybenzamine had little effect on cyclo-oxygenase activity whereas phentolamine markedly increased the rate of oxygen uptake. Both the (+)- and (-)-optical isomers of propranolol had no effect on either basal or adrenaline-stimulated oxygen uptake. In contrast, the (+)- and (-)-isomers of pindolol inhibited basal and adrenaline-stimulated uptake.