Effects Of Alpha 2-adrenoceptor Antagonists Research Articles

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.

Effect of alpha-2 adrenoceptor antagonists on colonic function in rats.

We studied the effect of alpha-2 adrenoceptor antagonists on colonic function stimulated by water-avoidance stress, 5-hydroxytryptamine (5-HT), bethanechol and castor oil by comparison with the effects of atropine and a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, ondansetron. Yohimbine, idazoxan and atropine, but not ondansetron, significantly inhibited water-avoidance stress-stimulated faecal excretion. Yohimbine and idazoxan inhibited neither 5-HT- nor bethanechol-stimulated faecal excretion. In contrast, atropine inhibited both 5-HT- and bethanechol-stimulated faecal excretion and ondansetron inhibited 5-HT-stimulated faecal excretion. Yohimbine did not inhibit the incidence of diarrhoea induced by castor oil, but idazoxan significantly inhibited diarrhoea observed during a 1-h period after the administration of castor oil. Both atropine and ondansetron inhibited diarrhoea during a 2-h period after the administration of castor oil. These findings suggest that alpha-2 adrenoceptor antagonists specifically inhibit colonic motor function stimulated by stress in rats.

The involvement of noradrenergic transmission in the morphine‐induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment

1. Our previous studies suggest that in addition to the cerebral dopaminergic systems the noradrenergic ones have a crucial role in the morphine-induced behavioural sensitization in mice. Therefore the effects of alpha2-adrenoceptor antagonist, idazoxan (1 and 3 mg kg(-1), i.p.) on morphine-induced locomotor hyperactivity as well as on morphine-induced changes in cerebral noradrenaline (NA) and striatal dopamine (DA) metabolism were studied in mice withdrawn for 3 days from 5 day repeated morphine treatment. The concentrations of NA, free 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 3-methoxytyramine (3-MT) were determined. 2. Acute morphine (10 mg kg(-1), s.c.) increased locomotor activity in control and in morphine-withdrawn mice; idazoxan alone did not alter the activity. Idazoxan pretreatment did not alter the locomotor hyperactivity induced by acute morphine in control mice but potentiated it in morphine-withdrawn mice. 3. Acute morphine elevated MOPEG less but increased DOPAC and HVA more clearly in morphine-withdrawn mice than in controls, and decreased 3-MT only in controls. Idazoxan alone did not alter the NA or DA metabolite concentrations in control mice, but elevated MOPEG as well as DOPAC in morphine-withdrawn mice. 4. In control mice idazoxan enhanced acute morphine's elevating effect on MOPEG. In withdrawn mice idazoxan counteracted the tolerance so that acute morphine elevated MOPEG in these mice to about similar level as in controls. 5. Idazoxan pretreatment abolished the HVA increasing effect of acute morphine both in control and withdrawn mice. In control mice idazoxan enhanced morphine's elevating effect on DOPAC and abolished morphine's decreasing effect on 3-MT. Idazoxan did not alter morphine's effects on DOPAC or 3-MT concentrations in withdrawn mice. 6. Our results show that in morphine-withdrawn mice idazoxan pretreatment reveals the morphine-induced locomotor sensitization. This most probably occurs by overcoming the tolerance towards the acute morphine-induced increase of cerebral NA turnover and release. It is suggested that in mice the cerebral noradrenergic in addition to the dopaminergic systems are major determinants of the behavioural sensitization to morphine.

Facilitation and depression of ATP and noradrenaline release from sympathetic nerves of rat tail artery.

1. Excitatory junction currents (EJCs) were used to measure ATP release; noradrenaline (NA) oxidation currents and fractional overflow of labelled NA, [3H]NA, were used to monitor the release of endogenous and exogenous NA, respectively, from post-ganglionic sympathetic nerves of rat tail artery. 2. During nerve stimulation with 100 pulses at 5-20 Hz the EJCs initially grew in size (maximally by 23 %, at 2-10 Hz), and then depressed, maximally by 68 % at 20 Hz. 3. The peak amplitude of NA oxidation currents in response to nerve stimulation with 100 pulses at 2-20 Hz grew in size with frequency, while the area was independent of frequency and roughly constant. 4. The size of the NA oxidation currents evoked by nerve stimulation with 4-100 pulses at 20 Hz grew linearly with train length between pulses 4-16. Between pulses 20-100 there was a train length-dependent depression of the signal. 5. Fractional overflow of [3H]NA in response to nerve stimulation with 5-100 pulses at 20 Hz behaved similarly to the EJCs. It initially grew roughly linearly between pulses 5-25, and then showed a dramatic depression similar to that of the EJCs. 6. The alpha2-adrenoceptor antagonists rauwolscine and yohimbine increased the overflow of [3H]NA and the amplitude of NA oxidation currents, but not that of the EJCs. 7. It is concluded that during high-frequency stimulation (i) the release of ATP and NA is first briefly facilitated then markedly depressed, (ii) facilitation and depression of the two transmitters are similar in magnitude and time course, and (iii) alpha2-adrenoceptor antagonists differentially modify EJCs and the NA signals. The results obtained in the absence of drugs are compatible with the hypothesis that ATP and NA are released in parallel, while the effects of alpha2-adrenoceptor antagonists seem to suggest dissociated release.

Inhibition of stress-stimulated colonic propulsion by alpha 2-adrenoceptor antagonists in rats.

Alpha2-adrenoceptor antagonists have been reported to stimulate colonic motor activity, but the effect on colonic motor dysfunction is unclear. We have investigated the effect of alpha 2-adrenoceptor antagonists on wrap-restraint stress-stimulated and normal colonic propulsion in rats. Colonic propulsion was evaluated by the transit of a charcoal marker along the colon. Faecal pellets output was also measured. A 30-min exposure to wrap-restraint stress starting 120 min after infusion of the charcoal marker significantly stimulated colonic transit with a concomitant increase in faecal pellets. Yohimbine and idazoxan, alpha 2-adrenoceptor antagonists, clonidine, an alpha 2-adrenoceptor agonist, and atropine suppressed wrap-restraint stress-stimulated colonic transit and faecal excretion in a dose-dependent manner. Ondansetron and YM060, 5-hydroxytryptamine3 (5-HT3) receptor antagonists, potently inhibited wrap-restraint stress-stimulated colonic transit, but only weakly inhibited faecal excretion. Neither alpha 2-adrenoceptor antagonists nor atropine had any significant effect on normal colonic transit, whereas clonidine and the 5-HT3 receptor antagonists inhibited it. alpha 2-Adrenoceptor antagonists as well as clonidine, atropine and 5-HT3 receptor antagonists inhibit the stress-induced colonic motor dysfunction in rats.

Effects of alpha2-adrenoceptor antagonists on metabolic processes of swine: II. Nitrogen balance responses.

We studied the effects of alpha2-adrenoceptor antagonists (A2AA) on nitrogen (N) partitioning. The diets fed contained 19.8% CP and 1.15% lysine. Pigs were fed the diet as a percentage of BW equaling approximately 90% of voluntary intake. In Trial 1, pigs (n = 11/treatment) were fed a basal diet and injected s.c. at 8-h intervals for 11 d with saline, RX821002 (25 mg/injection), or cimaterol (.6 mg/injection). Compared to saline-treated pigs, urinary N, as a percentage of N eaten, decreased among pigs injected with RX821002 (15%, P < .05) or cimaterol (17%, P < .05). In Trial 2, pigs got saline (n = 6) or 25 mg RX821002 (n = 6) as s.c. injections three times daily, or they were fed a diet containing 150 ppm RX821002 and injected thrice daily with saline (n = 6) for 11 d. The RX821002 lowered apparent DM and N digestibility (P < .05). Compared to controls, RX821002 lowered urinary N, as a percentage of N eaten, 15 and 18% when given by injections or per os, respectively, but effects were not significant. Trial 3 evaluated the effects of RX821002 fed at levels of 0 (n = 6), 37.5 (n = 5), 75 (n = 6), or 150 ppm (n = 6). Contrasts showed linear dose-dependent decreases in gain and apparent N digestibility (P < .05). Compared to untreated controls, urinary N, expressed as a percentage of N consumed, decreased 2, 12, and 10% among pigs fed diets with 37.5, 75, or 150 ppm RX821002, respectively, but effects were not significant. Trial 4 compared N balance in pigs (n = 6/treatment) fed basal diet or diet with 100 ppm RX821002 to that of pigs fed diets with 25 or 100 ppm yohimbine. Treatments reduced apparent N and DM digestibility (P < .05). Urinary N, as a percentage of N consumed, decreased 16 (P > .05), 18 (P < .05), and 24% (P < .05) for 100 ppm RX821002, 25 ppm yohimbine, or 100 ppm yohimbine, respectively. Data from Trials 2, 3, and 4 from control pigs (n = 18) or pigs fed A2AA (all A2AA sources and doses; n = 41) were pooled and analyzed. Feeding A2AA decreased apparent N and DM digestibility (P < .01). The fact that fecal moisture content was higher in pigs fed A2AA suggests rate of digesta passage increased and offers an explanation for reduced N and DM digestibility in treated pigs. Despite adverse effects of A2AA, efficiency of postabsorptive N metabolism increased. As a percentage of N consumed and compared to control pigs, urinary N decreased 15% (P < .01) and retained N increased 12% (P < .05) in animals fed A2AA. Data from these studies show net efficiency of N metabolism is improved in swine given A2AA.

Effects of alpha2-adrenoceptor antagonists on metabolic processes of swine: I. Effects on nonesterified fatty acid and plasma urea nitrogen concentrations in jugularly catheterized pigs.

The presence of alpha2-adrenoceptors in membranes from omental and s.c. adipose tissue from gilts and barrows was shown in saturation binding assays with [3H]yohimbine. Four trials tested effects of alpha2-adrenoceptor antagonists (A2AA) on plasma concentrations of NEFA and urea nitrogen (PUN). In Trial 1, barrows were given i.v. injections of saline, 200 microg/kg BW of one of three A2AA (efaroxan, idazoxan, or RX821002), or 25 microg/kg BW of isoproterenol. Concentrations of NEFA were measured in plasma harvested every 15 min from 1 h before to 2 h after treatment. Compared with results for saline-treated pigs, areas under the curve (AUC) for NEFA were increased (P < .05) by efaroxan, RX821002, and isoproterenol. In Trial 2, barrows received i.v. doses of saline, efaroxan (200 or 400 microg/kg BW), or RX821002 (200 or 400 microg/kg BW). Levels of NEFA were quantified in plasma obtained at 15-min intervals through 2 h after treatment. Among pigs treated with RX821002 at 400 microg/kg BW, mean NEFA AUC was more than three times greater (P < .05) than that for saline-treated animals. Trial 3 tested whether NEFA responses to A2AA were due to direct effects on alpha2-receptors or involved beta-adrenoceptor mediation. Pigs were first treated i.v. with saline or propranolol (1 mg/kg BW). One hour later, pigs were treated i.v. with RX821002 (400 microg/kg BW) or the beta-adrenoceptor agonist cimaterol (25 microg/kg BW). Compared to values for pigs treated with saline at both injections, NEFA AUC among pigs treated with saline at the first injection and RX821002 at the second doubled (P > .05). Plasma NEFA AUC among pigs treated with saline then cimaterol rose nearly fourfold (P < .05) compared with saline-treated controls. Mean NEFA AUC among propranolol-treated pigs was similar to values for saline-treated pigs, suggesting beta-adrenoceptor involvement in the effect of A2AA on NEFA. In Trial 4, pigs were treated s.c. 10 times at 8-h intervals with saline, RX821002 (400 microg/[kg BW x injection]), cimaterol (20 microg/[kg BW x injection]) or recombinant porcine somatotropin (rpST; 1 mg/[pig-injection]). After the 10th treatment, only cimaterol increased NEFA AUC compared to saline-treated controls (P < .05). Mean PUN AUC was reduced by RX821002 and rpST compared to controls; PUN among rpST-treated pigs was lower than that among RX821002-treated pigs (P < .05). In summary, A2AA increase lipolysis in swine by potentiating lipolytic effects of endogenous catecholamines on beta-adrenoceptors. Reduced PUN suggests improved nitrogen efficiency may result from treatment with A2AA.

Evaluating the effects of an alpha-2 adrenoceptor antagonist on erectile function in the human male

The effect of a new alpha-2 adrenoceptor antagonist on erectile function was assessed in 24 men with probable psychogenic erectile dysfunction. The drug was given in two dosages, together with placebo, by intravenous infusion in a balanced cross over design. Once plasma levels were established, erectile, subjective and haemodynamic responses to erotic fantasy and films were measured. Subjects were divided into two age groups, "Younger" (i.e. less than 45 years) and "Older" (greater than 45 years). There was a significant though modest increase in the duration of erectile response with the high dose of the drug, but only in the younger men. There were also drug effects on haemodynamic responses confined to the younger men, who showed markedly reduced responses during placebo administration when compared with the older dysfunctional men and with young "functional" volunteers. The findings raise the possibility that in younger men with psychogenic erectile failure, there is an inhibition of general arousal responses to erotic stimuli which is partially reversed by this drug. In the older men, the different pattern of response suggests that a) there may be a decline in response to the drug with age and b) other age-related factors are playing an important part in the aetiology of their erectile failure.

Effects of alpha-2 adrenoceptor antagonists on rough-and-tumble play in juvenile rats: evidence for a site of action independent of non-adrenoceptor imidazoline binding sites.

The pharmacological specificity of alpha-2 adrenoceptor involvement in the modulation of rough-and-tumble play behavior was assessed in juvenile rats. The alpha-2 adrenoceptor antagonists idazoxan and RX821002 both increased the frequency of pinning in individually housed rats that were given a brief opportunity to play. Dorsal contacts, a measure of play solicitation, were not consistently affected by these compounds. Since RX821002 shows little affinity for non-adrenoceptor imidazoline binding sites, it is likely that the facilitation of play following administration of these two compounds is due to blockade of alpha-2 receptors. The effect of RX821002 and idazoxan is unlikely to be an artifact associated with using rats that are reared in isolation, as RX821002 also increased pinning, as well as dorsal contacts, in group-housed rats that were isolated for a short period (4h) before the play session. The alpha-1 adrenoceptor antagonist prazosin, which also binds to alpha-2B receptors, reduced the frequency of both pinning and dorsal contacts. There was a strong trend for St 587, a centrally active alpha-1 agonist, to attenuate the effect of prazosin on play. While this leaves open the possibility that prazosin may be reducing play through alpha-1 blockade, antagonist activity at alpha-2B receptors cannot be ruled out. From these data, we conclude that the facilitation of play following idazoxan and RX821002 is likely due to blockade of alpha-2A adrenoceptors. These findings add further support for a specific role of alpha-adrenoceptors in the modulation of playfulness in the juvenile rat.

P-667 - Effects of alpha-2 adrenoceptor antagonists on the decline of sexual reflexes in dogs following ejaculation.

P-667 - Effects of alpha-2 adrenoceptor antagonists on the decline of sexual reflexes in dogs following ejaculation.

?1- and ?-adrenoceptor stimulation potentiate the anticonflict effect of a benzodiazepine

Interactions between different noradrenaline (NA)-active drugs and the benzodiazepine alprazolam (APZ) were examined in a modified Vogel's drinking conflict test in the rat. In a dose (0.5 mg/kg) which did not alter the behavior by itself, the alpha 2-adrenoceptor antagonist yohimbine consistently was found to enhance the anticonflict effect of APZ (0.5 mg/kg). The yohimbine induced potentiation of the APZ effect was counteracted both by the selective alpha 1-adrenoceptor antagonist prazosin (0.25 mg/kg) and the beta-adrenoceptor antagonist propranolol (2.0 mg/kg), but not by the selective beta 1-adrenoceptor antagonist metoprolol (2.0 mg/kg). Similar potentiating phenomena were obtained after co-administration of APZ (0.5 mg/kg) with the selective alpha 1-adrenoceptor agonist ST 587 (0.5-1.0 mg/kg) as well as with the suggested beta 2-adrenoceptor agonist clenbuterol (1.0 mg/kg). The results indicate that the potentiative effects of alpha 2-adrenoceptor antagonists on BDZ induced anticonflict action may be due to increased stimulation of alpha 1- and beta-adrenoceptors, via enhanced NA release. The findings are discussed in relation to the signal-to-noise hypothesis of NA function, and in relation to the suggested NA involvement in anxiety-related behavior.

Behavioral effects of alpha2 adrenoceptor antagonists and their interactions with ethanol in tests of locomotion, exploration and anxiety in mice

The behavioral effects of two highly selective alpha 2-adrenoceptor antagonists, atipamezole and idazoxan, were investigated in mice using the plusmaze test of anxiety and the holeboard test of directed exploration and locomotor activity. No anxiogenic effect, as assessed by the tendency to enter the closed as opposed to open arms of the plusmaze, was noted for either drug at any dose tested. Neither were there any significant effects on locomotor activity or directed exploration (head-dipping) in the holeboard, or total plusmaze arm entries at any dose of either drug. The co-administration of either atipamezole or idazoxan had no effect on either the anxiolytic effect of ethanol (2 g/kg) or its locomotor stimulant effect in the holeboard. Atipamezole (1.0 and 3.0 mg/kg) significantly reversed the ethanol-induced reduction in exploratory head-dipping; a similar trend was seen for idazoxan. There was also a significant potentiation of the ethanol-induced increase in the number of total arm entries made on the plusmaze caused by 1.0 mg/kg (but not 3.0 mg/kg) atipamezole and both 0.3 and 1.0 mg/kg idazoxan. The results suggest that some of the behavioral effects of ethanol can be reversed by alpha 2-adrenoceptor antagonists whilst others are unchanged.

Evidence that serotonin receptors are involved in the anticonvulsant effect of yohimbine in mice.

The threshold of seizures induced by electroconvulsive shock (ECS) was determined in mice and the effects of alpha 2-adrenoceptor antagonists (yohimbine, rauwolscine, idazoxan), alpha 2-adrenoceptor agonists (clonidine, B-HT 920), serotonin antagonists (methysergide, metergoline) and a serotonin agonist (quipazine) were studied. The interaction of yohimbine with clonidine, methysergide, metergoline and quipazine was also examined. It was found that yohimbine and rauwolscine elevated the seizure threshold, while idazoxan was ineffective. Clonidine and B-HT 920 were also ineffective, but quipazine elevated the seizure threshold. Methysergide and metergoline did not change the seizure threshold alone, but both of them antagonized the anticonvulsant effect of yohimbine. Clonidine failed to antagonize yohimbine's effects. Quipazine potentiated yohimbine's action. These results suggest that, in mice, the protective effect of yohimbine against ECS-induced seizures may be mediated via serotonin receptors and not via alpha 2-adrenoceptors.

Alpha 2-adrenergic receptors influence tyrosine hydroxylase activity in retinal dopamine neurons

Dopamine (DA) is a putative neurotransmitter in a population of interneurons in the mammalian retina that are activated by photic stimulation. Pharmacological studies were conducted to determine if alpha 2-adrenergic receptors influence the activity of retinal tyrosine hydroxylase (TH), a biochemical indicator of changes in the activity of the DA-containing neurons. TH activity was low in dark-adapted retinas and high in light-exposed retinas. Systemic administration of the alpha 2-adrenoceptor antagonists, yohimbine and piperoxane, to dark-adapted rats significantly stimulated TH activity. This effect was apparently mediated locally within the retina because the response could also be elicited by direct injection of yohimbine into the vitreous. The dose-response relationships for the effects of alpha 2-adrenoceptor antagonists on retinal TH activity were similar to those for the effects on brain noradrenergic neurons, where alpha 2-adrenoceptors have been shown to be involved in the autoregulation of neuronal activity. Clonidine, an alpha 2-adrenoceptor agonist, had no effect when administered alone to dark-adapted rats, but it attenuated the stimulatory effect of yohimbine. In contrast, clonidine decreased TH activity of light-exposed retinas, an effect that was reversed by yohimbine. These observations suggest that alpha 2-adrenoceptors influence the activity of retinal DA-containing neurons.