Peripheral postsynaptic alpha-adrenoceptor blocking properties of some new dihydrobenzofurane and imidazoline derivatives in pithed rats

Peripheral postsynaptic alpha-adrenoceptor blocking properties of six new dihydrobenzofurane and imidazoline derivatives have been investigated in pithed rat against the pressor effects of phenylephrine and cirazoline (alpha 1-agonists) and clonidine and azepexole (alpha 2-agonists). Except for (N-methylimidazolinyl-2)-2 dihydro-2,3 benzofurane (II) that acted neither on alpha 1- nor alpha 2-adrenoceptors, all the compounds revealed blocking effects - plus or minor - on both alpha 1- and alpha 2-adrenoceptors. (Imidazolinyl-2)-2-chloro-7 dihydro-2,3-benzofurane (IV) is equipotent in blocking both alpha 1- and alpha 2-adrenoceptors. 7-Methoxy-(imidazolinyl-2)-2 dihydro-2,3-benzofurane (III) and (imidazolinyl-2)-2-fluoro-7-dihydro-2,3-benzofurane (V) block more effectively alpha 1- than alpha 2-adrenoceptors whereas (imidazolinyl-2)-2-benzocyclobutane (VI) is more potent in blocking alpha 2- than alpha 1-adrenoceptors. (Imidazolinyl-2)-2-dihydro-2,3-benzofurane (I) is a preferential alpha 2-adrenoceptor blocking agent. The most effective agents on alpha 2-adrenoceptors are under further pharmacological investigations.     

Inhibition of the alpha 1 and alpha 2-adrenoceptor-mediated pressor response in pithed rats by raubasine, tetrahydroalstonine and akuammigine

The relative potencies of raubasine, tetrahydroalstonine (THA) and akuammigine on alpha 1- and alpha 2-adrenoceptors were assessed by comparing their effects on the rise in blood pressure induced by stimulation of the sympathetic outflow from the spinal cord or by injection of noradrenaline in pithed rats. Akuammigine was inactive in both cases. Raubasine preferentially antagonized the effects of electrical stimulation while THA antagonized the effects of injected noradrenaline. The results suggest that raubasine preferentially blocks alpha 1-adrenoceptors while THA is more selective for alpha 2-adrenoceptors.     

Pre- and postsynaptic alpha-adrenoceptor blocking activity of raubasine in the rat vas deferens.

1 The actions of raubasine, yohimbine and corynanthine at pre- and postsynaptic alpha-adrenoceptors were studied in the rat vas deferens. 2 Low frequency electrical stimulation of the isolated vas deferens of the rat produced regular contractions that were inhibited by low concentrations of clonidine. This inhibition was presynaptic in origin and involved alpha-adrenoceptors. 3 Presynaptic alpha-adrenoceptor antagonist activity was assessed by studying the effect of increasing antagonist concentrations on cumulative clonidine dose-response curves on the stimulated vas deferens. 4 Postsynaptic alpha-adrenoceptor antagonist activity in the isolated vas deferens was assessed by comparing control cumulative noradrenaline dose-response curves in the absence and in the presence of increasing concentrations of antagonists. 5 The results indicate that raubasine and corynanthine preferentially block postsynaptic alpha-adrenoceptors. Yohimbine is more potent in blocking pre- than postsynaptic alpha-adrenoceptors. The ration of the pre/postsynaptic potency declines in the order yohimbine less than raubasine less than corynanthine.     

The St 587-induced flexor reflex in pithed rats: a model to evaluate central alpha 1-receptor blocking properties

A combination of reserpine, nialamide and the specific alpha 1-adrenoceptor agonist St 587 [2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine] induced a marked increase of the electrically stimulated flexor reflex in pithed rats. This increased reflex - which lasted for more than 3 h - could be inhibited by the alpha 1-receptor antagonist prazosin but not by the alpha 2-adrenoceptor antagonist idazoxan (RX 781094). A range of different drugs was tested, including 17 neuroleptics. Most of the neuroleptics showed marked inhibition of the St 587-induced reflex. Bromperidol, butaclamol and fluperlapine were weak inhibitors while pimozide was without effect. The results showed close correlation to alpha 1-receptor affinities in vitro (r = 0.84, P less than 0.001) while no correlation was found to either D-2 receptor affinities or to 5-HT2 receptor affinities in vitro (r = 0.43, P less than 0.2 and r = 0.41, P less than 0.05, respectively). It is concluded that inhibition of the St 587-induced flexor reflex in pithed rats is an in vivo test model for central alpha 1-receptor blocking properties.     

Cardiovascular effects of acetaldehyde in pithed rats.

The influence of acetaldehyde (30 mg/kg i.v.) on blood pressure and heart rate in anesthetized and pithed rats was studied. In anesthetized rats we observed a small increase, and a subsequent considerable decrease in mean blood pressure. The latter did not occur in pithed rats. Stimulation of the circulatory system in anesthetized and in pithed rats was completely abolished by administration of phentolamine or reserpine. Both in anesthetized and in pithed rats acetaldehyde caused an increase in heart rate which was inhibited in animals treated earlier with propranolol or reserpine. Our results demonstrated that besides its peripheral action, acetaldehyde exerts central effects which cause severe hypotension.     

The effects of some autonomic blocking agents on the heart rates of anaesthetized and pithed rats

The effect of anaesthesia induced by pentobarbitone and urethane on the heart rate responses to autonomic blocking drugs was studied in rats. Under pentobarbitone anaesthesia cholinergic and β-adrenergic antagonists had little effect on heart rate except for those agents possessing partial agonist or general depressant properties. There was no response to pain or hypothalamic stimulation and β-adrenergic blockade to exogenous catecholamines was easily demonstrated. Under urethane anaesthesia, marked effects were seen in response to autonomic antagonists, to pain and to hypothalamic stimulation, β-adrenergic blockade was difficult to establish. Responses in pithed rats closely paralleled those in rats anaesthetized with pentobarbitone. It was concluded that whereas pentobarbitone depressed autonomic function urethane increased it. No evidence was found to support the view that the cardiovascular responses of the rat were different from those of other mammals. A warning was given of the dangers of misinterpreting results obtained from animals anaesthetized with urethane.     

Phenoxybenzamine-induced inhibition of cirazoline pressor responses in pithed rats pretreated with organic or inorganic calcium entry blocking drugs

In groups of propranolol-treated pithed rats pretreatment with either verapamil (1 mg/kg i.a., 20 min) or the inorganic calcium entry blocker (CEB), cobalt (23.8 mg/kg i.a., 20 min) reduced maximum obtainable pressor responses to the relatively selective alpha 2-adrenoceptor agonist B-HT 920 (0.1-1000 micrograms/kg i.v.) equally, by approximately 50%. Verapamil and cobalt at these doses had little or no effect upon pressor responses induced by the relatively selective alpha 1-adrenoceptor agonist cirazoline (0.1-1000 micrograms/kg i.v.). Phenoxybenzamine (0.1 mg/kg i.v., 15 min) displaced to the right and reduced by 44% the maximum obtainable pressor responses to cirazoline. Treatment of animals with the combination of either verapamil or cobalt followed by phenoxybenzamine, at the dose levels and pretreatment times given above, produced significantly greater inhibitions of cirazoline pressor responses (83% and 88% reduction in the maximum obtainable pressor responses to cirazoline respectively) than were observed following administration of phenoxybenzamine alone. Since yohimbine (1 mg/kg i.v.) did not significantly affect the residual responses to cirazoline following treatment with phenoxybenzamine the mechanism responsible for this interaction between CEBs and phenoxybenzamine is not mediated via postjunctional alpha 2-adrenoceptors. Additional studies are required to assess the involvement of a possible subtype of alpha 1-adrenoceptors which appear to mediate vascular responses sensitive to CEBs.     

Cardiovascular effects of copper in pithed rats

The pithed rat preparation was used to study the effects of copper (as cupric chloride) on the release and re-uptake of noradrenaline from sympathetic nerves. At the highest concentration which could be tested without failure of the preparation, there was a slight prolongation in the duration of the tachycardia obtained by electrical stimulation of the cardioacceleratory nerves to the heart. However, the tachycardia obtained after intravenous injection of tyramine was also similarly prolonged from which it is concluded that the phenomenon is not related to inhibition of neuronal re-uptake but is more likely due to alterations in the metabolism of noradrenaline or in the factors governing its diffusion from the synapse. Copper itself caused a dose-dependent increase in blood pressure which was not due to release of noradrenaline from sympathetic neurones. In addition to its own vasoconstrictor effect, it inhibited the increase in blood pressure obtained after administration of phenylephrine, tyramine and vasopressin. Since the extent of the inhibition of all three compounds was similar, it is concluded that the effect is non-specific inhibition of blood vessel contractility. In the pithed rat preparation, as in the chick biventer preparation (Lin-Shiau & Fu 1980), the acute effects of copper seem to be more clearly seen on muscle with little evidence being available to support potent neurotoxicity.     

Cardiovascular responses to milrinone in pertussis toxin-pretreated pithed rats.

The modulating effects of pertussis toxin on angiotensin II and B-HT 920-evoked hemodynamic changes were compared with those of milrinone to evaluate the possible role of guanine nucleotide regulatory proteins (G proteins) in the mechanism of action of milrinone. Both milrinone and pertussis toxin shifted the blood pressure dose-response curves of B-HT 920 to the right, but the responses to angiotensin II were decreased after milrinone pretreatment only. The increase in cardiac frequency evoked by milrinone and isobutylmethylxanthine (IBMX) was not sensitive to pertussis toxin. In contrast, the decrease in systolic blood pressure elicited by milrinone could be prevented by pertussis toxin pretreatment, suggesting the involvement of a regulatory protein. Milrinone and IBMX did not influence the effects of arecoline on blood pressure or heart rate in either normal or pertussis toxin-pretreated rats. It is concluded that milrinone may affect a G protein, but not the adenylate cyclase-associated inhibitory protein, Gi.     

Hypotensive effect of bopindolol in pithed rats

1. Effects of bopindolol, a β adrenoceptor antagonist with partial agonist activity, on the diastolic blood pressure and heart rate of pithed rats were compared with those of pindolol.2. Both bopindolol and pindolol reduced the diastolic blood pressure (DBP) in pithed rats. Bopindolol (3.0 mg/kg) and pindolol (1.0 mg/kg) produced similar decreases in DBP of about 8 mmHg; thus pindolol had a 3-fold higher hypotensive potency when compared with bopindolol.3. Both drugs also produced a dose-dependent decrease in heart rate.4. Propranolol (5 mg/kg) had no antagonistic effect on the decrease in DBP produced by either bopindolol or pindolol.5. These results suggest that both bopindolol and pindolol reduce DBP and heart rate in pithed rats through some mechanism independent of β-adrenoceptors.     

毁脊髓大鼠去甲肾上腺素能神经传递的负反馈调节

毁脊髓大鼠模型中,α肾上腺素受体拮抗剂酚妥拉明(phentolamine),易于拮抗外源性去甲肾上腺素(noradrenaline,NA)诱发的效应,而较难于抑制交感神经兴奋诱发的同样效应。对于交感神经兴奋诱发的心血管效应,酚妥拉明的拮抗效力则取决于电刺激的频率和刺激时程。本实验结果支持突触前α肾上腺素受体在一定条件下调节着去甲肾上腺素释放的学说。     

H3 receptor-mediated inhibition of the neurogenic vasopressor response in pithed rats.

In pithed rats, the H3 agonist R-(-)-alpha-methylhistamine (R alpha MeHA) inhibited the electrically induced increase in blood pressure without affecting the vasopressor response to exogenous noradrenaline. The effect of R alpha MeHA was not affected by the H1 and H2 antagonists dimetindene and ranitidine, but attenuated by the H3 antagonist thioperamide. At higher doses, R alpha MeHA itself increased basal blood pressure; this effect was not affected by the H1, H2 and H3 antagonists. In conclusion, the neurogenic vasopressor response can be modulated via H3 receptors, probably located presynaptically on postganglionic sympathetic nerve fibres.     

A further attempt to characterize the α2-adrenoceptor blocking properties of (imidazolyl-2)-2-benzodioxane 1–4 (170 150) in pithed rats

(Imidazolyl-2)-2-benzodioxane 1–4 (170 150) has been shown to possess α₂-adrenoceptor blocking properties. The present investigation attempted to further characterize the α₂-adrenoceptor blocking effect of 170 150. In pithed rats, 170 150 did not change the pressor effects of cirazoline a selective α₁-adrenoceptor stimulant. On the other hand, 170 150 significantly and competitively antagonized the effects of B-HT 933, B-HT 920 and clonidine, showing that it has a potent action on α₂-adrenoceptors since these three drugs act preferentially on α₂-adrenoceptors.     

alpha-Adrenoceptor and opioid receptor modulation of clonidine-induced antinociception.

1. The antinociceptive action of clonidine (Clon) and the interactions with alpha 1, alpha 2 adrenoceptor and opioid receptor antagonists was evaluated in mice by use of chemical algesiometric test (acetic acid writhing test). 2. Clon produced a dose-dependent antinociceptive action and the ED50 for intracerebroventricular (i.c.v.) was lower than for intraperitoneal (i.p.) administration (1 ng kg-1 vs 300 ng kg-1). The parallelism of the dose-response curves indicates activation of a common receptor subtype. 3. Systemic administration of prazosin and terazosin displayed antinociceptive activity. Pretreatment with prazosin produced a dual action: i.c.v. Clon effect did not change, and i.p. Clon effect was enhanced. Yohimbine i.c.v. or i.p. did not induce antinonciception, but antagonized Clon-induced activity. These results suggest that alpha 1- and alpha 2-adrenoceptors, either located at the pre- and/or post-synaptic level, are involved in the control of spinal antinociception. 4. Naloxone (NX) and naltrexone (NTX) induced antinociceptive effects at low doses (microgram kg-1 range) and a lower antinociceptive effect at higher doses (mg kg-1 range). Low doses of NX or NTX antagonized Clon antinociception, possibly in relation to a preferential mu opioid receptor antagonism. In contrast, high doses of NX or NTX increased the antinociceptive activity of Clon, which could be due to an enhanced inhibition of the release of substance P. 5. The results obtained in the present work suggest the involvement of alpha 1-, alpha 2-adrenoceptor and opioid receptors in the modulation of the antinociceptive activity of clonidine, which seems to be exerted either at spinal and/or supraspinal level.