Opposing central autonomic actions of alpha 1- and alpha 2-adrenoceptor antagonists on oculomotor tone

Electrical stimulation of the afferent sciatic nerve produces reflex mydriasis in anesthetized rats. The alpha 2-antagonist idazoxan (10-100 micrograms/kg i.v.) inhibited this reflex in a dose-dependent fashion. In contrast, the alpha 1-antagonist prazosin (30-300 micrograms/kg i.v.), produced a dose-related enhancement of the reflex. Single dose administration of the alpha 2-antagonists yohimbine (3.0 mg/kg i.v.), rauwolscine (3.0 mg/kg i.v.) and idazoxan (1.0 mg/kg) also blocked the reflex, whereas the alpha 1-antagonists phenoxybenzamine (3.0 mg/kg i.v.), corynanthine (1.0 mg/kg i.v.) and prazosin (1.0 mg/kg i.v.) potentiated this response. These studies demonstrate that alpha 2-antagonists block and alpha 1-adrenoceptor antagonists potentiate alpha 2-adrenoceptor-mediated inhibition of oculomotor tone.     

Phenoxybenzamine partially inhibits alpha 2-adrenoceptors without affecting their presynaptic function

The turnover of alpha-adrenoceptors was assessed by administering phenoxybenzamine (PBZ) intraperitoneally to rats in order to block the receptors irreversibly. The reappearance of the binding of [3H]prazosin, [3H]clonidine and [3H]rauwolscine in membranes from cerebral cortices was then measured. Maximum inhibition of binding occurred 3 hr after administration of phenoxybenzamine. The binding of [3H]prazosin was inhibited by 95% after administration of phenoxybenzamine (2 X 4 mg/kg, i.p.), and the half life (t1/2) for the alpha 1-adrenoceptor was 1.87 days. The "turnover" of binding for the alpha 2-adrenoceptor ligands ([3H]clonidine and [3H]rauwolscine) was similar: with doses of phenoxybenzamine up to 15 mg/kg (i.p.), the binding of both ligands was inhibited to a maximum of 30%. Maximum recovery occurred 3 days after treatment with phenoxybenzamine and the alpha 2-adrenoceptor has an apparent half life for recovery of 12 hr. Since only partial blockade of alpha 2-adrenoceptors was possible with phenoxybenzamine the possibility that these blocked sites included functional presynaptic autoreceptors was investigated. Clonidine (1 microM) attenuated K+-induced release of preloaded [3H]noradrenaline from cortical synaptosomes prepared from control rats by some 35%. Clonidine inhibited this release of [3H]noradrenaline to the same extent in synaptosomes prepared from rats treated with phenoxybenzamine 3 hr prior to sacrifice. This indicates that the alpha 2-adrenoceptors which are blocked by phenoxybenzamine are not part of the functional receptor population.     

Characterization of alpha-adrenoceptors mediating sympathetic vasoconstriction in rat autoperfused hindlimb: effects of SK&F 104078

In the autoperfused hindlimb of pithed rats, vasoconstrictor responses to intra-arterial infusions of the selective alpha 2-adrenoceptor agonist, B-HT 933, were antagonized by the alpha 2-adrenoceptor antagonist, rauwolscine (1 mg/kg i.v.), and by the selective postjunctional alpha 2-adrenoceptor antagonist, SK&F 104078 (1 mg/kg), but not by the selective alpha 1-adrenoceptor antagonist, prazosin (0.1 mg/kg). In contrast, responses to the selective alpha 1-adrenoceptor agonist, methoxamine, were antagonized by prazosin, but not by rauwolscine or SK&F 104078. Vasopressor responses to stimulation of sympathetic nerves were inhibited by prazosin, increased by rauwolscine, and not affected by SK&F 104078. The results indicate that vascular neuroeffector transmission in rat hindlimb is mediated by postjunctional alpha 1-adrenoceptors, and that SK&F 104078 is a selective antagonist of postjunctional alpha 2-adrenoceptor, and lacks the prejunctional alpha 2-adrenoceptor antagonist action of rauwolscine.     

Evidence that the population of postjunctional-adrenoceptors mediating contraction of smooth muscle in the rabbit isolated ear vein is predominantly alpha 2.

1. Noradrenaline (NA), phenylephrine and UK-14304 elicited concentration-dependent contractions of the rabbit isolated ear vein of similar maximal magnitude. The rank order of potency, UK-14304 greater than noradrenaline greater than phenylephrine, is consistent with that of an effect mediated through an alpha 2-subtype. 2. The potent and highly selective alpha 1-adrenoceptor antagonists prazosin and YM-12617, at concentrations as high as 1 microM, produced less than a 4 fold rightward displacement of the NA concentration-response curve. 3. The selective alpha 2-adrenoceptor antagonists rauwolscine, Wy-26703 and CH-38083 antagonized responses to noradrenaline in a competitive manner. For all three antagonists, the pA2 values were consistent with an effect at alpha 2-adrenoceptors. However, 0.1 microM YM-12617 increased the potency of rauwolscine 2 fold indicating the presence of a small population of postjunctional alpha 1-adrenoceptors. 4. The relative antagonist potency of the yohimbine diastereoisomers rauwolscine and corynanthine against noradrenaline (rauwolscine 30 fold greater than corynanthine) is also consistent with an effect at alpha 2-adrenoceptors. 5. Contractions elicited by noradrenaline in the rabbit isolated ear vein appear to be mediated predominantly by postjunctional alpha 2-adrenoceptors.     

alpha 2-Adrenoceptor agonists induced mydriasis in the rat by an action within the central nervous system.

1 The effects of intravenous administration of the selective alpha 2-adrenoceptor agonists clonidine, UK 14,304 and guanoxabenz on rat pupil diameter were investigated. 2 In rats anaesthetized with pentobarbitone, each agonist produced a marked dose-related increase in pupil diameter; the rank order of potency was: clonidine greater than UK 14,304 greater than guanoxabenz. 3 Pretreatment with the selective alpha 2-adrenoceptor antagonist, RX 781094 (0.5 mg/kg, i.v.), produced a parallel 30-40 fold shift to the right of the dose-pupil dilator response curves for the three agonists. Yohimbine (1.5 mg/kg, i.v.) produced about a 10 fold rightward shift of the dose-response curve for guanoxabenz. In contrast, the alpha 1-selective antagonist, prazosin (0.5 mg/kg, i.v.), failed to affect the dose-response relation for guanoxabenz. 4 Several antagonists of varying selectivities towards alpha 1- and alpha 2-adrenoceptors were tested for their ability to reverse the maximal mydriasis induced by guanoxabenz (0.3 mg/kg, i.v.). The rank order of potency of the antagonists producing a 50% reversal of this effect was: RX 781094 greater than yohimbine greater than piperoxan = rauwolscine greater than mianserin greater than RS 21361. Neither corynanthine nor prazosin reversed the guanoxabenz-induced mydriasis. 5 Topical application of RX 781094 (0.1 to 3% w/v solutions) onto one eye produced a slow reversal of guanoxabenz-induced mydriasis; the time course and degree of reversal were virtually the same in both eyes. 6 Intracerebroventricular administration of RX 781094 (1.25-15 micrograms total dose) caused a rapid dose-related reversal of the maximal mydriasis induced by guanoxabenz (0.3 mg/kg, i.v.). 7 Guanoxabenz (0.3 and 1.0 mg/kg, i.v.) did not produce any dilation of the physostigmine-constricted undamaged pupil of the pithed rat. Intravenous adrenaline was found to produce a small mydriatic effect, while atropine completely antagonized the effects of physostigmine in this preparation. 8 These results indicate that alpha 2-adrenoceptor agonists induce mydriasis in the rat through a central alpha 2-adrenoceptor mechanism. However, the site of action within the central nervous system remains to be determined.     

An attempt at selective protection from phenoxybenzamine of postjunctional alpha-adrenoceptor subtypes mediating contractions to noradrenaline in the rabbit isolated saphenous vein.

1. An attempt has been made, with the irreversible alpha-adrenoceptor antagonist phenoxybenzamine, to find the conditions under which postjunctional alpha 1-adrenoceptors in the rabbit isolated saphenous vein can be inactivated, such that postjunctional alpha 2-adrenoceptors can be studied in isolation. 2. Following exposure to various concentrations of phenoxybenzamine, no evidence was found for a selective inactivation of the postjunctional population of alpha 1-adrenoceptors: the "rauwolscine-resistant' (alpha 1-) and the "rauwolscine-sensitive' (alpha 2-) responses to (--)-noradrenaline were similarly affected. 3. However, in "receptor protection' experiments following exposure to a combination of phenoxybenzamine and the selective alpha 2-adrenoceptor antagonist rauwolscine, the remaining response to (--)-noradrenaline appeared to be mediated by a single population of postjunctional alpha 2-adrenoceptors: the response was insensitive to prazosin and rauwolscine was more potent than corynanthine. 4. Partial isolation of the alpha 1-adrenoceptor population was attempted by pre-exposure of the preparation to a combination of phenoxybenzamine and a selective alpha 1-adrenoceptor antagonist, i.e. prazosin or YM-12617. Following receptor protection, the inhibition produced by "selective' concentrations of either of these alpha 1-adrenoceptor antagonists were not significantly different from that observed in control preparations (no phenoxybenzamine). However, the selective alpha 2-adrenoceptor antagonists rauwolscine and CH-38083 were still able to inhibit part of the remaining responses to NA. This is interpreted as indicating that, in addition to protecting the putative postjunctional alpha 1-adrenoceptors, these procedures fail to produce complete inactivation of postjunctional alpha 2-adrenoceptors. 5. It is concluded that, although phenoxybenzamine appeared to be non-selective for the two populations of postjunctional alpha-adrenoceptors in the rabbit isolated saphenous vein, inclusion of a "selective' concentration of a competitive antagonist during the inactivation period results in differing degrees of functional protection of each subtype. Pharmacological isolation was possible for alpha 2-adrenoceptors but not convincingly for alpha 1-adrenoceptors.     

Antagonism of clonidine-induced hypothermia by alpha adrenoceptor antagonists in electrically stimulated mice

The involvement of receptor subtypes in clonidine-induced hypothermia in electrically stimulated mice was studied using various alpha-adrenoceptor antagonists. Yohimbine, the selective alpha 2-adrenoceptor antagonist significantly blocked the action of low dose (50 micrograms/kg i.p.) of clonidine pretreated with Minimal Threshold Shock (12 mA, 0.2 Sec), while prazosin, selective alpha 1-adrenoceptor antagonist partially blocked the action, suggesting predominant involvement of alpha 2 and partial involvement of alpha 1-adrenoceptors. Under similar conditions when clonidine was used in higher dose (500 micrograms/kg i.p.), its action was blocked by prazosin, phenoxybenzamine and yohimbine suggesting involvement of both alpha 1 and alpha 2-adrenoceptors. In case of animals pretreated with Maximal Threshold Shock (36 mA, 0.2 Sec) the hypothermic action of clonidine in lower dose was blocked by all the three antagonists viz. prazosin, phenoxybenzamine and yohimbine, suggesting involvement of both alpha 1 and alpha 2-adrenoceptors, however, when clonidine was used in the higher dose, the action was significantly antagonised by prazosin and partially by yohimbine, suggesting predominant involvement of alpha 1 and partial involvement of alpha 2-adrenoceptors.     

The effect of pertussis toxin treatment on alpha-1-adrenoceptor-mediated pressor responses in the pithed rat: dependence on agonist efficacy but not chemical class.

The role of pertussis-toxin-sensitive guanine nucleotide regulatory proteins (G proteins) in the signal transduction processes involved in post-junctional vascular alpha 1-adrenoceptor-mediated vasoconstriction has been investigated in the pithed rat using two chemical classes of alpha-adrenoceptor agonists, the phenethylamines and imidazolines, in order to determine if they utilize different signal transduction mechanisms. Pertussis toxin pretreatment (50 micrograms/kg, i.v., 3 days prior to experimentation) slightly inhibited the pressor response to the full alpha 1-adrenoceptor agonist of the phenethylamine class (-)-norepinephrine (in the presence of rauwolscine, 1 mg/kg, i.v.), whereas it markedly inhibited the pressor response to the partial alpha 1-adrenoceptor agonist of the imidazoline class oxymetazoline (in the presence of rauwolscine, 1 mg/kg, i.v.). However, after elimination of the alpha 1-adrenoceptor reserve for (-)-norepinephrine with phenoxybenzamine (0.1 mg/kg, i.v.), the pressor response to this agonist became sensitive to inhibition by pertussis toxin treatment. The pattern of inhibition of alpha 1-adrenoceptor-mediated pressor responses produced by pertussis toxin was similar to that produced by the calcium channel antagonist nifedipine (1 mg/kg, i.a.). The results support the hypothesis that vascular alpha 1-adrenoceptors may be coupled to a G protein which is sensitive to pertussis toxin and which couples the alpha 1-adrenoceptor to the influx of extracellular calcium, which possibly another G protein that is insensitive to pertussis toxin that couples the alpha 1-adrenoceptor to the release of intracellular calcium. The intrinsic efficacy of the agonist, and not its chemical class, determines which signal transduction mechanisms will be utilized.     

The alpha 1- and alpha 2-adrenoceptor involvement in the central cardiovascular action of clonidine in the conscious renal hypertensive cat

An attempt has been made to characterise the alpha-adrenoceptor subtype (alpha 1 or alpha 2) mediating the hypotensive and bradycardic action of clonidine in conscious renal hypertensive cats. The relatively selective alpha 2-adrenoceptor agonists clonidine, UK-14,304, guanfacine and lofexidine caused significant hypotension and bradycardia when given intracerebroventricularly (i.c.v.). This suggests that alpha 2-adrenoceptors can mediate hypotension and bradycardia. However, both alpha 1- and alpha 2-adrenoceptor antagonists, prazosin, UK-33,274, corynanthine, yohimbine, rauwolscine and RS21361 blocked the hypotensive effect of clonidine. These results suggest an alpha 1-adrenoceptor may also mediate the central hypotensive action of clonidine, or possibly that the central alpha-adrenoceptors in which clonidine acts, may show pharmacological differences to peripheral alpha 1- and alpha 2-subtypes.     

Further investigation of the sites of vascular alpha 1 and alpha 2 adrenoceptors in the anaesthetised spontaneously hypertensive rat

We have looked at the role played by alpha 1 and alpha 2 adrenoceptors in the control of blood pressure in the anaesthetised spontaneously hypertensive rat (SHR) by examining the blood-pressure-lowering effects of the alpha 1-adrenoceptor antagonist prazosin and the alpha 2-adrenoceptor antagonist rauwolscine in 5 groups of animals: unoperated, adrenal demedullated, shamoperated, sympathectomised with 6-hydroxydopamine, and vehicle treated. Prazosin (1 mg/kg) produced significant falls in diastolic blood pressure (DBP) in all groups of rat but the fall was significantly less in sympathectomised animals. In the presence of prazosin (1 mg/kg), rauwolscine (0.1-1 mg/kg) lowered DBP in all groups of rat except the adrenal demedullated animals. In the absence of prazosin, rauwolscine (0.1 mg/kg) produced a significant fall in DBP only in sympathectomised animals. These results demonstrate that alpha 2 adrenoceptors are involved in blood pressure control in the intact or sympathectomised SHR but not following adrenal demedullation, suggesting that circulating catecholamines rather than neurally released noradrenaline (NA) are responsible for these alpha 2-adrenoceptor-mediated pressor effects. In contrast, only alpha 1-adrenoceptor-mediated pressor responses are reduced by sympathectomy, suggesting that neurally released NA acts mainly on alpha 1-adrenoceptors.     

Pharmacological analysis of postjunctional alpha-adrenoceptors mediating contractions to (-)-noradrenaline in the rabbit isolated lateral saphenous vein can be explained by interacting responses to simultaneous activation of alpha 1- and alpha 2-adrenoceptors.

1. The pharmacological characteristics of the alpha-adrenoceptor population in the rabbit isolated saphenous vein has been examined with (-)-noradrenaline (NA), as principal agonist, and a number of antagonists with selectivity for either alpha 1- or alpha 2-adrenoceptors. 2. The rank order of potency of various agonists is consistent with a population of alpha 2-adrenoceptors; UK-14304 greater than (-)-noradrenaline = (-)-adrenaline greater than B-HT 920 = cirazoline greater than phenylephrine greater than amidephrine, but the rank order of pA2 values for the antagonists against (-)-noradrenaline: BDF-6143 greater than rauwolscine = prazosin greater than CH-38083 = YM-12617 greater than Wy-26703 = phentolamine greater than corynanthine, is indicative of a mixed population of alpha 1- and alpha 2-adrenoceptors or, alternatively, a new subtype with characteristics of both the alpha 1- and alpha 2-subtypes. 3. Further evidence for two discrete populations of alpha-adrenoceptors is provided by, (a) the potent but non-competitive effect of prazosin against (-)-noradrenaline, (b) the presence of a component of the contractions elicited by NA and phenylephrine which is resistant to the selective alpha 2-adrenoceptor antagonists rauwolscine and CH-38083: these responses were inhibited by the selective alpha 1-adrenoceptor antagonists prazosin and YM-12617, but not by the selective alpha 2-adrenoceptor antagonist BDF-6143 and, (c) the relative potency of the yohimbine diastereoisomers rauwolscine and corynanthine against NA, phenylephrine and UK-14304. 4. In spite of the overwhelming evidence for a population of postjunctional alpha 2-adrenoceptors, prazosin was similarly effective against all agonists and failed to discriminate between those with putative selectivity for alpha 1- and alpha 2-adrenoceptors. This suggests an interaction of the effects of agonists at the two alpha-adrenoceptor subtypes. 5. An attempt has been made to reconcile a number of paradoxical observations with regard to the identification of postjunctional alpha 2-adrenoceptors in vitro, and it is suggested that in many of the isolated blood vessels presently available for examination both subtypes reside on the same smooth muscle cell. The pharmacological consequences of multiple subtypes of receptors mediating the same response is considered.     

Are beta- and alpha 2-adrenoceptors co-regulated during their stimulation? Behavioral studies

The effects of beta-, and alpha 1-antagonists on the clenbuterol- and clonidine-induced depression of the exploratory activity was measured in rats in the open field test. The ability of clenbuterol (0.5 mg/kg) to reduce exploration was antagonized by 1-propranolol, significantly reduced by rauwolscine and unchanged by corynanthine and prazosin. Clonidine (0.2 mg/kg)-induced hypoactivity was significantly reduced by all the used adrenergic antagonists. A combined treatment with non-sedative doses of clenbuterol and clonidine significantly reduced exploration. Results suggest that both beta- and alpha 2-adrenoceptors are involved in clenbuterol- and clonidine-induced sedation. Moreover, they may indicate the existence of beta- and alpha 2-adrenoceptor interaction.     

Activation of alpha 2-adrenoceptors attenuates the inotropic effect of field stimulation in atria

Guinea-pig left atria were driven to contract at a rate of 0.5 Hz by stimulation with punctate electrodes. For additional field stimulation, a train of one to eight field pulses (30 V; 0.05-0.4 ms duration) was applied during each refractory period. Cholinergic effects were blocked by atropine and thus the resulting increase of the contractile force was caused by noradrenaline released from sympathetic nerve endings. Trains of several short field pulses delivered in the refractory period after each contraction produced a significantly greater inotropic effect than one single pulse of the same total duration delivered in each refractory period. Phentolamine, rauwolscine and idazoxan, by blocking prejunctional alpha 2-adrenoceptors selectively increased the inotropic effect of single field pulses. Selective blockers of alpha 1-adrenoceptors (prazosin, corynanthine) were ineffective in this respect. The effect of alpha 2-adrenoceptor blockers persisted in the presence of noradrenaline uptake blockers (cocaine or desipramine plus corticosterone) or phenylephrine, but was overcome by the alpha 2-adrenoceptor agonists, clonidine and guanabenz. It is concluded that activation of presynaptic alpha 2-adrenoceptors limits the release of noradrenaline by long-lasting single field pulses. Autoinhibition of transmitter release was not seen with trains of short field pulses.     

Mechanism of ketanserin-induced sympatho-inhibition.

Experiments were undertaken to determine if sympatho-inhibition produced by ketanserin is due to antagonism of central nervous system alpha 1-adrenoceptors rather than central 5-HT2 receptors and if (like prazosin) it produces sympatho-inhibition indirectly via a central (presynaptic) alpha 2-adrenoceptor mechanism. Administration of ketanserin (0.03-3.0 mg/kg i.v.) caused a dose-related depression of sympathetic-cholinergic electrodermal responses evoked by electrical stimulation of the hypothalamus in pentobarbital anesthetized cats. No effect of ketanserin was observed on electrodermal responses evoked by preganglionic sympathetic nerve stimulation nor did the more specific 5-HT2 receptor antagonist, cinanserin, produce a central sympatholytic effect at dosages up to 3 mg/kg i.v. Pretreatment with alpha 2-adrenoceptor blockers yohimbine, idazoxan, or rauwolscine significantly antagonized ketanserin-induced sympatho-inhibition. Depletion of central nervous system (CNS) monoamines totally prevented ketanserin-induced sympatho-inhibition although clonidine (30 micrograms/kg i.v.) continued to be effective. These results suggest that ketanserin acts in the CNS to reduce sympathetic reactivity by blocking alpha 1-adrenoceptors and not 5-HT2 receptors. In this regard, ketanserin appears to act in a manner similar to other alpha 1-adrenoceptor antagonists (e.g. prazosin and indoramin) by an apparent presynaptic facilitation of alpha 2-adrenoceptor mediated tonic inhibition descending from the lower brainstem.     

Permissive role of spinal alpha 1-adrenoceptors in sudomotor efferents

The electrodermal potential (EDP) recorded in the forepaws of anaesthetized cats in response to stimulation of the cholinergic-sympathetic nervous system at different levels was taken as a measure for sudomotor activity. Electrical stimulation of the hypothalamus with square wave pulses (1 ms duration, 0.5-64 Hz, 2 s train length) at intervals of 1 min induced rate-dependent EDPs which were inhibited at all rates of stimulation by intravenous (i.v.) injection of doses less than 40 micrograms/kg of the alpha 1-adrenoceptor blocking drug prazosin. However, prazosin (50-500 micrograms/kg i.v.) did not impair EDPs induced by preganglionic stimulation (0.5-64 Hz) or by injection of the nicotinic ganglion stimulant DMPP (50 micrograms/kg i.v.). Prazosin (50 micrograms/kg i.v.) inhibited EDPs induced by unilateral electrical stimulation (square wave pulses, 1 ms duration, 16 Hz, 2 s train length, 1 min intervals) of the spinal cord at C 1 in cats with an axotomy at the level of the medulla oblongata, thus indicating a spinal site of prazosin action and suggesting a permissive role of spinal catecholamines by activation of alpha 1-adrenoceptors. In spinal preparations pretreated with 250 micrograms/kg yohimbine i.v. to block inhibition by alpha 2-adrenoceptors of catecholamine reuptake, cocaine 2.5 mg/kg i.v. potentiated EDPs induced by spinal stimulation with 8 Hz. This effect could be antagonized by 50 micrograms/kg prazosin or 1000 micrograms/kg corynanthine i.v. In spinal preparations pretreatment with 5 mg/kg reserpine i.p. for depletion of catecholamines and 250 micrograms/kg yohimbine i.v., EDPs (16 Hz) were smaller than in undepleted preparations. Under these conditions injection of 100 micrograms/kg clonidine i.v. caused amplification of EDPs. This effect was antagonized by 50 micrograms/kg prazosin i.v. After i.v. pretreatment with 250 micrograms/kg yohimbine the i.v. injection of 2.5 mg/kg cocaine also potentiated EDPs which were induced by hypothalamic stimulation in intact cats. The results indicate that catecholaminergic neurons influence sudomotor activity by interaction with efferents of the cholinergic-sympathetic nervous system at the level of the spinal cord. Catecholamines seem to facilitate impulse transmission in non-catecholaminergic synapses by activation of alpha 1-adrenoceptors.     

Spinal alpha 1- and alpha 2-adrenoceptors mediate facilitation and inhibition of spinal motor transmission, respectively

The role of descending noradrenergic fibers in the spinal motor systems was investigated using spinal reflexes in acutely spinalized rats. In rats pretreated with the MAO inhibitor clorgyline-HCl (1 mg/kg, i.v.), L-3,4-dihydroxyphenylalanine (L-dopa) (5 mg/kg, i.v.), a precursor of dopamine and noradrenaline, markedly potentiated the mono- (MSR) and polysynaptic reflexes (PSR). Selective blockade of alpha 1-adrenoceptors by pretreatment with prazosin-HCl abolished these facilitatory effects on the MSR and the PSR and revealed the inhibitory effect of L-dopa on the PSR. The depression of PSR was antagonized by the alpha 2-antagonist piperoxan. Clonidine-HCl (0.05 mg/kg, i.v.), a so-called alpha 2-agonist, and tizanidine-HCl (0.1 mg/kg, i.v.) decreased the MSR and the PSR in rats pretreated with prazosin. These inhibitions were antagonized by piperoxan. These results suggest that alpha 1- and alpha 2-adrenoceptors mediate facilitation and attenuation of motor transmission in the rat spinal cord, respectively.     

Modulation of noradrenaline release in the pithed rabbit: a role for angiotensin II

This study in the pithed rabbit with electrically stimulated sympathetic outflow (spinal region, T-8; 3 Hz) was conducted to determine the contribution of the renin-angiotensin system to noradrenaline release in vivo. The rate of noradrenaline release (spillover) into the plasma was determined from the endogenous plasma noradrenaline level and the simultaneously determined noradrenaline plasma clearance. In the pithed rabbit, infusion of angiotensin II (0.1 microgram/kg/min i.v.) failed to increase the noradrenaline release rate and only slightly increased blood pressure. On the other hand, the angiotensin-converting enzyme inhibitor captopril (1 mg/kg i.v.) decreased both blood pressure and the noradrenaline release rate. Bilateral nephrectomy was performed to reduce endogenous angiotensin II formation; and in this case, infusion of angiotensin II markedly increased the noradrenaline release rate and blood pressure, whereas captopril had no effect on either parameter. These results suggest that angiotensin II modulates noradrenaline release in vivo through activation of facilitatory prejunctional angiotensin II receptors, and that in the pithed rabbit these receptors are probably maximally activated by endogenously synthesized angiotensin II. The actions of angiotensin II on noradrenaline release open the possibility that increases in blood pressure in the pithed rabbit--by decreasing renin release via intrarenal baroreceptors and hence decreasing angiotensin II formation--may lead to decreased noradrenaline release. This was investigated using phenylephrine (6 micrograms/kg/min i.v.), a selective alpha 1-adrenoceptor agonist, and adrenaline (1 microgram/kg/min i.v.), and alpha 1/alpha 2-agonist. Both drugs increased blood pressure and decreased the noradrenaline release rate. After bilateral nephrectomy, the inhibitory effect of phenylephrine on noradrenaline release was abolished, whereas that of adrenaline was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influences of the endothelium and hypoxia on alpha 1- and alpha 2-adrenoceptor-mediated responses in the rabbit isolated pulmonary artery.

1. The effects of the inhibitor of nitric oxide synthase, N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M), mechanical disruption of the endothelium and hypoxia on contraction to noradrenaline (alpha 1- and alpha 2-adrenoceptor agonist), phenylephrine (alpha 1-adrenoceptor agonist) and UK 14304 (alpha 2-adrenoceptor agonist) were compared in the rabbit isolated pulmonary artery. The effects of the selective antagonists rauwolscine (10(-6) M, alpha 2-adrenoceptors) and prazosin (10(-7) M, alpha 1-adrenoceptors) on the contractions to noradrenaline before and after exposure to L-NAME were also assessed. 2. Noradrenaline, phenylephrine and UK 14304 all produced concentration-dependent increases in vascular tone. The responses to noradrenaline were sensitive to both rauwolscine and prazosin (effect of prazosin >> rauwolscine). L-NAME increased the potency of both noradrenaline and UK 14304, and also the maximum tension achieved. It had no effect on the responses to phenylephrine. After L-NAME, contractions to noradrenaline, although still sensitive to both rauwolscine and prazosin, were now more sensitive to inhibition by rauwolscine. 3. Endothelium removal augmented the potency and maximum contractions to noradrenaline, phenylephrine and UK 14304. 4. Hypoxia decreased both the potency of phenylephrine and its maximum contractile response, but increased the maximum response to noradrenaline without effecting responses to UK 14304. 5. In conclusion, in the rabbit pulmonary artery, augmentation of contractile responses to noradrenaline by L-NAME involves a potentiation of alpha 2-adrenoceptor-mediated contraction probably through an effect on the synthesis of endothelium-derived nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta 1-adrenoceptor antagonism by urapidil prior to and after the alpha 2-antagonist rauwolscine in anesthetized dogs

The purpose of this investigation was to evaluate the in vivo beta-adrenoceptor antagonistic properties of urapidil, a new antihypertensive alpha 1-adrenoceptor blocking agent. In dogs anesthetized with pentobarbital, the cardioaccelerator nerve was isolated, decentralized and stimulated electrically to elicit adrenergically mediated increases in heart rate. Dobutamine was administered (3-30 micrograms/kg i.v.) to elicit increases in heart rate by the direct stimulation of beta-adrenoceptors. Urapidil 2 mg/kg i.v. had no significant effect on cardioaccelerator nerve-induced tachycardia, but 5 mg/kg i.v. decreased the response by 27%. Heart rate responses to dobutamine were suppressed slightly by the low dose of urapidil and to a greater degree by the high dose of urapidil, whereas the pressor response to dobutamine was markedly attenuated at both dose levels. Neurally or dobutamine-elicited tachycardia remaining after urapidil treatment was eliminated by propranolol (1 mg/kg i.v.). When the selective alpha 2-antagonist rauwolscine was administered (1000 micrograms/kg i.v.), tachycardic responses to nerve stimulation increased 49% above control, and urapidil (5 mg/kg) given subsequently, caused a 48% reduction in the response. These data indicate that urapidil has weak beta 1-blocking activity more clearly seen after blockade of alpha 2-adrenoceptors.     

Alpha-adrenoceptor antagonism by apoyohimbine and some observations on the pharmacology of alpha-adrenoceptors in the rat anococcygeus and vas deferens

alpha-Adrenoceptor antagonism of several test drugs was assessed against adrenergic contractile responses to field stimulation in rat vas deferens and anococcygeus, the prejunctional inhibitory effect of xylazine in vas deferens and the contractile effects of alpha-adrenoceptor agonists in anococcygeus. Against the adrenergic nerve-induced contraction in vas deferens, the potency series was WB 4101 greater than prazosin greater than apoyohimbine greater than corynanthine greater than yohimbine greater than rauwolscine. Against the inhibitory effect of xylazine in vas deferens the potency series was apoyohimbine greater than rauwolscine = yohimbine greater than WB 4101 much greater than prazosin and corynanthine. In anococcygeus, against the contractile responses to adrenergic nerve stimulation or to the agonists amidephrine, noradrenaline and xylazine, the potency series was apoyohimbine greater than corynanthine greater than rauwolscine. These results show that apoyohimbine is more potent than the yohimbine sterioisomers as an antagonist at alpha 1- and alpha 2-adrenoceptors but is not more selective. The assay methods employed confirm the current classification of 'alpha'-receptors and drugs.