PRESYNAPTIC DOPAMINE RECEPTORS MEDIATE THE INHIBITORY ACTION OF DOPAMINE AGONISTS ON STIMULATION-EVOKED PRESSOR RESPONSES IN THE RAT

1 The effects of the dopamine agonists TL-99, M-7 (N, N-dimethyl analogues of aminotetralins) and N, N-din propyldopamine (NNPD) on stimulation-evoked pressor responses and tachycardia in pithed Sprague-Dawley rats were investigated when pressor responses to the compounds per se had subsided. Various antagonists were used to characterise the effects of the dopamine agonists. 2 M-7 (3 μg/kg i.v.) and NNPD (1 mg/kg i.v.), but not TL-99 (1–30 μg/kg i.v.), inhibited pressor responses evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 3 M-7 (3 μg/kg i.v.), but neither NNPD (1 mg/kg i.v.) nor TL-99 (1–30 μg/kg), inhibited tachycardia evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 4 The inhibition of stimulation-evoked pressor responses by M-7 and NNPD was prevented by pimozide, metoclopramide and sulpiride but not by yohimbine, atropine, cimetidine or propranolol. 5 The inhibition of stimulation-evoked tachycardia by M-7 was prevented by yohimbine (and to a certain extent by sulpiride) but not pimozide, metoclopramide, atropine or cimetidine. 6 Pressor responses elicited by TL-99, M-7 and NNPD were selectively antagonised by yohimbine, but not by prazosin, indicating that these responses were mediated by stimulation of vascular postsynaptic α₂-adrenoreceptors. 7 This study demonstrates that, in the rat, presynaptic dopamine receptors exist on sympathetic pre- or postganglionic nerve endings to blood vessels, but not on sympathetic pre- or postganglionic nerve endings to the heart, where inhibition by M-7 of stimulation-evoked tachycardia is mediated by stimulation of presynaptic α₂-adrenoreceptors.     

INVOLVEMENT OF α1-ADRENOCEPTORS IN CHRONOTROPIC RESPONSES TO ENDOGENOUSLY RELEASED AMINES IN THE PITHED RAT

1. In pithed rats, yohimbine (1 mg/kg i.v.) enhanced the positive chronotropic responses to spinal stimulation of cardiac sympathetic nerves with eight pulses delivered at 2 or 4 Hz, indicating that auto-inhibition was operating, but did not increase responses to shorter lengths of trains of 8 pulses at 8, 16 or 32 Hz which did not allow sufficient time for auto-inhibition to come into effect. 2. The positive chronotropic response to cardiac sympathetic nerve stimulation with eight pulses at 8 Hz of about 60 beats/min was not affected by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg), but was reduced to about 20% of the control value by propranolol (1 mg/kg). 3. In the presence of propranolol, the residual positive chronotropic responses to cardiac sympathetic nerve stimulation were virtually abolished by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg). 4. The positive chronotropic response to tyramine (0.1 mg/kg i.v.) was reduced from 100 to 12 beats/min by propranolol (1 mg/kg), and the residual response was abolished by prazosin. 5. The findings indicate that noradrenaline released from cardiac sympathetic terminals by nerve stimulation or by tyramine acts on alpha 1-adrenoceptors to produce a positive chronotropic response that is revealed when beta-adrenoceptors are blocked.     

POSITIVE CHRONOTROPIC REPONSES TO CARDIAC α1-ADRENORECEPTOR ACTIVATION IN THE PITHED RAT

• 1 Adrenaline (0.1–10 μg/kg), noradrenaline (0.1–10 μg/kg) and phenylephrine (1–100 μg/kg) acted on both cardiac α₁- and β-adrenoreceptors to induce positive chronotropic responses in the pithed rat.
• 2 When β-adrenoreceptors were blocked by propranolol (1 mg/kg), the residual chronotropic responses were due to activation of α₁-adrenoreceptors since they were significantly reduced by prazosin (10–100 μg/kg).
• 3 Methoxamine (10–300 μg/kg) acted solely on cardiac α₁-adrenoreceptors to induce positive chronotropic responses which were abolished by prazosin (10–100 μg/kg) alone, as has been demonstrated previously for amidephrine.
• 4 The rank order of potency for eliciting the positive chronotropic response to α₁-adrenoreceptor activation was adrenaline > noradrenaline > phenylephrine > methoxamine.
• 5 The positive chronotropic responses to adrenaline (3–10 μg/kg), noradrenaline (3–10 μg/kg) and phenylephrine (30–100 μg/kg) produced by activating α₁-adrenoceptors had a slower time course than did the chronotropic responses produced by activation of β-adrenoreceptors.

     

POSITIVE CHRONOTROPIC RESPONSES PRODUCED BY α-ADRENORECEPTORS IN THE PITHED RAT

• 1 Phenylephrine (1–100 γg/kg, intravenously) produced dose-dependent increases in heart rate and blood pressure in the pithed rat.
• 2 The positive chronotropic response to phenylephrine (10 μg/kg) was reduced in a dose-dependent manner by propranolol (0.01–0.3 mg/kg), but higher doses of propranolol (up to 3 mg/kg) did not reduce the response by more than about 50%. The residual response was virtually abolished by phentolamine (0.3 mg/kg) or prazosin (3 μg/kg). Labetalol (3 mg/kg) which has both α- and β-blocking activity, also abolished the positive chronotropic response.
• 3 The pressor response to phenylephrine (1–30 μg/kg) was enhanced by propranolol (1 mg/kg) and abolished by phentolamine (1 mg/kg) and prazosin (30 μg/kg). Labetalol (3 mg/kg) reduced the response to phenylephrine by 73%.
• 4 Propranolol (0.3 mg/kg) completely blocked the chronotropic and vasodepressor effects of isoprenaline (0.1 μg/kg).
• 5 It is concluded that phenylephrine acts on both α₁- and β₁-adrenoreceptors to produce an increase in heart rate, on α₁-adrenoreceptors to produce vasoconstriction and on β₂-adrenoreceptors to produce vasodilation. This latter effect is usually masked by the predominant vasoconstrictor action.

     

MODULATION BY β-ADRENORECEPTORS OF SPONTANEOUS CONTRACTIONS OF RAT URINARY BLADDER

• 1 Propranolol (0.1 mg/kg i.v.) but not metoprolol (0.2 mg/kg i.v.) pretreatment increased the spontaneous motility triggered by progressive filling of rat urinary bladder without a concomitant effect on bladder capacity, except at high filling volumes. Compared to controls, the spontaneous motility of urinary bladder in propranolol pretreated rats displayed a higher frequency, indicating the existence of a tonic sympathetic inhibition.
• 2 β-adrenoreceptor stimulation by isoprenaline (0.1–10 μg/kg i.v.) or terbutaline (0.1–1 mg/kg i.v.) in vivo produced a dose dependent inhibition of bladder spontaneous motility which was antagonized by propranolol (0.1 mg/kg i.v.) but not by metoprolol (0.2 mg/kg i.v.). Propranolol (0.2 mg/kg i.v.) pretreatment did not antagonize the inhibition of bladder motility produced by intravenous papaverine (0.5 mg/kg).
• 3 Propranolol (0.1 mg/kg i.v.) significantly antagonized the isoprenaline-induced tachycardia (β₁ mediated) and fall in diastolic blood pressure (β₂ mediated) while metoprolol (0.2 mg/kg i.v.) antagonism was confined to β₁ mediated responses.
• 4 Isoprenaline (0.25–1.5 μM) inhibited in a concentration dependent manner field stimulation induced contractions of rat detrusor muscle strips as did tetrodotoxin (0.5 μM). Hexamethonium (50 μM) had no inhibitory effect.
• 5 Our in vivo findings support the view that β₂-adrenoreceptors are responsible for modulating bladder motility mainly by suppressing the onset of spontaneous contractions.

     

EVIDENCE FOR MEDETOMIDINE AS A SELECTIVE AND POTENT AGONIST α2-ADRENORECEPTORS

• 1 The activity on α-adrenoreceptors of medetomidine (±)-4-(α,2,3-trimethylbenzyl)imidazole), an α-methyl derivative of detomidine, has been characterized in vivo and in vitro using detomidine, MPV 207, MPV 295, azepexole, clonidine and xylazine for reference purposes.
• 2 Medetomidine (1–100 μg/kg i.v.) was a hypotensive and bradycardic compound in anaesthetized rats. Furthermore, it induced vasopressor (PD₅₀ 1.7 μg/kg) and sympatho-inhibitory (ID₅₀ 1.6 μg/kg) actions in pithed rats, the effects being antagonized by idazoxan (0.3 mg/kg i.v.) but not by prazosin (0.1 mg/kg i.v.). Medetomidine (30–300 μg/kg i.m.) had an α₂-adrenoreceptor mediated sedative effect on chicks.
• 3 Medetomidine was, overall, more potent than detomidine, MPV 207, clonidine, xylazine, MPV 295 or azepexole in central (sedation in the chick) and peripheral (cardiac presynaptic in the pithed rat) actions on α₂-adrenoreceptors. Clonidine had, however, about an equal potency to medetomidine in the vascular smooth muscle of the pithed rat.
• 4 Like detomidine and MPV 295, medetomidine had no agonistic activity in the rat aortic ring, but high concentrations antagonized methoxamine-induced contractions, giving a pA₂ value of 5.68 for α₁-adrenoreceptor antagonism.
• 5 The overall lipophilicity (log P') of medetomidine in the octanol/buffer (pH 7.4, 24–26°C, HPLC technique) was 2.80.
• 6 In summary, the experimental data suggest that medetomidine is a lipophilic compound with selective α₂-adrenoreceptor-stimulating properties and high potency. It may, therefore, prove to be a suitable pharmacologic tool for interventions in α₂-adrenoreceptor mediated effects in the autonomic nervous system.

     

Sgd 101/75: cardiovascular effects in various animal preparations; interactions with vascular postjunctional alpha 1- and alpha 2-adrenoceptors.

The effect of the imidazolidine Sgd 101/75 (2-[2-methylindazol-4-imino]-imidazolidine HCl) on blood pressure, as well as its alpha-adrenoceptor agonist activity and affinity for these receptors, were examined in various animal preparations. After both intravenous administration to conscious spontaneously hypertensive rats and intravenous injection or infusion via the vertebral artery in chloralose-anaesthetized cats, Sgd 101/75 (1-10 mg kg-1) elicited pressor responses. Intracisternal application of Sgd 101/75 (1 mg kg-1) to chloralose-anaesthetized cats did not affect blood pressure. In the pithed rat and pithed cat the vasopressor responses to i.v. Sgd 101/75 were effectively antagonized by prazosin (0.1-1.0 mg kg-1, i.v.) but much less by yohimbine (1 mg kg-1, i.v.). Sgd 101/75 proved a less potent and less selective displacing agent of [3H]-clonidine- and [3H]-prazosin-binding in rat brain membranes than clonidine. The results suggest that Sgd 101/75 is a selective alpha 1-adrenoceptor agonist, devoid of any centrally or peripherally mediated hypotensive activity; this is probably caused by the low capacity of Sgd 101/75 for stimulating alpha 2-adrenoceptors.     

A COMPARISON OF THE MUSCARINIC ANTAGONIST ACTIONS OF PANCURONIUM AND ALCURONIUM

• 1 In the pithed rat, muscarine (2.5–10μg/kg i.v.) normally produced bradycardias, but tachycardias were seen in the presence of pancuronium (0.1–1.0mg/kg i.v.) and alcuronium (0.1–5.0mg/kg i.v.).
• 2 The tachycardia was probably a result of muscarinic receptor stimulation, because it was antagonized by atropine (10μg/kg i.v.) and pirenzepine (10–30μg/kg i.v.). The location of these muscarinic receptors is probably within the sympathetic ganglia since the tachycardias were inhibited by pretreatment with propranolol (1mg/kg i.v.) or reserpine (5mg/kg i.p. 24 h prior to study).
• 3 In the rat isolated atria preparation, pancuronium was 86 times more potent as an antagonist of the effects of muscarine than in the rat isolated superior cervical ganglion. The mechanism of action in both tissues may be non-competitive.
• 4 Pancuronium selectivity antagonized atrial inhibitory muscarinic responses compared to excitatory muscarinic responses in sympathetic ganglia in the rat.

     

Intrinsic pressor activity of midaglizole, an alpha-2 adrenoceptor antagonist, in pithed rats

Midaglizole (3 and 30 mg/kg, i.v.) increased blood pressure in pithed rats. The pressor response was not inhibited by intravenous prazosin (0.3 mg/kg), yohimbine (1 mg/kg), ketanserin (1 mg/kg) or diphenhydramine (5 mg/kg). Diltiazem (1 mg/kg) antagonized the hypertension. Idazoxan (10 mg/kg) also increased blood pressure, and the pressor response was inhibited by prazosin, but not by yohimbine. These results suggest that the vascular effect of midaglizole is due to a mechanism different from that of idazoxan.     

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.     

Pre- and postsynaptic effects of alpha-agonists in the anococcygeus muscle of the pithed rat.

In the pithed rat electrically induced contractions of the anococcygeus muscle were inhibited by clonidine (0.1--3.0 microgram/kg, i.v.), mecamylamine (1 mg/kg, i.v.) and guanethidine (1 mg/kg, i.v.). Only the inhibition produced by clonidine was antagonised by yohimbine (0.3 mg/kg, i.v.). At higher concentrations (10 microgram/kg, i.v.) clonidine increased the resting tension of the tissue; this effect was antagonised by phentolamine (1 mg/kg, i.v.). The anococcygeus muscle of the pithed rat was used to simultaneously assess pre- and postsynaptic alpha-adrenoceptor agonist activity. Guanfacin was more selective and tiamenidine less selective than clonidine for presynaptic alpha-adrenoceptors. Naphazoline and oxymetazoline were selective postsynaptic alpha-adrenoceptor agonists.     

The interaction between prazosin and clonidine at alpha-adrenoceptors in rats and cats.

In pithed rats prazosin (10μg/kg, i.v.) caused a prolonged antagonism of the hypertensive response to clonidine and (?)-noradrenaline, probably due to inhibition of vascular, postsynaptic α-adrenoceptors. The clonidine-induced reduction of the tachycardia evoked in pithed rats by electrical stimulation of cardiac sympathetic nerve fibres was antagonized by piperoxan and less effectively by prazosin, thus suggesting that prazosin displays a modest degree of cardiac presynaptic α-adrenoceptor blocking activity apart from its predominantly postsynaptic affinity. Prazosin (1 mg/kg, i.p.) significantly affected the hypotensive effect of clinidine (2 and 6 μg/kg, i.v.), but not the bradycardia induced by clonidine in pentobarbitone-anaesthetized, normotensive rats. Prazosin proved to be an effective hypotensive drug in anaesthetized cats. This action was peripheral as no central nervous origin could be demonstrated. Prazosin in low doses significantly reduced the central hypotensive effect of clonidine (1 μg/kg), injected into the left vertebral artery of chloralose-anaesthethized cats. Since the intravenous pretreatment with low doses of prazosin did not alter the central hypotensive response to clonidine, the interaction was likely to have occured within the brain-stem. Presumably, postsynaptic α-adrenoceptors in the brain, similarly to those in the periphery are inhibited by prazpsin, thereby preventing the central hypotensive effect of clonidine. It is submitted that clonidine and prazosin should not be combined in antihypertensive therapy in patients.     

EVALUATION OF THE SELECTIVITY OF α-ADRENORECEPTOR BLOCKING DRUGS FOR POSTSYNAPTIC α1- AND α2-ADRENORECEPTORS IN A SIMPLE ANIMAL MODEL

• 1 The increase in diastolic pressure of pithed, normotensive rats was determined after i.v. administration of the α-adrenoreceptor agonists L-phenylephrine and B-HT 933.
• 2 α-Adrenoreceptor antagonists varied widely in their relative inhibitory effects towards either L-phenylephrine- or B-HT 933-induced vasoconstrictor responses. Prazosin displayed the highest affinity for the postsynaptic α-adrenoreceptor triggered by L-phenylephrine. The rank order of potency was further: phentolamine > dihydroergotamine > clozapine > corynanthine > azapetine > yohimbine > piperoxan > tolazoline > mianserin > rauwolscine. On the other hand, the rank order of potency towards B-HT 933 was: dihydroergotamine > rauwolscine > yohimbine > phentolamine > piperoxan > prazosin > tolazoline > mianserin > corynanthine > azapetine > clozapine. These data are in general agreement with the classification for α1-(triggered by L-phenylephrine) and α2-(triggered by B-HT 933) adrenoreceptors. Both populations are present postsynaptically in vascular smooth muscle of the pithed rat and are involved in vasoconstriction.
• 3 The ratio of K_B post α2/K_B post α1 was calculated as a measure of selectivity for either α-adrenoreceptor site. The α-adrenoreceptor antagonists used cover a 20,000-fold range of activity ratios. The antagonists most selective for either type were prazosin (α1) and rauwolscine (α2). The selectivity of the α-adrenoreceptor antagonists for postsynaptic α1- and α2-adrenoreceptors in the intact circulatory system of the pithed rat is comparable with the reported selectivity of these blocking agents for α1 (postsynaptic)- and α2 (presynaptic)-adrenoreceptors in the rabbit isolated pulmonary artery.
• 4 It is concluded that two distinct types of postsynaptic α-adrenoreceptors participate in vasoconstriction in the pithed rat. Apart from the classical α1-adrenoreceptor, vascular smooth muscle of the pithed rat contains postsynaptic α2-adrenoreceptors resembling those previously found mainly presynaptically. The presence of separate classes of postsynaptic α1- and α2-adrenoreceptors in the intact circulatory system of the pithed rat offers the possibility to use this relatively simple animal model as an in vivo test system for the pharmacological characterization of α-adrenoreceptor agonists and antagonists.

     

EFFECTS ON BLOOD PRESSURE OF NORADRENALINE AND ISOPRENALINE ADMINISTERED INTO THE THIRD VENTRICLE OF THE BRAIN OF ANAESTHETIZED AND CONSCIOUS CATS

• 1 Noradrenaline administered into the third ventricle of the brain (IIIv) of both conscious and anaesthetized cats induced increases in blood pressure accompanied by small and variable heart rate effects. The pressor responses were reduced after autonomic ganglion blockade indicating their likely central origin.
• 2 Noradrenaline when administered either into a lateral cerebral ventricle (i.c.v.) in conscious and anaesthetized cats or into the cisterna magna (i.c.) in anaesthetized cats induced falls in blood pressure accompanied by bradycardia.
• 3 Pressor responses to IIIv noradrenaline in conscious cats were partly blocked by either propranolol or thymoxamine indicating a possible involvement in the responses of excitatory adrenoreceptors of both α and β types.
• 4 Pressor responses induced by IIIv isoprenaline in conscious cats were blocked by propranolol but not by thymoxamine suggesting the effect is mediated solely via excitatory β-adrenoreceptors.
• 5 In anaesthetized cats prior i.c. administration of noradrenaline reduced the pressor responses induced by IIIv noradrenaline.
• 6 In conscious cats i.v. clonidine reduced pressor responses to IIIv noradrenaline without depressing peripheral vascular noradrenaline sensitivity.
• 7 The results suggest the involvement of excitatory and inhibitory α-adrenoreceptors and of excitatory β-adrenoreceptors in central blood pressure control. It is also concluded that activation of inhibitory α-adrenoreceptors in the hind brain region can suppress the cardiovascular effects of stimulating excitatory α- and β-adrenoreceptors located in the region of the third ventricle.

     

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.     

Postsynaptic alpha 1- and alpha 2-adrenoceptors in the circulatory system of the pithed rat: selective stimulation of the alpha 2-type by B-HT 933

The antagonism by yohimbine (1 mg/kg, i.v.) of vasopressor responses in pithed rats was most pronounced towards B-HT 933 (dose ratio 18.3) and moderate towards clonidine (dose ratio 3.7) and especially L-phenylephrine (dose ratio 2.5). Prazosin (0.1 mg/kg, i.v.) had no effect on the pressor responses to B-HT 933, moderately affected those to clonidine (dose ratio 3.9), but strongly diminished those to L-phenylephrine (dose ratio 53). Phentolamine (1 mg/kg, i.v.) was devoid of a differential antagonism. The results obtained suggest a subclassification of postsynaptic alpha-adrenoceptors into alpha 1- and alpha 2-subtypes mediating pressor effects. B-HT 933 is a selective agonist and yohimbine an antagonist of postsynaptic alpha 2-adrenoceptors. L-Phenylephrine preferably stimulates and prazosin preferentially occupies the alpha 1-adrenoceptors. Clonidine is a potent agonist of both types and phentolamine behaves as a non-selective antagonist.     

Selective alpha 2-adrenoceptor agonist activity of the novel inotropic agent, ASL-7022: comparison with dobutamine

ASL-7022 is a novel inotropic agent capable of increasing the force of myocardial contraction at doses which produce little effect on heart rate. The inotropic selectivity of ASL-7022, like that of dobutamine, has been proposed to result, in part, from agonist activity at alpha-adrenoceptors. Following beta-adrenoceptor blockade, ASL-7022 and dobutamine increase diastolic blood pressure in pithed rat, with both compounds being equal in potency. The pressor activity of ASL-7022 was selectively antagonized by yohimbine (1 mg/kg i.v.) and was unaffected by prazosin (0.1 mg/kg i.v.), whereas the converse was true for dobutamine. These results indicate that the pressor effects of ASL-7022 and dobutamine are mediated by different populations of postjunctional vascular alpha-adrenoceptors in pithed rat, with ASL-7022 selectively stimulating alpha 2-adrenoceptors and dobutamine selectively activating alpha 1-adrenoceptors.     

B-HT 958, a new α-adrenoceptor agonist with a high pre/postsynaptic activity ratio

Summary B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo [5,4-d] azepine) was a potent agonist at presynaptic and a less potent agonist at postsynaptic -adrenoceptor sites. Presynaptically this was shown in pithed rats by the inhibition of tachycardia evoked by sympathetic nerve stimulation (0.2 Hz). The 50% inhibitory dose (ID 50) was 0.3 mg/kg i.v. Moreover in isolated perfused cat hearts, the drug inhibited the tachycardia and the outflow of noradrenaline induced by sympathetic nerve impulses. These effects of B-HT 958 were antagonized by phentolamine or yohimbine. At postsynaptic sites high doses of B-HT 958 increased the blood pressure of decentralized rats. The dose which increased pressure by 30 mm Hg (PD30) was 46.3 mg/kg i.v. This effect was antagonized by rauwolscine 5 mg/kg i.v. After pretreatment with reserpine (7.5 mg/kg i.p., 18 h) B-HT 958 proved much more potent (PD30=0.6 mg/kg i.v.), and its effect was strongly antagonized by yohimbine but hardly by prazosin. The dose of yohimbine which shifted the dose-response curve of B-HT 958 by the factor of 10 (D 10) to the right was 1.8 mg/kg i.v., the corresponding dose of prazosin was 1,900 mg/kg i.v. (extrapolated).B-HT 958 showed also -adrenoceptor blocking properties. This was demonstrated presynaptically in pithed rats by the drug-induced augmentation of tachycardia elicited by electrical stimulation at high frequency (6.4 Hz). At postsynaptic sites B-HT 958 antagonized the blood pressure increase caused by B-HT 920 (₂; D 10=1.1 mg/kg i.v.) but not that caused by methoxamine (₁).It is concluded that B-HT 958 is a partial agonist at peripheral ₂-adrenoceptors. In doses of about 1 mg/kg and with low frequency sympathetic stimulation (<6.4 Hz) it acts presynaptically as agonist; in this dose the drug acts postsynaptically mainly as antagonist.Preliminary results were presented at the 23rd spring meeting of the German Pharmacological Society, March 16–19, 1982, Mainz FRG     

Effect of yohimbine on urethane-induced hyperglycemia in rats

Urethane is a widely used anesthetic and yohimbine is a well-known alpha 2-adrenergic antagonist. In fasted Wistar rats urethane at an anesthetic dose (1.25 g/kg, i.p.) caused an increase in plasma glucose, while pentobarbital at an anesthetic dose (40 mg/kg, i.p.) did not. Urethane caused no change in plasma glucose in adrenalectomized rats. The hyperglycemic effect of urethane was not inhibited by pretreatment with propranolol (1 mg/kg, p.o.) or prazosin (10 mg/kg, p.o.), but was reduced by pretreatment with phentolamine (10 mg/kg, p.o.) or yohimbine (10 mg/kg, p.o.). Urethane caused an elevation of plasma adrenaline, and yohimbine reduced the elevation. In addition, the pretreatment of yohimbine potentiated the urethane-induced increase in plasma insulin. These results indicate that yohimbine may inhibit the urethane-induced hyperglycemia that is mediated by the central and peripheral alpha 2-adrenergic systems.     

Mechanism of action of the anti-shock effect of CCK-8: influence of CCK antagonists and of sympatholytic drugs

In an experimental model of haemorrhagic shock that causes 100% mortality in rats within 30 min, the intravenous bolus injection (20 micrograms/kg) of sulfated cholecystokinin octapeptide (CCK-8) induces a prompt and sustained rise in blood pressure and pulse amplitude, all treated animals still surviving at the end of the experiment (2 h). This effect of CCK-8 is completely blocked by reserpine (5 mg/kg i.p.), significantly antagonized by prazosin (0.1 mg/kg i.v.) and yohimbine (1 mg/kg i.v.), and unaffected by practolol (15 mg/kg i.v.) and proglumide (0.2 mg/kg i.v.); it is completely antagonized by the intravenous (0.01-0.05 mg/kg), but not by the intracerebroventricular (0.002 mg/kg) injection of the 'peripheral' CCK antagonist, L-364,718. The present data indicate that the cardiovascular effects of CCK-8 in haemorrhagic shock involve peripheral CCK receptors, and require the functional integrity of the sympathetic nervous system.