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.

     

SELECTIVE STIMULATION OF VASCULAR POSTJUNCTIONAL α1-ADRENORECEPTORS BY (-)-AMIDEPHRINE IN RATS AND CATS

• 1 The vasopressor and chronotropic responses of (-)-amidephrine and the receptor types involved were studied in pithed rats of different strains and in pithed cats.
• 2 The increase in diastolic pressure of pithed rats after i.v. administration of (-)-amidephrine was not influenced by pretreatment with propranolol (1 mg/kg, i.v.), reserpine (2 times 5mg/kg in 48 h i.p.) or yohimbine (1 mg/kg, i.v.), but was strongly antagonized by prazosin (0.1 mg/kg, i.v.). In pithed cats, the pressor responses were antagonized by prazosin (1 mg/kg, i.v.) but much less so by yohimbine (1 mg/kg, i.v.).
• 3 (-)-Amidephrine elicited minor positive chronotropic responses in pithed rats and pithed cats. This tachycardia was not influenced by propranolol (1 mg/kg, i.v.) but was abolished by prazosin (0.1 – 1.0 mg/kg).
• 4 The results show that (-)-amidephrine acts as a selective agonist at vascular postjunctional α-adrenoreceptors in pithed rats and pithed cats. The positive chronotropic effects are attributable to stimulation of α-adrenoreceptors in the heart.

     

DIRECT CARDIAC ACTIONS OF PHENYLEPHRINE WHEN USED IN ASSESSMENT OF BAROREFLEX FUNCTION IN THE RAT

• 1 In pentobarbitone-anaesthetised wistar rats, the baroreflex bradycardia in response to the vasopressor agent phenylephrine was converted to a tachycardia by propranolol.
• 2 In pithed wistar rats, phenylephrine produced a marked tachycardia which was mediated largely by β-adrenoreceptors since propranolol markedly antagonised the response. A component of the tachycardia was mediated by α₁-adrenoreceptors since the tachycardia to phenylephrine in the presence of propranolol was antagonised by prazosin and mimicked by the α₁adrenoreceptor agonist amidephrine.
• 3 It is concluded that phenylephrine is not a useful agent for assessment of baroreflex funtion in the rat due to its marked cardiac stimulant actions.

     

ADRENORECEPTORS IN THE HUMAN PENIS

• 1 Adrenaline, noradrenaline and phenylephrine caused contraction of the corpus cavernosum muscle of the human penis. These sympathomimetic amines did not produce inhibitory effects even in the presence of the α-adrenoreceptor blocker, phentolamine. The effect of dopamine was similar to that produced by these three sympathomimetic amines. Higher doses of isoprenaline and salbutamol also contracted this preparation.
• 2 Cocaine and guanethidine enhanced the motor response to adrenaline, noradrenaline and phenylephrine while the action of dopamine was blocked by these two drugs.
• 3 The motor response to adrenaline, noradrenaline and phenylephrine was antagonized by phentolamine and often potentiated by the β-adrenoreceptor blocking drug, propranolol. The contractions produced by high doses of salbutamol and isoprenaline were also abolished by phentolamine. These findings indicate that the motor response to sympathomimetic amines is the result of activation of α-adrenoreceptors in the corpus cavernosum muscle.
• 4 At low doses, isoprenaline and salbutamol relaxed the corpus cavernosum muscle strip. The inhibitory action was blocked by low concentrations of the β-adrenoreceptor antagonist, propranolol but not by practolol (β₁-adrenoreceptor antagonist) and butoxamine (β₂-adrenoreceptor antagonist). β-adrenorecepcors are present in the corpus cavernosum muscle but these are unlikely to be either of the β₁ or β₂ type. The possible existence of a third type of β-adrenoreceptor is suggested.

     

THE EFFECT OF β-ADRENORECEPTOR ANTAGONISTS ON THE INHIBITION OF PENDULAR MOVEMENTS OF RABBIT ILEUM PRODUCED BY PERIARTERIAL SYMPATHETIC NERVE STIMULATION AND SOME SYMPATHOMIMETIC AMINES

• 1 The effects of propranolol and of the selective β₁ and β₂-adrenoreceptor blocking drugs atenolol and ICI 118,551 were determined on the inhibitory responses of isolated segments of rabbit ileum to noradrenaline, isoprenaline and salbutamol and to periarterial sympathetic nerve stimulation.
• 2 Responses to isoprenaline (0.04–10.24 μM) and salbutamol (1.4–89.6 μM) were blocked by propranolol in concentrations up to 5.0 and 12.8 μM, respectively. Responses to sympathetic nerve stimulation were reduced but responses to noradrenaline (0.03-1.92 μM) were unaffected by propranolol in concentrations up to 10.0 and 5.0 μM, respectively.
• 3 Atenolol in concentrations up to 30.0 μM blocked responses to isoprenaline (0.04-2.56 μM) but did not affect responses to noradrenaline, salbutamol or sympathetic nerve stimulation in concentrations up to 3.0,3.0 and 1.0 μM, respectively. However, when responses to noradrenaline and sympathetic nerve stimulation were reduced by phentolamine (1.0 μM), atenolol then produced further reductions.
• 4 Responses to isoprenaline (0.04-2.56 μM) and salbutamol (1.4–89.6 μM) were blocked by ICI 118,551 in concentrations up to 0.5 μM. Responses to sympathetic nerve stimulation were reduced but responses to noradrenaline were unaffected by ICI 118,551 in concentrations up to 0.01 and 0.3 μM, respectively.
• 5 Salbutamol (0.1 μM.) increased the inhibitory response to sympathetic nerve stimulation and this effect was blocked by ICI 118,551 (0.01 μM).
• 6 It was concluded that blockade of β₂-adrenoreceptors, presumably located on sympathetic nerve terminals, decreases the release of transmitter noradrenaline and that blockade of β₁-adrenoreceptors, presumably located in longitudinal smooth muscle cells, reduces the response to transmitter noradrenaline when α-adrenoreceptors are also blocked.

     

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.

     

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.

     

THE EFFECTS OF INTRAVENOUS 6-HYDROXYDOPAMINE ON PERIPHERAL α-ADRENORECEPTORS

• 1 Peripheral α-adrenoreceptor-mediated responses were studied in conscious intact rabbits and in animals pretreated with intravenous 6-hydroxydopamine (50 mg/kg).
• 2 Treatment caused a large decrease in noradrenaline in plasma and peripheral tissue but only small falls in blood pressure.
• 3 There was a shift to the left in pressor dose-response curves to the α-adrenoreceptor agonist phenylephrine and the mixed α₁/α₂-adrenoreceptor agonist noradrenaline in 6-hydroxydopamine-pretreated animals. The α1-adrenoreceptor antagonist prazosin was less effective at blocking the phenylephrine pressor response in these animals.
• 4 There was no change in pressor responses to the α₂-adrenoreceptor selective agonists clonidine and guanabenz and α-adrenoreceptor antagonists were equally effective at blocking this pressor response in 6-hydroxydopamine-pretreated and in intact rabbits.
• 5 In conscious animals 6-hydroxydopamine pretreatment causes alteration in responses mediated by postsynaptic α₁-but not postsynaptic α₂-adrenoreceptors. These changes may help maintain blood pressure in the 6-hydroxydopamine treated rabbits.

     

Myocardial chronotropic and inotropic responsiveness in vitro after chronic α-adrenoreceptor blockade in the rat

1 Positive chronotropic and inotropic myocardial responses to different adrenoreceptor agonists were studied using isolated right atria and left ventricular papillary muscles from rats treated orally for 5 weeks with prazosin, an α₁-antagonist, or vehicle (distilled water). 2 Chronotropic responses to the α-adrenoreceptor agonists isoprenaline and salbutamol were similar in atria from both groups of rats, with no differences in their basal rates, maximum rate increases or pD₂ values for either agonist. 3 Basal contractile force of field-stimulated papillary muscles was similar in both prazosin-treated (0.089 ± 0.014 g mg^-1) and control groups (0.104 ± 0.035 g mg^-1). In response to noradrenaline, force increased maximally by 145 ± 30% and 131 ± 30% above resting levels respectively, and pD₂ values for this β- and α-agonist showed no changes after chronic prazosin treatment. Inotropic responses to isoprenaline were also not different with maximum increases in force of 94.5 ± 20.2% for prazosin-treated and 84.5 ± 18.5% for controls, and similar pD₂ values. 4 However, in response to the α-agonist phenylephrine (in the presence of propranolol), maximum increases in force were greater in relation to the noradrenaline maxima after prazosin treatment (48.8 ± 4.2%) than in controls (32.0 ± 4.3%, P<0.02). pD₂ values for phenylephrine were also significantly higher after long-term α-blockade (5.71 ± 0.10 vs 5.30 ± 0.19 for controls, P<0.05). 5 Long-term α-blockade in the rat therefore led to supersensitivity of α-mediated inotropism in the heart, but both β-mediated inotropic and chronotropic responses were unaffected. These results show selectivity of action of chronic prazosin treatment on α-receptors in the rat heart.     

Effects of clonidine on the negative chronotropic response induced by vagal stimulation in the rat

The effects of clonidine on the negative chronotropic response induced by stimulation of vagus nerve were studied in the presence of propranolol in reserpinized and anesthetized rats. When the heart rate was decreased by stimulation of the vagus nerve, clonidine significantly inhibited vagally induced heart rate decrease (negative chronotropic response) in dose dependent manner. This inhibitory effect of clonidine was virtually abolished by phentolamine, α₁ ^? and α₂ ^? antagonist, and partially antagonized by prazosin, α₃ ^? antagonist. On the other hand, when the heart rate was decreased by the infusion of bethanechol, a muscarinic parasympathetic stimulant, clonidine had no effect on the bethanechol-induced heart rate decrease. These results suggest that clonidine inhibits vagally induced negative chronotropic response by activation of presynaptic α-adrenoceptors located on the parasympathetic cholinergic nerve terminal in the heart and this effect of clonidine is more related to α₂ ^?adrenoceptors than α₁ ^?adrenoceptors.     

Smooth Muscle Layer-Specific Variations in the Autonomic Innervation of Bovine Myometrium

• 1.To clarify the autonomic innervation regulating longitudinal muscle (LM) and circular muscle (CM) motility in the bovine uterus, functional (nerve stimulation, adrenergic drug responsiveness) and biochemical studies (catecholamine content, radioligand binding) were conducted on parous luteal-phase myometrium.
• 2.Electrical field stimulation (EFS; 60 V, 0.5-msec duration) caused tetrodotoxin (1 μM)-sensitive contractions in a frequency-dependent manner (0.5–20 Hz) in both LM and CM layers.
• 3.The EFS-induced LM contractions were potentiated by propranolol and conspicuously decreased by phentolamine, yohimbine, idazoxan or guanethidine, but were unaffected by prazosin or atropine.
• 4.On the other hand, CM contractions were only slightly decreased by phentolamine, idazoxan, yohimbine and guanethidine, but were insensitive to propranolol, prazosin or atropine.
• 5.The noradrenaline content in LM was about five times higher than that in CM.
• 6.Noradrenaline, adrenaline, clonidine, xylazine, UK14,304 and phenylephrine caused concentration-dependent contractions of both smooth muscle layers.
• 7.Clonidine, UK14,304 and xylazine were more potent contractile agents than noradrenaline and phenylephrine.
• 8.The contractile response to noradrenaline was competitively antagonized by yohimbine, but not by prazosin.
• 9.Binding studies using [³H]-prazosin and [³H]-rauwolscine revealed that the bovine myometrium contained both α₁- and α₂-adrenoceptors, but the α₂-type receptor was dominant in both LM (94% of α-adrenoceptors) and CM (88%) layers.
• 10.The distribution of α-adrenoceptors was muscle layer-specific; that is, the concentration of α₁-receptors in LM was the same as in CM, but the concentration of α₂-receptors in LM was 2.6 times higher than that in CM.
• 11.The results of the present study indicate that there are layer-specific variations in the functional innervation of the parous bovine myometrium (exclusive adrenergic innervation in LM and adrenergic [minor] plus nonadrenergic, noncholinergic innervation [major] in CM), and that α₂-adrenoceptors, which were responsive to the excitatory response of endogenous and exogenous noradrenaline, were dominant in both muscle layers of the bovine myometrium.

     

ANALYSIS OF THE ANTAGONISM BY PRAZOSIN OF NORADRENALINE AND PHENYLEPHRINE INDUCED CONTRACTIONS OF THE RAT ANOCOCCYGEUS MUSCLE*

• 1 Blockade of α-adrenoreceptors was analyzed with prazosin in the rat anococcygeus muscle contracted with noradrenaline (NA) and phenylephrine (PHE).
• 2 Prazosin (1.1 times 10^–8– 8.8 times 10^–7M) competitively blocked phenylephrine-induced contractions (pA₂= 8.93 ± 0.04, slope = 0.85 ± 0.07) whilst its antagonism of NA was non-competitive (pA₂= 8.45 ± 0.04, slope = 0.46 ± 0.03).
• 3 At higher concentrations, (1.76 times 10^–5– 5.28 times 10^–6M) prazosin competitively antagonized NA-induced contractions (pA₂= 7.58 ± 0.11, slope = 0.93 ± 0.09).
• 4 Phentolamine also reduced the effect of NA competitively (pA₂= 8.11 ± 0.09, slope = 0.82 ± 0.26).
• 5 It is concluded that low concentrations of prazosin selectively blocked an α₁-adrenoreceptor component of NA-mediated response whilst higher concentrations of prazosin non-selectively blocked both α₁- and α₂-adrenoreceptors.

     

CHARACTERIZATION OF THE ADRENORECEPTOR ACTIVITIES OF ISOPRENALINE IN THE FIELD STIMULATED RAT VAS DEFERENS: SELECTIVE SUPERSENSITIVITY TO β2-MEDIATED RESPONSES FOLLOWING RESERPINE TREATMENT

1 Low concentrations of isoprenaline (EC₅₀= 45.6 nM) inhibited contractions in the isolated field stimulated rat vas deferens. This inhibitory effect was markedly attenuated by the postjunctional β₂-adreno-receptor antagonist timolol, but not affected by the prejunctional α₂ or postjunctional α₁-adrenoreceptor antagonists rauwolscine and prazosin, respectively. 2 In vas deferens of rats previously treated with reserpine, the postjunctional β₂-adrenoreceptor-mediated inhibitory response to isoprenaline was markedly potentiated. 3 High concentrations of isoprenaline (EC₅₀= 1.5 uM) also inhibited contractility in tissues in which postjunctional β₂-adrenoreceptors were maximally blocked by high concentrations of timolol. This contractile inhibition produced by isoprenaline was abolished by rauwolscine but not significantly altered by prazosin or pretreatment of the rats with reserpine indicating stimulation of prejunctional α₂-adreno-receptors. 4 Rauwolscine pretreatment unmasked an ability of isoprenaline (EC₅₀= 17.1 juM) to produce enhancement of field stimulation-induced contractions. This response was abolished by prazosin but was unaffected by timolol or reserpinization indicating an action upon postjunctional α₁-adrenoreceptors. 5 The data indicate isoprenaline activates adrenoreceptor mechanisms in the field stimulated rat vas deferens by a direct action not dependent upon endogenous catecholamines and with an order of activity of β₂>α₂>α₁. Pretreatment with reserpine produces rapid and selective development of supersensitivity to the postjunctional β₂-mediated inhibitory response of isoprenaline in this preparation.     

THE INHIBITORY EFFECT OF CLONIDINE ON THE OESTROGEN-PRIMED RAT ISOLATED UTERUS

• 1 The investigation was undertaken to study the mechanism of the inhibitory effects of clonidine on the oestrogen-primed rat isolated uterus.
• 2 Clonidine produced dose-dependent relaxations of the rat isolated uterus which were competitively blocked by yohimbine but not by prazosin.
• 3 Metiamide, a specific H₂-histamine receptor antagonist, inhibited clonidine-induced responses only at a high concentration (1.0 times 10^-6M).
• 4 Propranolol, a β-adrenoreceptor antagonist produced competitive antagonism of the clonidine responses.
• 5 Like clonidine, noradrenaline also produced dose dependent relaxations of the rat isolated uterus. The responses to noradrenaline were not antagonized by either prazosin or yohimbine but were competitively antagonized by propranolol. 7 It is concluded that clonidine inhibits the uterus via an action on α₂-adrenoreceptors and possibly also to a lesser extent on H₂-histamine receptors, leading ultimately to release of noradrenaline from endogenous stores which causes relaxation by acting on β-adrenoreceptors.

     

DIFFERENTIAL ACTIVATION OF ADRENOCEPTOR SUBTYPES BY NORADRENALINE APPLIED FROM THE INTIMAL OR ADVENTITIAL SURFACES OF RAT ISOLATED TAIL ARTERY

• 1 The vasoconstrictor effects of noradrenaline applied to the intimal and adventitial surfaces of perfused segments of rat tail artery in the presence and absence of endothelium were studied.
• 2 Noradrenaline was about six times more potent as a vasoconstrictor when applied to the intimal than to the adventitial surface. Cocaine (25 μmol/L) enhanced responses to adventitial noradrenaline to a greater extent than those to intimal noradrenaline. A high concentration of propranolol (1 μmol/L) had a similar effect.
• 3 The vasoconstriction elicited by adventitial noradrenaline declined from a peak whereas that to intimal noradrenaline remained steady. A low concentration of propranolol (0.1 μmol/L) abolished the decline in the response to adventitial noradrenaline.
• 4 The α₁- and α₂-adrenoceptor antagonists prazosin (1 nmol/L) and idazoxan (100 nmol/L) significantly reduced responses to intimal and adventitial noradrenaline in the presence or absence of endothelium.
• 5 Removal of endothelium enhanced responses to intimal but not adventitial noradrenaline. Idazoxan produced a significantly greater reduction of responses to noradrenaline in the absence than in the presence of endothelium, and was more effective against intimal than adventitial noradrenaline. Similar effects were produced by the nitric oxide synthase inhibitor l-NAME (30 μmol/L).
• 6 It was concluded that noradrenaline acts on both α₁- and α₂-adrenoceptors to produce vasoconstriction: the α₁-adrenoceptors appear to be uniformly distributed, whereas α₂-adrenoceptors are located nearer the intima. Intimal noradrenaline also acts on endothelial α₂-adrenoceptors to release EDRF which counteracts the vasoconstrictor action of noradrenaline. Adventitial noradrenaline also acts on β-adrenoceptors located near the adventitia to counteract the vasoconstriction produced by activation of α-adrenoceptors and its action is reduced by neuronal uptake.

     

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.     

Effects of isoprenaline,adrenaline and selective α1- and α2- adrenoceptor stimulation on hypoxic pulmonary vasoconstriction in rat isolated perfused lungs

In the rat pulmonary vasculature perfused with blood in situ vasoconstriction induced by hypoxia was reversed by isoprenaline (doses > 1 ng) and adrenaline (doses > 30 ng) and exacerbated by phenylephrine but not UK 14304. Doses of adrenaline < 30 ng had no effect, except in the presence of propranolol (1 μM) or phentolamine (3 μM) when they caused vasoconstriction and vasodilation respectively, showing that, at dose levels < 30 ng, adrenaline's β- adrenoceptor vasodilator properties were balanced by its α- adrenoceptor vasoconstrictor properties. The pressor effects of adrenaline, in the presence of propranolol, were antagonised by prazosin (0.1 μM) but not by equi-molar concentrations of rauwolscine. These results suggest that the α- adrenoceptor agonist property of adrenaline is of benefit to its use as an inhaled bronchodilator because unopposed β- adrenoceptor stimulation can reverse hypoxic pulmonary vasoconstriction in poorly ventilated regions of the lung, promote further ventilation/ perfusion mismatching and lower PaO₂. They further suggest that adrenaline affects pulmonary vascular tone in the rat via α₁- adrenoceptors, stimulation of α₂- adrenoceptors having no effect.     

PHARMACOLOGICAL CHARACTERIZATION OF α-ADRENORECEPTOR SUBTYPES IN RAT ISOLATED THORACIC AORTA

• 1 The subtype of α-adrenoreceptor mediating contraction in rat isolated thoracic aorta was classified pharmacologically using preferential agonists and antagonists, and by utilizing mixed agonist and antagonist interactions.
• 2 Noradrenaline was 8 to 10-times more potent at contracting the aorta than phenylephrine and both agonists were about 1000 and 10,000-fold respectively more potent than azepexole (a preferential α2,-agonist).
• 3 Prazosin (a preferential α₁,-antagonist) inhibited the dose-response curves to noradrenaline and phenylephrine 100 and 1000-times respectively more effectively than either phentolamine or rauwolscine (a preferential α₂-antagonist). Furthermore, prazosin (5 times 10^-9M). completely abolished contractions elicited by a single concentration of azepexole (3 times 10^-4M).
• 4 In mixed antagonist studies, rauwolscine (5 times 10^-7M) failed to shift the dose-response curves to nor-adrenaline and phenylephrine obtained in the presence of prazosin (5 times 10^-9M).
• 5 In mixed agonist experiments, azepexole (3 times 10^-4M) acted as a partial antagonist toward phenylephrine-induced contractions.
• 6 The results suggest that the α-adrenoreceptor of the rat thoracic aorta is predominantly, if not exclusively, of the α₁-subtype.

     

THE INTERACTION BETWEEN ENALAPRILAT AND SELECTED α-ADRENOCEPTOR ANTAGONISTS IN ISOLATED RAT TAIL ARTERIES

1. Isolated perfused rat tail artery preparations were used to investigate the effects of the angiotensin converting enzyme inhibitor enalaprilat on the actions of a series of α-adrenoceptor antagonists. The agonist used was phenylephrine. 2. Enalaprilat (1 μmol/L) potentiated the competitive α₁-adrenoceptor antagonist actions of phentolamine (10–100 nmol/L) and yohimbine (0.3–3.0 μmol/L) as well as the non-competitive antagonist action of phenoxybenzamine (50–100 pmol/L). 3. The competitive α₁-adrenoceptor antagonist action of prazosin (1–10 nmol/L) was not affected by enalaprilat. 4. For the competitive α₁-adrenoceptor antagonists, including prazosin, there appeared to be an inverse relationship between antagonist potency and the extent of potentiation by enalaprilat. 5. The results support the hypothesis and angiotensin II modulates vascular smooth muscle α₁-adrenoceptor function.     

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.