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.

     

THE LACK OF β-ADRENOCEPTOR INVOLVEMENT IN THE CARDIAC ACTION OF Δ1-TETRAHYDROCANNABINOL IN RATS

1. Rat isolated hearts perfused with Δ¹-THC (0·5 μ/ml) showed a reduction in the rate of beating which was not altered by pretreatment with propranolol (2 μg/ml), atropine (4 μg/ml) or hexamethonium (4 μ/ml). 2. Propranolol (2 μg/ml) also caused a decrease in the rate of beating, which was not affected by pretreatment with Δ¹-THC (0·5 μg/ml). 3. In pithed rats, propranolol (2 mg/kg, i.v.) caused a decrease in the pulse rate, which was not altered by prior administration of Δ¹-THC (1 mg/kg, i.v.). 4. In both preparations, the responses to isoprenaline were markedly reduced or abolished by propranolol, but they were unaffected by Δ¹-THC. 5. It is concluded that the hypotensive and cardiac slowing actions of Δ¹-THC are not mediated by activation of parasympathetic nerves or by β-adrenoceptor blockade.     

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.

     

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.

     

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.

     

Characterization of 5-hydroxytryptamine (5-HT) receptor subtypes influencing colonic motility in conscious dogs

We examined the effects of exogenous 5-hydroxytryptamine (5-HT) and selective 5-HT receptor agonists and antagonists on proximal, middle and distal colonic motility in conscious fasted dogs with extraluminal force transducers implanted chronically. 5-HT (0.003–0.1 mg/kg i.v.) dose-dependently enhanced motility along the entire length of the colon. The 5-HT (0.03 mg/kg i.v.)-induced response was inhibited by 0.1–1.0 mg/kg i.v. methysergide, a 5-HT_/12 antagonist, at all recording sites and by 0.1–1.0 mg/kg i.v. ketanserin, a 5-HT_2A antagonist, at the middle and distal sites only. At 1 mg/kg i.v., YM060, a 5-HT₃ antagonist, reduced the amplitude of the initial transient high-amplitude contractions induced by 5-HT, but did not affect the tonic contraction induced by 5-HT. At doses up to 3 mg/kg i.v.,2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino) ethyl ester (SDZ205-557), a 5-HT₄ antagonist, and hexamethonium (up to 10 mg/kg i.v.) did not affect 5-HT-induced responses at any recording site. Renzapride, a 5-HT₄ agonist, also stimulated motility along the entire length of the colon at 0.3 mg/kg i.v.. The renzapride-induced response was inhibited by 1 mg/kg i.v. SDZ205-557 or 3 mg/kg i.v. hexamethouium. m-Chlorophenylbiguanide (m-CPBG), a 5-HT₃ agonist, (1 mg/kg i.v.) produced a transient high-amplitude contraction at all recording sites and this contraction was eliminated by pretreatment with 0.03 mg/kg i.v. YM060. The contraction produced by m-CPBG declined rapidly, so the increase in the motility index by m-CPBG was not significant at any recording site. Of the antagonists tested, 0.1–1 mg/kg i.v. methysergide produced a delayed and prolonged contractile response at the middle and distal sites. The onset of the response was delayed about 20 min after application and the response was maintained over the subsequent 60-min observation period. The methysergide (1 mg/kg i.v.)-induced response was inhibited by 3 mg/kg i.v. hexamethonium. The other antagonists, ketanserin, YM060 and SDZ205-557, had no contractile effect at any recording site.These results indicate that exogenous 5-HT stimulates motility along the entire length of the fasted canine colon and that 5-HT-induced responses in the proximal colon are mediated mainly by 5-HT₁, whereas those in the middle and distal colon are mediated by both 5-HT₁ and 5-HT₂ receptors. Renzapride and methysergide also stimulate colonic motility via additional mechanisms. The activation of 5-HT₄ receptors and the blockade of endogenous 5-HT inhibitory regulation via 5-HT₁ receptors may be involved in the action of renzapride and methysergide respectively.     

THE POSTGANGLIONIC EXCITATORY INNERVATION OF THE MOUSE URINARY BLADDER AND ITS MODULATION BY PREJUNCTIONAL GABAB RECEPTORS

• 1 Field stimulation produced reproducible contractions of the mouse isolated urinary bladder whose amplitude was frequency-related. These contractions were partially sensitive to atropine (3 μM), unaffected by hexamethonium (10 μM.) and almost abolished by tetrodotoxin (0.5 μM). Atropine (3 μM) suppressed contractions produced by exogenous acetylcholine thereby indicating atropine-resistance of the nerve-mediated contractions.
• 2 Nerve-mediated contractions of the mouse urinary bladder were enhanced by physostigmine (0.1-0.5 μM) and inhibited by hemicholinium-3 (0.5 mM) thus confirming the presence of a cholinergic component in the excitatory postganglionic innervation.
• 3 Atropine (3 μM) inhibition of the nerve-mediated contractions increased with increasing duration and strength of the train of stimulation.
• 4 The nerve-mediated contractions of the mouse bladder were unaffected by phentolamine (0.2 μM), propranolol (0.3 μM) or indomethacin (5 μM).ATP (1mM) the major candidate for the role of nonadrenergic-noncholinegic (NANC) excitatory neurotransmitter in the mammalian urinary bladder produced a contraction of the mouse isolated bladder.
• 5 Exposure to the stable ATP analogue α,β-methylene ATP (APCPP) or β,γ-methylene ATP (APPCP) produced a partial desensitization of the nerve-mediated response which, for APCPP, was greater in the presence than in the absence of atropine (3 μM). In the presence of atropine (3 /zM) and after APCPP desensitization the amplitude of the response to field stimulation amounted to about 20% of the original response and was sensitive to tetrodotoxin, indicating that it is nerve-mediated.
• 6 GABA (0.001-0.3 mM) inhibited the amplitude of field stimulation induced contractions of mouse urinary bladder. This effect was mimicked by the selective GABA_B receptor agonist, (±)-baclofen, but not by the selective GABA_A receptor agonist, homotaurine. GABA and (±)-baclofen exhibited cross-desensitization.
• 7 The GABA- or (±)-baclofen-induced inhibition of the nerve-mediated contractions were reduced by previous exposure to homotaurine (1 mM) or to 5-aminovaleric acid (2 mM), two GABA_B receptor antagonists. On the other hand the inhibitory effects of GAB A or (±)-baclofen were unaffected by picrotoxin (0.1 mM), a selective GABA_A receptor antagonist.
• 8 The inhibitory effect of GABA on nerve-mediated contractions was reduced in the presence of atropine or hemicholinium-3 as well as following desensitization of P₂-purinoreceptors. The action of GABA was unaffected by phentolamine, propranolol or indomethacin.
• 9 GABA had no effect toward field stimulation-induced contractions in the presence of tetrodotoxin (0.5 μM.) (pulse width 30 msec) thus indicating the neurogenic origin of its inhibitory effect. GABA had no effect on bladder contractions induced by acetylcholine or ATP.
• 10 These findings indicate that the postganglionic excitatory innervation of the mouse urinary bladder involves a cholinergic as well as a NANC component which may be due to release of endogenous ATP. It appears that in this preparation GABA inhibits the nerve-mediated contractions through prejunctional GABA_B receptors whose activation reduces neurotransmitter release from postganglionic nerve endings.

     

AN INVESTIGATION INTO THE MECHANISMS OF THE CARDIOVASCULAR EFFECTS OF 5-HYDROXYTRYPTAMINE IN CONSCIOUS NORMOTENSIVE AND DOCA-SALT HYPERTENSIVE RATS

• 1 The actions of intravenously administered 5-hydroxytryptamine (5-HT) have been analysed in conscious DOCA-salt hypertensive rats using selective 5-HT receptor agonists and antagonists to determine the receptor mechanisms involved and to compare them with those in conscious normotensive rats.
• 2 In both normotensive and hypertensive rats 5-HT, 3 and 10 μg i.v., produced a complex triphasic effect on blood pressure consisting of an initial short lasting depressor response, which was followed by a pressor response and then, finally, a hypotensive phase. Marked decreases in heart rate were observed immediately after dosing, which were followed by small increases in rate.
• 3 The selective 5-HT₃-receptor agonist, 2-methyl 5-HT, 3–30 μg i.v., produced immediate and marked dose-related decreases in blood pressure and heart rate in both normotensive and DOCA-salt hypertensive rats. The 5-HT₃-receptor antagonist, MDL 72222, 0.03 and 0.1 mg/kg i.v., antagonised these effects in both normotensive and DOCA-salt hypertensive rats. Treatment with MDL 72222, 0.3 mg/kg i.v., abolished the initial depressor response and bradycardia produced by 5-HT.
• 4 The 5-HT₂ receptor agonist, α-methyl 5-HT, 3–30 μg i.v., produced dose-related increases in blood pressure which were significantly greater in magnitude in DOCA-salt hypertensive than normotensive rats. Bradycardia was observed consistently at 30 μg only. The 5-HT₂ receptor antagonist, ketanserin, 0.03-0.3 mg/kg i.v., caused a dose-dependent antagonism of the pressor responses produced by α-methyl 5-HT, but had no effect on the increases in blood pressure produced by angiotensin. Ketanserin also antagonised the pressor responses produced by 5-HT in rats pretreated with MDL 72222.
• 5 5-Carboxamidotryptamine (5-CT), the selective ‘5-HT₁-like’ receptor agonist, at doses of 0.1–3 μg i.v. produced dose-related decreases in blood pressure which were more pronounced in the DOCA-salt hypertensive rats than in normotensive rats. These depressor responses were dose-dependently antagonised by methiothepin, 0.3 and 1 mg/kg, i.v. which did not antagonise the depressor responses produced by isoprenaline 0.1 μg/kg i.v. In rats pretreated with MDL 72222 and ketanserin, 5-HT produced dose-related depressor responses which were also antagonised by methiothepin 1 mg/kg i.v. and presumably mediated by 5-HT₁-like receptors.
• 6 In this study, selective 5-HT receptor agonists and antagonists have been used to mimic and block, respectively, the various phases of the 5-HT response. It is concluded that in the conscious rat, the complex cardiovascular effects of 5-HT involve stimulation of at least three different 5-HT receptors (for nomenclature see Bradley, Engel, Feniuk, Fozard, Humphrey, Middlemiss, Mylecharane, Richardson & Saxena, 1986). The initial depressor response and bradycardia involves activation of 5-HT₃-receptors, the secondary vasopressor effect, which is significandy greater in DOCA-salt than normotensive rats results from stimulation of 5-HT₂ receptors and the late vasodepressor response is due to vasodilatation via ‘5-HT₁-like’ receptors.

     

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.

     

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.     

THE CHRONIC EFFECTS OF β-ADRENORECEPTOR ANTAGONISTS ON THE EFFLUX OF TRITIATED NORADRENALINE FROM SYMPATHETIC NERVES OF THE PITHED RAT

• 1 The effect of chronic administration of two β-adrenoreceptor blocking drugs, propranolol and timolol, on transmitter noradrenaline release from sympathetic nerves has been investigated in vivo using the pithed rat preparation.
• 2 Oral treatment for 4 weeks with either propranolol (46.3 mg/kg/day) or timolol (7.1 mg/kg/day) significantly raised the stimulation frequency threshold for release of radioactivity on stimulation of the whole spinal outflow of the pithed rat after i.v. injection of ³H-NA.
• 3 No differences in the stimulation-evoked rise in mean arterial pressure were observed between control or treated rats nor was the heart rate response to stimulation altered after timolol treatment. However, in propranolol treated rats the mean rises in heart rate were significantly higher with 3 and 30 Hz stimulation than in control rats.
• 4 Timolol treatment significantly increased the blood concentration and lowered the heart content of ³H-NA whilst propranolol treatment did not significantly change either blood or heart levels.
• 5 Log dose-response curves for mean rises in heart rate after i.v. isoprenaline were not shifted to the right in either propranolol or timolol treated pithed rats. With the lowest doses of isoprenaline (1 and 25 ng), the mean rises in heart rate in timolol treated rats were significantly greater than in the controls.
• 6 Thus chronic administration of propranolol or timolol decreased the stimulation-induced increase in plasma ³H-NA but this change in release was not related to reduced rises in blood pressure or heart rate.

     

Critical role of dose in protection by propranolol against ventricular fibrillation in a pig model of acute myocardial ischemia

We hypothesized that the antiarrhythmic efficacy of propranolol during acute myocardial ischemia could be dose related. Propranolol was administered in two equally divided doses 30 min before and 10 min after ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Only the lowest dose of propranolol, i.e., 0.1 mg/kg intravenously (i.v.) (plasma level 22 +/- 2 ng/ml) decreased the incidence of ventricular fibrillation (VF), i.e. 3 of 12 versus 16 of 20 in control group (p less than 0.01). VF incidence with propranolol 0.5 or 3 mg/kg was 4 of 6 and 8 of 9, respectively (both NS vs. control group). Propranolol 0.1 mg/kg did not change left ventricular (LV) blood flow. Propranolol 3 mg/kg reduced blood flow in the peripheral ischemic myocardium to 13.2 +/- 1.2 versus 19.2 +/- 1.4 ml/100 g/min in control group (p less than 0.01), and in the midischemic zone to 4.4 +/- 0.5 versus 7.0 +/- 0.9 ml/100 g/min in control group (p less than 0.001). Propranolol 0.1 mg/kg prevented a disparity of levels of cyclic AMP from arising between ischemic and non-ischemic myocardium, whereas propranolol 3.0 mg/kg did not. Furthermore, LV mechanical function was suppressed by propranolol 3 mg/kg. Only the lowest dose of propranolol (i.e., 0.1 mg/kg) decreased the incidence of VF in this model.     

Dopamine receptor subtypes that induce hyperactive urinary bladder response in anesthetized rats

In anesthetized rats, SKF 38393 (10 mg/kg, i.v.) did not facilitate urinary bladder motility, but bromocriptine (BR, 5 mg/kg, i.v.) alone and the combination of BR (1 mg/kg, i.v.) and SKF 38393 (1 mg/kg, i.v.) induced a hyperactive bladder response (HBR). Both HBR induced by BR alone or BR and SKF 38393 combined was suppressed by SCH 23390, sulpiride or haloperidol. These results indicate that HBR is mediated by the activation of D-2 receptors, and the effects of D-2 agonists on bladder motility are potentiated by the simultaneous stimulation of D-1 receptors.     

ROLE OF DOPAMINE AND α-ADRENORECEPTORS IN THE CONTROL OF GASTRIC EMPTYING IN THE RAT: POSSIBLE INVOLVEMENT IN THE MECHANISM OF ACTION OF METOCLOPRAMIDE

• 1 The object of the study was to investigate the effects of dopamine receptor and a-adrenoreceptor agonists and antagonists on the gastric emptying of a liquid test meal in conscious rats and the possible involvement of these receptors in the mechanism of action of metoclopramide.
• 2 The gastric emptying of a liquid test meal in conscious chronic gastric fistula rats was delayed following subcutaneous administration of either 6,7-ADTN (1-50 mgikg) or clonidine (0.05-1 mgikg). Phenylephrine (0.2–10 mg/kg s.c.) had no effect on gastric emptying, suggesting that dopamine and a2-, but not al-adrenoreceptors may be involved in the control of gastric emptying in the rat.
• 3 Phentolamine (0.2–5 mg/kg s.c.) and prazosin (0.1–0.5 mg/kg s.c.) potentiated the delay in gastric emptying induced by 6,7-ADTNY whilst yohimbine (1–5 mg/kg s.c.) and prazosin (0.1–0.5 mg/kg s.c.) reversed the delay in emptying induced by clonidine. All three a-adrenoreceptor antagonists also delayed gastric emptying in the absence of agonist. Propranolol(0.2–5 mgikg s.c.) had no effect on either normal or delayed gastric emptying.
• 4 Both metoclopramide (1–10 mg/kg s.c.) and haloperidol (0.02–0.5 mgikg s.c.) reversed the 6,7-ADTN-induced delayed emptying but not the clonidine-induced delayed emptying. In addition, metoclopramide (5–10 mg/kg s.c.), but not haloperidol, increased gastric emptying in the absence of agonist.
• 5 In conclusion, these results show that dopamine and a-adrenoreceptors may be involved in the control of gastric emptying in the rat. However, it would appear that a2-adrenoreceptors are unlikely to be involved in the mechanism of action of metoclopramide. Although there is some evidence that peripheral dopamine receptors may be involved, the fact that metoclopramide significantly increased gastric emptying in the absence of 6,7-ADTN suggests that its dopamine receptor antagonist properties may contribute only in part towards its mechanism of action.

     

Effects of intravenous propranolol and metoprolol and their interaction with isoprenaline on pulmonary function,heart rate and blood pressure in asthmatics

Summary The effects of propranolol (0.06 mg/kg i.v.), the selective ₁-receptor antagonist metoprolol (0.12 mg/kg i.v.) and a placebo on pulmonary function, heart rate and blood pressure have been compared in asthmatics. The interaction of these drugs with increasing doses of isoprenaline on the same variables was also studied. The two-blockers reduced resting heart rate to the same extent, indicating the same degree of blockade of cardiac-receptors. Both-blockers reduced the basal forced expiratory volume in one second (FEV₁), and the effect tended to be more pronounced after propranolol. Isoprenaline caused a dose-dependent increase in FEV₁ and vital capacity (VC). These effects were almost completely blocked by propranolol, whereas after metoprolol the changes approached that of the placebo. The isoprenaline-induced increase in heart rate and fall in diastolic blood pressure was also inhibited to a considerably greater extent by propranolol than by metoprolol. The results show a selectivity of metoprolol for so-called ₁-receptors and indicate that metoprolol may be used in asthmatics provided that it is combined with ₂-receptor-stimulating drugs.     

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.

     

In vivo effects of drugs that act on the autonomic nervous system on the rat urinary bladder contraction accompanying micturition

We prepared an experimental system to study the effects of drugs on urinary bladder contraction and micturition simultaneously in rats anesthetized with urethane (1 g/kg, s.c.) and alpha-chloralose (25 mg/kg, s.c.). When Tyrode's solution was infused at a constant rate (0.8-1 ml/10 min) through a needle inserted into the bladder from the left ureter, the bladder pressure gradually and then steeply rose, and micturition took place. These changes in bladder pressure and micturition were constantly repeated. In this model, drugs which partially inhibited the bladder contractile force, e.g., atropine (0.01-1 mg/kg, i.v.) and hexamethonium (C6, 5 mg/kg, i.v.) increased the frequency of bladder contraction instead of decreasing the amount of solution excreted from the penis by bladder contraction. The rate of afferent discharges during bladder filling was increased after injection of atropine or C6, and this increase was considered to be responsible for the induction of the increase in the frequency of bladder contraction. Drugs which inhibited the bladder contraction and interrupted micturition, e.g., C6 (20 mg/kg, i.v.) raised the bladder pressure until the solution leaked from the penis. As phentolamine (5 mg/kg, i.v.) or propranolol (1 mg/kg, i.v.) did not facilitate bladder motility but rather inhibited it, the inhibitory action of sympathetic nerves on bladder motility was considered to be weak in rats. This model was useful for studying the effect of drugs on bladder motility and micturition reflex.     

The influence of the intrinsic sympathomimetic activity of β-adrenoceptor antagonists on haemodynamic effects in anaesthetized dogs

1. The effects of propranolol, atenolol (ICI 66,082), practolol and pindolol on heart rate and maximal left ventricular dp/dt, atrioventricular conduction time, mean aortic flow and diastolic blood pressure during cardiac pacing were investigated over a wide dose range (0.025-4.0 mg/kg, i.v.) in dogs anaesthetized with pentobarbitone. 2. Propranolol and atenolol produced similar reductions in haemodynamic parameters. Propranolol had no further effect in dogs pretreated with atenolol. 3. Practolol tended to cause smaller reductions in the haemodynamic parameters than either propranolol or atenolol. Subsequent administration of propranolol still had some depressant activity. 4. Pindolol produced a biphasic response, with depression of cardiac function at the low doses (0.025 and 0.1 mg/kg), but a reversal of effect as the dose was increased. 5. It is therefore concluded that, in anaesthetized dogs, the intrinsic activity of practolol and pindolol limits the fall in heart rate, cardiac conduction, aortic flow and maximal dp/dt observed with β-adrenoceptor blockade. With pindolol, however, the influence of intrinsic activity is observed only in high doses related to β-adrenoceptor blockade.     

Noradrenaline contracts rat retinal arterioles via stimulation of α(1A)- and α(1D)-adrenoceptors

The aim of this study was to characterize the α?-adrenoceptor subtype(s) involved in the noradrenaline-induced contraction of retinal arterioles in rats. In vivo ocular fundus images were captured with a digital camera equipped with a special objective lens. By measuring changes in diameter of retinal arterioles in the fundus images, retinal vascular response was assessed. The systemic blood pressure and heart rate in the animals were also continuously recorded. Following blockade of β?/β?-adrenoceptors with propranolol, noradrenaline (0.03-3 μg/kg/min, i.v.) decreased the diameter of retinal arterioles and increased the mean blood pressure in a dose-dependent manner. The highest dose (3 μg/kg/min, i.v.) of noradrenaline caused a small increase in heart rate. The α(1A)-adrenoceptor antagonist RS100329 (0.1 mg/kg, i.v.) and the α(1D)-adrenoceptor antagonist BMY 7378 (1 mg/kg, i.v.) significantly prevented noradrenaline-induced contraction of retinal arterioles and pressor responses whereas the α(1B)-adrenoceptor antagonist L-765314 (1 mg/kg, i.v.) did not. The α(1A)-adrenoceptor agonist, A 61603 (0.03-0.3 μg/kg/min, i.v.), also caused contractile responses of retinal arterioles and pressor responses. These responses were almost completely prevented by RS100329 (0.1 mg/kg, i.v.), but not by BMY 7378 (1 mg/kg, i.v.). These results suggest that the contractile effects of noradrenaline on retinal arterioles and peripheral resistance vessels are, at least in part, mediated by stimulation of α(1A)- and α(1D)-adrenoceptors. Furthermore, it is likely that the α?-adrenoceptor subtype(s) involved in rat vascular responses are similar in both retinal and peripheral circulation.     

Dopaminergic Involvement in Improving Effects of Dynorphin A-(1-13) on Galanin-Induced Impairment of Passive Avoidance Learning in Mice

The present study was designed to clarify whether dopaminergic systems are involved in the effects of dynorphin A-(1-13), an endogenous κ-opioid receptor agonist, on the galanin-induced impairment of passive avoidance learning in mice. Galanin (0·3 μg, i.c.v.) shortened step-down latency of passive avoidance learning, while the dopamine D₁ receptor agonist SKF 38393 (3 and 10 mg/kg, s.c.), the dopamine D₂ receptor agonist RU 24213 (0·3 and 1 mg/kg, s.c.), the dopamine D₁ receptor antagonist SCH 23390 (0·01 and 0·03 mg/kg, i.p.) or the dopamine D₂ receptor antagonist S(−)-sulpiride (10 and 30 mg/kg, i.p.) failed to influence it. Dynorphin A-(1-13) (3 μg, i.c.v.) and SKF 38393 (10 mg/kg, s.c.) markedly improved the galanin (0·3 μg, i.c.v.)-induced shortening of step-down latency. However, RU 24213 (0·3 and 1 mg/kg, s.c.), SCH 23390 (0·01 and 0·03 mg/kg, i.p.) or S(−)-sulpiride (10 and 30 mg/kg, i.p.) did not affect the galanin (0·3 μg, i.c.v.)-induced shortening of step-down latency. In contrast, SCH 23390 (0·3 mg/kg, i.p.) significantly reversed the improving effects of dynorphin A-(1-13) (3 μg, i.c.v.) on the galanin (0·3 μg, i.c.v.)-induced dysfunction of passive avoidance learning, although SKF 38393 (1 and 3 mg/kg, s.c.), RU 24213 (0·3 and 1 mg/kg, s.c.) or S(−)-sulpiride (10 and 30 mg/kg, i.p.) did not influence the effects of dynorphin A-(1-13) (3 μg, i.c.v.). These results suggest that dynorphin A-(1-13) improves the galanin-induced amnesia resulting from indirect stimulation of dopamine D₁ receptors. © 1997 John Wiley & Sons, Ltd.