Involvement of both dopaminergic and α-adrenergic receptors in the hypomotility induced by dibenzoyl-6,7-ADTN

The dopaminergic prodrug dibenzoyl-6,7-ADTN (DB-6,7-ADTN) can enter the brain following intraperitoneal injection and be hydrolysed to produce low concentrations of the dopamine agonist 6,7-ADTN. Intraperitoneal injections of DB-6,7-ADTN produce a decrease in motor activity and in the present study this response has been characterised, and the underlying mechanisms examined. Doses of 10–100 μmol/kg DB-6,7-ADTN elicit a strong hypomotive response, which is dose dependent. Treated animals are significantly less active than controls. DB-6,7-ADTN hypomotility was significantly attenuated by the non-sedative dopamine receptor antagonist sulpiride (62 μmol/kg, i.p.), but haloperidol (0.3 μmol/kg, i.p.) and cis-flupenthixol (0.45 μmol/kg, i.p.) were without effect. The hypomotility due to DB-6,7-ADTN was also antagonised by yohimbine (13 μmol/kg, i.p.) and piperoxane (21 μmol/kg i.p.), drugs which act mainly by blocking presynaptic (α₂) adrenergic receptors. Prazosin (1.5 μmol/ kg, i.p.), a postsynaptic (α₁) adrenergic blocker, did not affect the hypomotility, and nor did a range of other neurotransmitter antagonists. DB-6,7-ADTN (50 μmol/kg, i.p.) was also found to antagonise the α-methyltyrosine (α-MT, 1.02 mmol/kg, i.p.) induced fall in noradrenaline and dopamine levels in brain and spinal cord. Inhibition of the effects of DB-6,7-ADTN on noradrenaline and dopamine turnover by yohimbine and sulpiride, respectively, suggests that 6,7-ADTN (derived from the prodrug) has alpha adrenergic as well as dopaminergic activity. The results are discussed in connection with the hypomotive effects of other dopamine agonists.     

A central site of action for benzamide facilitation of gastric emptying

Gastric emptying of the fed guinea-pig was measured using a non-invasive X-ray fluoroscopic technique to determine passage from the stomach of polystyrene-coated barium sulphate spheroids. Peripherally administered metoclopramide (0.1-10 mg/kg i.p.), clebopride (1-10 mg/kg i.p.), (-)-sulpiride (40 mg/kg i.p.), haloperidol (1 mg/kg i.p.) and domperidone (1-10 mg/kg i.p.) failed to modify gastric emptying. Stress inhibited emptying, and this was considered to explain the effects of eserine and high dose metoclopramide. Gastric emptying was decreased by peripherally administered atropine (0.5 mg/kg i.p.) and apomorphine (0.1-0.5 mg/kg s.c.); the apomorphine response was antagonised by pretreatment with haloperidol, domperidone, (-)-sulpiride, metoclopramide and clebopride but not by prazosin + propranolol. Gastric emptying was facilitated by intracerebroventricular (i.c.v.) administrations of metoclopramide and clebopride (40, 100 and 200 micrograms) but not by i.c.v. domperidone, haloperidol, fluphenazine or (-)-sulpiride (100, 200 micrograms) and was inhibited by i.c.v. apomorphine (100, 200 micrograms); the response to i.c.v. apomorphine was antagonised by i.c.v. pretreatments with haloperidol, domperidone, (-)-sulpiride, metoclopramide and clebopride (40-50 micrograms). Facilitation of emptying by i.c.v. metoclopramide was prevented by peripheral pretreatment with atropine (0.5 mg/kg i.p.). It is concluded that the actions of apomorphine and metoclopramide/clebopride to respectively inhibit and facilitate gastric emptying may be mediated, at least in part, via central mechanisms. Whilst apomorphine's action may be mediated via dopamine receptor mechanisms, metoclopramide and clebopride act at additional unspecified sites, metoclopramide's action being expressed via cholinergic mechanisms.     

Involvement of both dopaminergic and alpha-adrenergic receptors in the hypomotility induced by dibenzoyl-6,7-ADTN

The dopaminergic prodrug dibenzoyl-6,7-ADTN (DB-6,7-ADTN) can enter the brain following intraperitoneal injection and be hydrolysed to produce low concentrations of the dopamine agonist 6,7-ADTN. Intraperitoneal injections of DB-6,7-ADTN produce a decrease in motor activity and in the present study this response has been characterised, and the underlying mechanisms examined. Doses of 10-100 mumol/kg DB-6,7-ADTN elicit a strong hypomotive response, which is dose dependent. Treated animals are significantly less active than controls. DB-6,7-ADTN hypomotility was significantly attenuated by the non-sedative dopamine receptor antagonist sulpiride (62 mumol/kg, i.p.), but haloperidol (0.3 mumol/kg, i.p.) and cis-flupenthixol (0.45 mumol/kg, i.p.) were without effect. The hypomotility due to DB-6,7-ADTN was also antagonised by yohimbine (13 mumol/kg, i.p.) and piperoxane (21 mumol/kg i.p.), drugs which act mainly by blocking presynaptic (alpha 2) adrenergic receptors. Prazosin (1.5 mumol/kg, i.p.), drugs which act mainly by blocking presynaptic (alpha 2) adrenergic receptors. Prazosin (1.5 mumol/kg, i.p.), a postsynaptic (alpha 1) adrenergic blocker, did not affect the hypomotility, and nor did a range of other neurotransmitter antagonists. DB-6,7-ADTN (50 mumol/kg, i.p.) was also found to antagonise the alpha-methyltyrosine (alpha-MT, 1.02 mmol/kg, i.p.) induced fall in noradrenaline and dopamine levels in brain and spinal cord. Inhibition of the effects of DB-6,7-ADTN on noradrenaline and dopamine turnover by yohimbine and sulpiride, respectively, suggests that 6,7-ADTN (derived from the prodrug) has alpha adrenergic as well as dopaminergic activity. The results are discussed in connection with the hypomotive effects of other dopamine agonists.     

Stimulatory effect of N-[4-[2-(dimethylamino)-ethoxy] benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803) on normal and delayed gastrointestinal propulsion

To estimate the effect of a new gastroprokinetic agent, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803), on non-ulcer dyspepsia, the influence of HSR-803 on gastrointestinal propulsion was assayed in dogs, rats and mice in comparison with some gastroprokinetic agents. HSR-803 (30 mg/kg, p.o.) significantly enhanced gastric emptying in dogs, and it significantly improved the delayed gastric emptying induced by dopamine (0.4 mg/kg, i.p.) and morphine (1 mg/kg, s.c.) in rats. Metoclopramide (30 mg/kg, p.o.) also significantly restored the dopamine-induced delay, but at a dose of 10 mg/kg, p.o., it enhanced the morphine-induced delay in gastric emptying in rats. HSR-803 (10-100 mg/kg, p.o.) increased small intestinal transit in mice in a dose-dependent manner, and the effect was abolished by atropine (0.3 mg/kg, i.p.). Metoclopramide also increased small intestinal transit, but domperidone and cisapride had no effect. In delayed small intestinal transit in mice, HSR-803 (10-100 mg/kg, p.o.) improved the morphine (0.3 mg/kg, s.c.)-induced delay in a dose-dependent manner. In conclusion, because of the promotion of normal and delayed gastrointestinal propulsion, HSR-803 seems to be a promising gastroprokinetic agent for the treatment of non-ulcer dyspepsia. The action of HSR-803 is likely to be exerted through cholinergic stimulation.     

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.     

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.

     

Acotiamide hydrochloride (Z-338) enhances gastric motility and emptying by inhibiting acetylcholinesterase activity in rats

In clinical trials, acotiamide hydrochloride (acotiamide: Z-338) has been reported to be useful in the treatment of functional dyspepsia. Here, we investigated the effects of acotiamide on gastric contraction and emptying activities in rats in comparison with itopride hydrochloride (itopride) and mosapride citrate (mosapride). We also examined in vitro the compound's inhibitory effect on acetylcholinesterase (AChE) activity derived from rat stomach. In in vivo studies, acotiamide (30 and 100mg/kg s.c.) and itopride (100mg/kg s.c.) markedly enhanced normal gastric antral motility in rats. In gastric motility dysfunction models, acotiamide (100mg/kg s.c.) and itopride (100mg/kg s.c.) improved both gastric antral hypomotility and the delayed gastric emptying induced by clonidine, an α(2)-adrenoceptor agonist. In contrast, mosapride (10mg/kg s.c.) had no effect on these models. Like the AChE inhibitors itopride (30 mg/kg s.c.) and neostigmine (10 μg/kg s.c.), acotiamide (10mg/kg s.c.) also clearly enhanced gastric body contractions induced by electrical stimulation of the vagus, which were abolished by atropine and hexamethonium, whereas mosapride (3 and 10mg/kg s.c.) did not. In in vitro studies, acotiamide concentration-dependently inhibited rat stomach-derived AChE activity (IC(50)=2.3 μmol/l). In addition, stomach tissue concentrations of acotiamide after administration at 10mg/kg s.c. were sufficient to produce inhibition of AChE activity in rat stomach. These results suggest that acotiamide stimulates gastric motility and improves gastric motility dysfunction in rats by inhibiting AChE activity, and may suggest a role for acotiamide in improving gastric motility dysfunction in patients with functional dyspepsia.     

Possible involvement of β₁ receptors in various emetogen-induced increases in salivary amylase activity in rats

We investigated the inhibitory effects of β₁- or β₂-adrenoceptor (AR) antagonists on salivary amylase secretion produced by various emetic agents, such as cisplatin, apomorphine, and lithium chloride (LiCl), or the non-emetic agent β_1/2-AR agonist isoprenaline in rats. We also determined the inhibitory effect of metoclopramide, a dopamine D₂–receptor antagonist, on increases in the salivary amylase activity induced by apomorphine or granisetron, a 5-HT₃–receptor antagonist, on LiCl-induced increased salivary amylase activity. Isoprenaline (0.01 mg/kg, s.c.) produced an increase in salivary amylase and the increase was inhibited by the β_1/2-AR antagonist propranolol (5 mg/kg, s.c.) and β₁-AR antagonist atenolol (2 mg/kg, s.c.) but not by the β₂-AR antagonist butoxamine (8 mg/kg, s.c.). The increased amylase activity induced by cisplatin (15 mg/kg, i.v.), apomorphine (3 mg/kg, s.c.), or LiCl (120 mg/kg, i.p.) was inhibited significantly by atenolol (2 mg/kg, s.c.) but not by butoxamine (8 mg/kg, s.c.). In addition, increases in amylase activities induced by apomorphine and LiCl were inhibited significantly by metoclopramide (10 mg/kg, i.v.) and granisetron (3 mg/kg, i.v.), respectively. These results suggest that salivary amylase secretion induced by various emetogens is involved in β₁-adrenoceptor activity and that salivary amylase activity is useful to detect emetogens with no direct β₁-AR activation in rats, a species that does not exhibit vomiting.     

Effects of chronic lithium pretreatment on apomorphine-induced penile erection

• 1.1. The effects of chronic lithium pretreatment (600 mg/l in drinking rats, 30 days) on penile erection (PE) induced by apomorphine were investigated in rats. This treatment resulted in a serum Li concentration after 30 days of 0.31 ± 0.01 mmol/l.
• 2.2. Subcutaneous (s.c.) administration of mixed Dl/D2 dopamine receptor agonist apomorphine (0.05–0.5 mg/kg) induced PE in a biphasic manner. The maximum effect was obtained with 0.1 mg/kg of the drug while the response decreased with increasing doses of apomorphine from 0.1 to 0.5 mg/kg.
• 3.3. Pretreatment of animals with 0.0125-0.1 mg/kg of D1 dopamine receptor antagonist SCH 23390 or D2 dopamine receptor antagonist sulpiride (12.5–100 mg/kg) decreased apomorphine-induced PE. Combination of SCH 23390 (0.025 mg/kg) with sulpiride (12.5 mg/kg) caused a stronger inhibitory effect on apomorphine response. This indicates that both D1 and D2 dopamine receptors may be involved in PE induced by apomorphine.
• 4.4. The response induced by apomorphine (0.05-0.5 mg/kg) was decreased in animals pretreated with chronic lithium. The inhibitory effect of sulpiride on apomorphine response, increased in animals pretreated with lithium, in contrast the inhibitory effect of SCH 23390 did not change in this condition. However, a combination of SCH 23390 with sulpiride increased inhibitory effect on apomorphine response in lithium pretreated rats.
• 5.5. It is concluded that chronic lithium inhibits PE induced by dopaminergic mechanism(s).

     

Characterisation of alpha2-adrenoceptor subtypes involved in gastric emptying, gastric motility and gastric mucosal defence

The effect of clonidine on ethanol-induced gastric mucosal damage, gastric emptying and gastric motility was compared. The clonidine-induced gastroprotective effect (0.03-0.09 micromol/kg, s.c.) was antagonised by yohimbine (5 micromol/kg, s.c.), prazosin (0.23 micromol/kg; alpha2B-adrenoceptor antagonist) and naloxone (1.3 micromol/kg, s.c.). Clonidine also inhibited the gastric emptying of liquid meal (0.75-3.75 micromol/kg, s.c.) and gastric motor activity (0.75 micromol/kg, i.v.) stimulated by 2-deoxy-D-glucose (300 mg/kg, i.v.). Inhibition of gastric emptying and motility was reversed by yohimbine (5 and 10 micromol/kg, s.c., respectively), but not by prazosin (0.23 micromol/kg, s.c.) or naloxone (1.3 micromol/kg, s.c.). Oxymetazoline-an alpha2A-adrenoceptor agonist-inhibited both gastric emptying (0.67-6.8 micromol/kg, s.c.) and motility (0.185-3.4 micromol/kg, i.v.), whereas it failed to affect gastric mucosal lesions. The results indicate that in contrast to the gastroprotective effect, which is mediated by alpha2B-adrenoceptor subtype, alpha2A-adrenoceptor subtype may be responsible for inhibition of gastric emptying and motility. However, the site of action (central, peripheral, both) remains to be established.     

Effects of adenosine analogues on apomorphine-induced penile erection in rats

• 1.1. In the present work, the effect of adenosine agonists and antagonists on apomorphine-induced penile erection (PE) has been studied.
• 2.2. Subcutaneous (s.c.) injection of the nonselective D1/D2 dopamine receptor agonist apomorphine (0.05–0.5 mg/kg) induced PE in a biphasic manner. The maximum effect was obtained with 0.1 mg/kg of the drug. The response decreased with increasing doses of apomorphine, from 0.1 to 0.5 mg/kg.
• 3.3. Intraperitoneal (i.p.) injections of adenosine agonists 5′-N-ethylcarboxamidoadenosine (NECA) and N⁶-cyclohexyladenosine (CHA) decreased the response of apomorphine. Apomorphine-induced PE was increased by low doses (25, 50 mg/kg, i.p.) and decreased by high doses (75, 100 mg/kg, i.p.) of the adenosine antagonist theophylline, respectively. Inhibition of PE induced by NECA and CHA was antagonized by 8-PT pretreatment.
• 4.4. Intracerebroventricular (i.c.v.) administration of CHA, NECA, and theophylline produced the same effects as i.p. injections of these agents on PE responses. It is concluded that A-1 and A-2 adenosine receptor activation may inhibit PE induced by dopaminergic mechanism(s), which can be prevented by 8-PT pretreatment.

     

NON-ATROPINIC ANTICHOLINERGIC ACTION OF QUINIDINE ON THE FERRET STOMACH

• 1 The effect of quinidine on the cholinergic response of the ferret gastric corpus was investigated in vivo and in vitro.
• 2 In vivo, the atropine sensitive contractions of the gastric corpus evoked by stimulation of the cervical vagus in the anaesthetized ferret were antagonized by quinidine (10–30 mg/kg).
• 3 In vitro, quinidine (10 μg/ml) antagonized the contractile response elicited by transmural stimulation (T.M.) of strips of corpus. At this dose of quinidine, the response to acetylcholine at doses adjusted to match the response to T.M. stimulation were unaffected. At higher doses of quinidine (50 μg/ml) the response to stimulation of the non-cholinergic, non-adrenergic inhibitory neurones was also antagonized.
• 4 These results indicate that, at low doses, quinidine has an inhibitory effect on the cholinergic neurones.

     

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 SOME DOPAMINE ANTAGONISTS ON CHOLINERGIC MECHANISMS IN THE GUINEA-PIG ILEUM

• 1 Activation of prejunctional muscarinic and opiate receptors on cholinergic neurones of the guinea-pig ileum by acetylcholine (ACh) or morphine was seen as an inhibition of twitch responses to transmural electrical stimulation. These inhibitory responses were antagonised by metoclopramide and DL308-IT but no other antagonist used blocked the morphine responses apart from sulpiride in very high concentrations (100 μM and above).
• 2 Prejunctional and postjunctional responses to ACh on the guinea-pig ileum were measured in the presence of increasing concentrations of some muscarinic and dopamine antagonists. Atropine, hyoscine, chlorpromazine, cis-flupenthixol and thioridazine showed no selectivity in their antagonism of either response to ACh. Benzhexol selectively antagonised the postjunctional response whereas metoclopramide and DL308-IT showed greater selectivity for the prejunctional effect which they antagonised competitively. Sulpiride, a compound chemically related to metoclopramide, blocked neither the prejunctional nor postjunctional ACh responses. Clozapine antagonised the postjunctional ACh responses whilst apparently potentiating the prejunctional inhibition by ACh.
• 3 It was concluded that pharmacological differences may exist between prejunctional and postjunctional muscarinic receptors for ACh and that the antipsychotic actions of dopamine antagonists are unlikely to involve blockade of prejunctional ACh or opiate receptors.

     

Erythromycin accelerates gastric emptying in a dose-response manner in healthy subjects

STUDY OBJECTIVES: To evaluate whether a dose-response curve exists for erythromycin, determine the lowest effective dose of erythromycin needed to improve gastric motility, and compare erythromycin's effectiveness with that of metoclopramide in improving gastric emptying. DESIGN: Randomized, crossover, multiintervention trial. SETTING: Inpatient clinical research center. SUBJECTS: Ten healthy volunteers (four men, six women) from the general population. INTERVENTION: On each study day, the subjects were infused with erythromycin 0.75 mg/kg, 1.5 mg/kg, or 3.0 mg/kg; metoclopramide 10 mg; or placebo, in random order. Subjects then drank Ensure 200 ml mixed with acetaminophen 1.5 g. Gastric emptying was estimated by comparing the area under the curve after 60 minutes for acetaminophen absorption using four timed blood draws. MEASUREMENTS AND MAIN RESULTS: Erythromycin increased gastric emptying in a dose-response manner. Erythromycin 3.0 mg/kg and metoclopramide 10 mg were associated with statistically significant increases in liquid gastric emptying compared with placebo. During infusion, nausea and stomach cramping were associated with the 3.0-mg/kg dose of erythromycin; drowsiness was associated with metoclopramide. CONCLUSION: In patients requiring intravenous erythromycin for gastric motility, the 3.0-mg/kg dose seems the most effective, with a reasonable side effect profile.     

Gastric emptying in diabetic gastroparetic dogs: ffects of SK-951,a novel prokinetic agent

We examined whether delayed gastric emptying could be produced by diabetes in dogs. Diabetes was produced by a single injection of streptozotocin (30 mg/kg i.v.), and diabetic hyperglycemia was observed from 2 to 15 months after injection. The plasma acetaminophen concentration, which is an indirect indicator of the gastric emptying rate, was delayed in 2 of 5 diabetic dogs from 15 months after the induction of diabetes. The effects of SK-951, a benzofuran derivative, on delayed gastric emptying were also examined in diabetic gastroparetic dogs in comparison with those of cisapride. SK-951 (1 mg/kg i.v.) significantly enhanced delayed gastric emptying in diabetic dogs, but cisapride (1 mg/kg i.v.) had no effect. In addition, SK-951 increased the plasma glucose levels in a manner correlated with its effect on gastric emptying. The present study suggested that SK-951 may be useful in the treatment of diabetic gastroparesis.     

Diadenosine tetraphosphate-gating of cardiac K(ATP) channels requires intact actin cytoskeleton

The effects of endotoxin on gastric emptying of a solid nutrient meal and the neural mechanisms involved in such a response were investigated in conscious rats. The intraperitoneal (i.p.) administration of E. coli endotoxin (40 microg/kg) significantly reduced the 4-h rate of gastric emptying of a standard solid nutrient meal. Ablation of primary afferent neurons by systemic administration of high doses of capsaicin (20+30+50 mg/kg s.c.) to adult rats did not modify the rate of gastric emptying in control animals but prevented the delay in gastric transit induced by endotoxin. Local application of capsaicin to the vagus nerve rather than application of capsaicin to the celiac ganglion significantly repressed endotoxin-induced delay in gastric emptying. Neither treatment modified the rate of gastric emptying in vehicle-treated animals. Blockade of CGRP receptors (CGRP 8-37, 100 microg/kg i.v.) did not alter gastric emptying in control animals but significantly prevented endotoxin-induced inhibition of gastric emptying. In contrast, a tachykinin receptor antagonist ([D-Pro2, D-Trp7.9]-substance P, 2 mg/kg i.p.) significantly reduced the rate of gastric emptying in control animals and did not modify the inhibitory effects of endotoxin. Adrenergic blockade with phentolamine (3 mg/kg i.p.) +/- propranolol (5 mg/kg i.p.) or muscarinic antagonism with atropine (0.1 mg/kg i.p.) failed to reverse the delay in gastric emptying induced by endotoxin. These observations indicate that endotoxin-induced delay in gastric emptying of a solid nutrient meal is mediated by capsaicin-sensitive afferent neurons.     

N-NITRO-L-ARGININE AND INDOMETHACIN DO NOT AFFECT ENDOTHELIN-INDUCED CONSTRICTION OF LARGE AND SMALL CORONARY ARTERIES IN THE ANAESTHETIZED GREYHOUND

• 1 The aim of this study was to investigate whether endothelin-l (ET-1)-induced constriction of large and small coronary arteries in the anaesthetized greyhound is modulated by the endogenous release of nitric oxide or prostanoids.
• 2 ET-1 (1–100 ng/kg) and the α₁-adrenoceptor agonist phenylephrine (0.5-2 pg/kg), when injected directly into the circumflex coronary artery, caused dose-dependent decreases in epicardial coronary artery diameter and coronary vascular conductance without affecting systemic arterial pressure or the rate and force of cardiac contraction.
• 3 Inhibition of NO synthesis with N-nitro-L-arginine (NOLA, 5 mg/kg, i.c.) decreased coronary artery diameter, coronary conductance and heart rate and increased arterial pressure. The coronary vasoconstrictor response to ET-1 was unaffected by NOLA. By contrast, NOLA significantly increased the phenylephrine-induced constriction of the epicardial coronary artery but not the resistance vessels.
• 4 Indomethacin (5 mg/kg, i.v.), an inhibitor of cyclo-oxygenase, significantly decreased epicardial coronary artery diameter but did not affect coronary conductance. Indomethacin had no effect on the coronary vascular responses to ET-1 or phenylephrine. Combined treatment with NOLA plus indomethacin also failed to affect the coronary vasoconstrictor effects of ET-1.
• 5 Basal release of NO and vasodilator prostanoids modulated resting coronary vascular tone but did not Influence the vasoconstrictor responses to endothelin in either large or small coronary arteries.

     

MODIFICATION OF THE VASOMOTOR ACTIONS OF METHYSERGIDE IN THE FEMORAL ARTERIAL BED OF THE ANAESTHETIZED DOG BY CHANGES IN SYMPATHETIC NERVE ACTIVITY

• 1 Methysergide has been shown to have a remarkably selective vasoconstrictor action in the carotid arterial bed of the anaesthetized dog following intravenous administration. However we have now shown that under conditions which produce sympathetic blockade methysergide will also constrict the femoral arterial bed and the mechanism involved has been investigated.
• 2 Methysergide (10–100 μg/kg i.v.) produced small but variable effects on femoral arterial blood flow in the anaesthetized dog. However following ganglion blockade (mecamylamine 5 mg/kg i.v.), section of the lumbar sympathetic chain between L₄-L₅ or catecholamine depletion with syrosingopine, methysergide consistently caused dose-related decreases in femoral arterial flow which were associated with increases in femoral arterial vascular resistance.
• 3 Intravenous infusion of methysergide (10 μg/kg/min) or 5-hydroxytryptamine (5-HT, 10 μg/kg/min) inhibited the increases in femoral arterial vascular resistance produced by stimulation of the lumbar sympathetic chain by 70% and 44% respectively whilst increases in vascular resistance produced by close intra-arterially administered noradrenaline were potentiated by 25% and 11% respectively.
• 4 Our results show that the vasomotor actions of methysergide in the dog femoral arterial bed are dependent on the degree of sympathetic activity. This suggests that in the dog the post-junctional vasoconstrictor action of methysergide can be masked by a pre-junctional inhibitory effect on sympathetic nerves which may be mediated through stimulation of a specific pre-junctional receptor for 5-HT.

     

THE PROPORTIONAL CUMULATIVE AREA UNDER THE CURVE OF PARACETAMOL USED AS AN INDEX OF GASTRIC EMPTYING IN DIABETIC PATIENTS WITH SYMPTOMS OF GASTROPARESIS

1. The foreshortened 2 h method of measuring liquid gastric emptying (i.e. the proportional cumulative area under the curve of paracetamol) was utilized in diabetic patients in order to detect both gastroparesis and the influence of metoclo-pramide, a known prokinetic drug, on this condition. 2. Metoclopramide, 10 mg intravenously, caused a significant increase in the median PC_AUC from 20 min onwards. 3. In this study delayed gastric emptying was defined as a %PC_AUC without pretreatment lower than the 5% percentile at 40, 60 and 90 min for normal volunteers. According to this criterion seven of the 10 patients with clinical symptoms of gastroparesis and/or peripheral neuropathy had delayed gastric emptying. 4. The PC_AUC method would therefore seem to be a reliable model for investigating gastric emptying in diabetics and the effects of various prokinetic drugs on this condition.