A method for simultaneous measurement of intragastric, intraduodenal, and intracolonic pressures in the bilaterally vagotomized spinal rat.

A method has been developed where quantitative evaluation of intragastric (IGP), intraduodenal (IDP), and intracolonic (ICP) pressures (cm H2O) can be obtained in the bilaterally vagotomized spinal rat. The preparation is very sensitive to 5-hydroxytryptamine (5-HT) and 5-HT-agonists, carbachol, histamine, dopamine, and/or noradrenaline. The effects of drugs on IGP, IDP, and ICP (increase or decrease) can be assessed and a dose-response curve before and after antagonists can be computed. The described experimental model is simple, reliable, reproducible, and appropriate to study and differentiate the different gastrointestinal system receptors that seem to be involved in the modulation of gastrointestinal motility. The additional advantage in using this method is that drug effects on the motility of stomach, duodenum, and colon can be investigated simultaneously.

The role of dopamine (D2), alpha and beta-adrenoceptor receptors in the decrease in gastrointestinal transit induced by dopamine and dopamine-related drugs in the rat.

This study analyses the effects of dopamine receptor agonists and antagonists on rat gastrointestinal transit (GIT) in an attempt to identify the mechanisms involved. Dopamine (DA), apomorphine, quinpirole, bromocriptine and fenoldopam were given by subcutaneous (s.c.), intrathecal (i.t.), intracisternal (i.c.) and/or intraperitoneal (i.p.) routes. In general, DA (200 micrograms, i.t.), apomorphine (3, 5 and 10 mg/kg, s.c.; or 10, 30 and 100 micrograms, i.t.), and bromocriptine (1, 5 and 10 mg/kg, s.c.) elicited decreases in gastrointestinal transit which were significantly antagonized by the D2 receptor antagonists domperidone or alizapride (both 5 mg/kg, s.c.), but remained unaffected by the D1 receptor antagonist SCH 23390 (5 mg/kg, s.c.). Similarly, DA (50, 100 and 200 micrograms, i.c.) and apomorphine (12 and 50 micrograms; i.c.) produced dose-dependent decreases in gastrointestinal transit amenable to blockade by the classical DA receptor antagonist haloperidol (10 micrograms, i.c.). The responses to apomorphine (3, 5 and 10 mg/kg, s.c.) were unaltered by 6-hydroxydopamine (100 mg/kg, i.p.)-induced sympathectomy but were antagonized by both propranolol (1 mg/kg, s.c.) and phentolamine (5 mg/kg, s.c.). Significantly, after bilateral (cervical) vagotomy, gastrointestinal transit was markedly reduced, but apomorphine (5 mg/kg, s.c.) apparently further reduced gastrointestinal transit. The D1 agonists fenoldopam (5, 10 and 20 mg/kg, s.c.) significantly reduced GIT. Fenoldopam-induced antitransit effects were markedly modified by the D1 receptor antagonist, SCH 23390 (5 mg/kg, s.c.); only the response induced by 5 mg/kg of fenoldopam was apparently antagonized by SCH 23390. The mixed D2 and D3 receptor agonist quinpirole (4 and 8 mg/kg, s.c.; or 8 mg/kg, i.p.; 200 micrograms, i.t.) did mimic DA eliciting significant reductions in gastrointestinal transit which, however, were not antagonized by domperidone (5 mg/kg, s.c.). Taken together, the present results support the contention that the decrease in rat gastrointestinal transit induced by DA and apomorphine may be mediated by an interaction with central and/or peripheral D2 receptors. The presence of dopamine receptors (D2) in the alimentary canal are strengthened by antitransit effect of fenoldopam and bromocriptine in the gastrointestinal tract.

Gastrointestinal effects of 5-hydroxytryptamine and related drugs.

This paper deals with the effects of 5-hydroxytryptamine (5-HT; serotonin) and related drugs on the gastrointestinal tract (GIT). The nomenclature and classification of 5-HT receptors, as well as their putative role in the GIT are updated in this review. Besides its effects on the cardiovascular system, which have been extensively described, several lines of evidence suggest a role for 5-HT in regulating gastrointestinal functions. 5-HT is present in the gastrointestinal tissues, and can elicit contraction or relaxation by activation of a wide variety of mechanisms and receptors. At least four main types of receptors (5-HT1, 5-HT2, 5-HT3 and 5-HT4) have been described and all the four types seem to influence the GIT. In this respect, the 5-HT2, and in some cases the 5-HT1 receptors, appear to be present on the gastrointestinal smooth muscle, while 5-HT3 and 5-HT4 are mainly neuronal.

5-Hydroxytryptamine-induced increase in left ventricular dP/dtmax does not suggest the presence of ventricular 5-HT4 receptors in the pig.

Although 5-hydroxytryptamine (5-HT) increases porcine atrial force and rate via 5-HT4 receptors, its effect on left ventricular contractility is not known. Therefore, using the maximum rate of rise of left ventricular pressure (LVdP/dtmax) as an index of cardiac contractility, we have attempted to analyze the possible role of ventricular 5-HT4 receptors in the anaesthetized pig. The full agonists at 5-HT4 receptors, 5-HT and 5-methoxytryptamine (each 3, 10 and 30 micrograms.kg-1), and the beta-adrenoceptor agonist, isoprenaline (0.01, 0.03 and 0.1 micrograms.kg-1), increased heart rate, LVdP/dtmax and cardiac output. For a given degree of tachycardia, the increase in LVdP/dtmax by isoprenaline was substantially more than that observed with either 5-HT or 5-methoxytryptamine. The 5-HT4 receptor partial agonist, renzapride (3, 10, 30, 100 and 300 micrograms.kg-1), also increased heart rate and LVdP/dtmax dose-dependently. When the heart was paced at 150 beats.min-1, increases in LVdP/dtmax as well as cardiac output (except with the highest doses) by 5-HT, 5-methoxytryptamine and isoprenaline were clearly attenuated. However, the magnitude of attenuation of LVdP/dtmax responses by cardiac pacing was more marked in the case of 5-HT and 5-methoxytryptamine than with isoprenaline. The effects of renzapride (300 micrograms.kg-1) and tropisetron (0.3 and 3 mg.kg-1) on increases in heart rate and LVdP/dtmax by 5-HT, 5-methoxytryptamine and isoprenaline were also studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of 5-HT1-like receptors in the increase in intragastric pressure induced by 5-hydroxytryptamine in the rat.

The study concerned the effects of 5-hydroxytryptamine (5-HT) on intragastric pressure in bilaterally vagotomized spinal rats. Intravenous (i.v.) bolus injections of 5-HT (2.5, 5.0 and 10 micrograms/kg) produced dose-dependent increases in intragastric pressure; these effects were not modified by atropine (up to 0.2 mg/kg) or mepyramine (1 mg/kg), but were blocked by the mixed 5-HT1-like and 5-HT2 receptor antagonists, methiothepin (0.1, 0.3 and 0.5 mg/kg i.v.) and methysergide (0.5, 1 and 2.5 mg/kg i.v.). However, metergoline (0.5, 1 and 2 mg/kg i.v.) did not markedly modify this effect of 5-HT; only the response induced by 5 micrograms/kg 5-HT was significantly antagonized by the highest dose of metergoline. In contrast, neither the 5-HT2 receptor antagonist, ketanserin (0.5, 1 and 1.5 mg/kg i.v.), nor the 5-HT3 receptor antagonist, ICS 205-930 (0.5, 1 and 3 mg/kg i.v.), influenced the 5-HT-induced increase in intragastric pressure. In addition, 5-carboxamidotryptamine (25, 50 and 100 micrograms/kg i.v.) and RU 24969 (50, 100 and 200 micrograms/kg i.v.) mimicked the aforementioned effects of 5-HT but were weaker than 5-HT. These data suggest that the 5-HT-induced increase in intragastric pressure in the spinal and bilaterally vagotomized rat is mediated by an atypical 5-HT1-like receptor, which, based on the low agonist potency of 5-carboxamidotryptamine and RU 24969 and the resistance to blockade by metergoline, does not seem to correspond to either the 5-HT1A, 5-HT1B, 5-HT1C or the 5-HT1D receptor subtypes.

Hypotension and bradycardia after intrathecal ketanserin and phentolamine in the rat.

Intrathecal administration of ketanserin and phentolamine elicited dose-dependent falls in arterial blood pressure and heart rate in anaesthetized rats without attenuation of the pressor responses to i.v. injections of phenylephrine. It is concluded that both ketanserin and phentolamine can decrease arterial blood pressure by acting within the spinal cord.

Analgesic effect of tramadol in the rat.

The analgesic effect of tramadol was studied in the rat using tail flick and hot plate tests following intrathecal and subcutaneous administrations. Tramadol had only a short-lasting analgesic effect (20 min) on intrathecal administration which may be due to rapid removal from the subarachnoid space. Its analgesic effects were antagonized by pretreatment with naloxone. It seems that the opiate system may involve in the analgesic effect of tramadol, while the noradrenergic, serotonergic and cholinergic systems may play a modulating role.

Role of dopamine receptors in gastrointestinal motility.

Apomorphine (3.5 and 10 mg/kg, s.c.) and morphine (1.3 and 10 mg/kg, s.c.) produced a dose-dependent decrease in gastrointestinal transit of charcoal dust in rats. The involvement of dopamine in such a constipatory effect was found to be mediated to a greater extent by DA2 than by DA1 receptors, using a specific DA1 antagonist (SCH 23390) and DA2 antagonists (alizapride, domperidone). The decrease in apomorphine (50 micrograms) and dopamine (100 and 200 micrograms)-induced gastrointestinal transit after intracisternal administration was antagonized by haloperidol. These results provide evidence for the involvement of dopamine receptors in the constipatory effects of apomorphine and morphine in rats.

Aprotinin reduces hypothermic mortality--an experimental model.

In order to test the postulate that post-hypothermic damage may be caused by protease activation, the effect of the administration of aprotinin on hypothermic mortality was investigated in anaesthetized rabbits. A group of 6 animals received 40.000 KIU aprotinin intravenously prior to the induction of hypothermia by surface cooling and this was followed by a further 35.000 KIU each hour for 5 h. The animals were cooled to 29 degrees C and then rewarmed. A control group received equal volumes of physiological saline. The aprotinin treated animals survived, whereas all the control group died within 7 days, 5 of them within 24 h. The haemodynamic, biochemical and haematological changes in the two groups are reported.

Analysis of the tachycardiac response to 5-hydroxytryptamine in the spinal guinea-pig.

The mechanism of the increase in heart rate caused by 5-hydroxytryptamine (5-HT) in the spinal guinea-pig was investigated. Administration of 5-HT (15, 30, 60 and 120 micrograms.kg-1 i.v.) elicited dose dependent increases in heart rate. The responses to 5-HT were not modified by methiothepin (0.5 and 1.5 mg.kg-1), ketanserin (0.5-4.5 mg.kg-1) or MDL 72222 (0.5-4.5 mg.kg-1) but were antagonized by the beta-adrenoceptor antagonists, propranolol (0.1-1 mg.kg-1) or atenolol (0.5-4.5 mg.kg-1). Indalpine, which is known to interfere with the uptake of 5-HT by nerve terminals and blood platelets, significantly reduced the effects of 5-HT at a dose (5 mg.kg-1) that also affected the tachycardia elicited by tyramine. The increase in heart rate caused by tyramine in reserpinized animals was attenuated and, unlike normal animals where the responses to 5-HT remained constant after repeated administration, there was a quickly developing tachyphylaxis to 5-HT. These results show that the increase in heart rate elicited by 5-HT in spinal guinea-pigs is not mediated by any of the currently characterized 5-HT receptors ('5-HT1-like', 5-HT2 and 5-HT3), and that a major part of the tachycardia seems to be mediated by a release of catecholamines by a mechanism similar, though perhaps not identical, to that for tyramine. Another as yet unidentified mechanism could be involved besides though perhaps not identical, to that for tyramine. Another as yet unidentified mechanism could be involved besides this action.

Acute diarrhoeal disease in rabbit: bacteriological diagnosis and efficacy of oral rehydration in combination with loperamide hydrochloride.

Acute outbreaks of diarrhoea with high mortality rates are frequently observed in rabbits. Amongst various aetiological factors Escherichia coli or its toxins have been found to be commonly incriminated. Sulphonamides or antibiotics are used to treat rabbits with bacterial diarrhoea. The result of the antibiotic treatment is moderately successful. We had good results using oral rehydration treatment in combination with loperamide hydrochloride (Immodium) in a colony of rabbits with E. coli diarrhoea.

Ketamine-induced dysrhythmia and its antagonism: a case report.

Ketamine is normally considered as being anti-dysrhythmic. A case report is presented here in which small subanaesthetic doses of ketamine were administered to reinforce spinal analgesia. Initial doses were followed by a dysrhythmia, which appeared to be repeatedly counteracted by further small doses of the drug. The cardiac pharmacology of ketamine is discussed, as is the relevance of the chance finding of mitral valve prolapse.

Gastrointestinal transit following intrathecal or subcutaneous narcotic analgesics.

This paper reports investigations on the effects on gastrointestinal transit of subcutaneous or intrathecal administration of opiates: morphine, sufentanil and alfentanil. Subcutaneous administration of opiates produced a significant dose-dependent decrease in transit of a charcoal meal test. Intrathecal administration of morphine to Wistar rats with catheter chronically implanted in the subarachnoid space did not cause a decrease in gastrointestinal transit. However, in freshly prepared rats with intrathecal catheter in the subarachnoid space, morphine significantly decreased intestinal transit of charcoal meal. In addition, sufentanil and alfentanil, on intrathecal administration in rats with chronically implanted catheters, caused a marked dose-dependent slowing of the passage of meal. Prior s.c. administration of the opiate antagonist naloxone completely blocked the depression of gastrointestinal transit caused by high doses of intrathecal sufentanil and s.c. administered morphine.

Serotonin agonists and antagonists in experimental hypertension.

Serotonin (5-hydroxytryptamine; also called 5-HT) modifies cardiovascular activity by central as well as peripheral sites of action. When 5-HT is injected within the central nervous system, depending upon the dose and site of administration, either a pressor or a depressor effect is observed. Recent findings suggest that this depressor effect may be mediated by central "5-HT1-like" receptors, since certain compounds that exhibit a high affinity for the 5-HT1A binding site can reduce blood pressure by a central action in both hypertensive and normotensive animals. Peripherally, 5-HT elicits vasodilatation (both directly and indirectly via presynaptic sympathoinhibition and release of vasodilator substances from endothelium) or vasoconstriction (with associated amplification of noradrenaline response) of mainly "large" conductance arteries mediated by, respectively, "5-HT1-like" and 5-HT2 receptors. Of the various antagonists at 5-HT receptors, it is only ketanserin that effectively lowers arterial blood pressure. However, since it is unlikely that the very low concentrations of 5-HT in plasma exert a significant influence on the maintenance of peripheral vascular resistance, the blockade of 5-HT2 receptors by ketanserin does not seem to explain the reduction of blood pressure in hypertension. Indeed, apart from the undoubtedly potent 5-HT2 receptor blockade, ketanserin also has alpha 1-adrenoceptor antagonist, central vasomotor depressant, and "direct" vasodilator properties, which can explain its antihypertensive action.

Effect of intrathecal and intracarotid administration of ketamine on blood pressure and heart rate in rats.

Intrathecal and intracarotid effects of ketamine were investigated in anaesthetized rats. Ketamine was administered in the subarachnoid space in doses ranging from 300 to 1500 micrograms X kg-1. In these doses ketamine produced a short-lasting hypotension and bradycardia which may be due to inhibition of sympathetic outflow from thoraco-lumbar region. On the other hand when ketamine (5 mg X kg-1) was injected into the cerebral circulation it produced a rise in blood pressure and heart rate, probably through a cholinergic mechanism.

A study on the influence of ketamine on systemic and regional haemodynamics in conscious rabbits.

Effects of ketamine hydrochloride (2, 6 and 18 mg X kg-1, i.v.) were investigated on systemic and regional haemodynamics using a radioactive microsphere method in conscious rabbits. Ketamine decreased respiratory frequency in a dose-dependent manner for up to 5 min. A significant fall in the mean arterial blood pressure (with the two highest doses), together with a short lasting tachycardia, was observed with ketamine. The cardiac output and blood flow to many tissues were not changed by this anaesthetic agent. However, increased blood flow was noticed in discrete regions of the brain (cerebral hemispheres) and heart (left ventricular endocardium). Vasodilation in the cerebral hemispheres with this agent producing dissociative anaesthesia is in contrast to the generally observed decrease in cerebral blood flow with other anaesthetic agents.