Indomethacin-induced ileitis is associated with tensiometric, vascular and oxidative changes in the experimental rat model.

BACKGROUND: Indomethacin-induced enteritis is a model of inflammatory bowel disease. MATERIALS AND METHODS: To further characterize this model, rats received two injections of indomethacin (7.5 mg kg(-1)) 24 h apart and histological damage of intestinal mucosa, oxidative stress, alterations of intestinal motility and mesenteric vascular bed (MVB) reactivity were investigated after 5 days. RESULTS: The results show that indomethacin caused several histological and functional changes at the ileal level. In particular, response to carbachol as well as the nonadrenergic-noncholinergic inhibitory response to electrical field stimulation (EFS) was lower in the treated than control rats. Moreover, nitric oxide (NO)-component of the inhibitory response was higher in the treated than control rats. Mesenteric vessels preparations from the treated rats showed increased noradrenaline (NA)-induced perfusion pressure, whereas relaxant responses to acetylcholine, although not significantly reduced in the treated rats, had a higher nitrergic component. This finding suggests that vascular dysfunction may contribute to chronic inflammation. Indomethacin injection also determined acute and severe oxidative stress in ileum mucosa. CONCLUSIONS: In conclusion, our study contributes to further characterize the rat model of indomethacin-induced enteritis and suggests that it is suitable for drug screening in rats, as this model can be obtained in a very short period and is simple and reproducible.

Involvement of kappa-opioid receptors in peripheral response to nerve stimulation in kappa-opioid receptor knockout mice.

1 The present study aimed to evaluate the role of kappa-opioid receptors at two peripheral sites, the vas deferens and the proximal colon, in kappa-opioid receptor knockout mice. We investigated the role of the kappa-opioid receptor in the vas deferens twitch response and in the colonic "off-contraction", a rebound contractile response which follows the inhibitory response to low frequencies stimulation (10, 20, 30 Hz) and which has been suggested to "locally" reproduce the contractile component of the peristaltic reflex. 2 Transmural stimulation of the vas deferens at lower frequencies (10 Hz, 10 V, 1 ms pulse trains lasting 0.5 s) evoked a contractile response that was significantly higher in the preparations from knockout mice because of lack of kappa-opioid receptors than in wild type mice. A selective kappa-opioid receptor agonist, U-50,488H, induced a dose-dependent inhibition of the electrically stimulated contraction in vas deferens. The percentages of reduction of the twitch response were significantly lower in knockout mice than in wild type mice after treatment with U-50,488H. The reduction of twitch response caused by U-50,488H was not reversed by administration of nor-binaltorphimine (nor-BNI) (5 x 10-6 m), a selective kappa-opioid receptor antagonist, in preparations from both knockout mice and wild type mice. U-50,488H has no effect on postsynaptic adrenergic receptors, as its administration did not affect the direct contractile response to noradrenaline. 3 Transmural stimulation (5 Hz, 20 V, 2 ms pulse trains lasting 30 s) induced inhibition of spontaneous activity of colonic strips during the period of stimulation, followed by an "off-contraction" after the cessation of stimulation. The statistical evaluation of the "off-contraction" responses between the two strains showed no significant difference. The off-contraction, measured in specimens from knockout mice, was inhibited concentration-dependently by U-50,488H (P < 0.01) and significantly less than from wild type mice. 4 The effect of U-50,488H was not reversed by administration of nor-BNI (5 x 10-6 m), either in preparations from knockout mice or from wild type mice. 5 Our data may suggest that kappa-opioid receptors are involved in some peripheral responses to the nerve stimulation, as indicated by the effect of U-50,488H, a selective kappa-opioid receptor agonist. However, the involvement of kappa-opioid receptor was also present, although less apparent, in kappa -opioid receptor knockout mice, suggesting either that this drug acts not only on kappa-opioid receptors but also on other receptor sites, such as kappa-like receptors. An alternative interpretation can be related to a sodium channel blocking action of U-50,488H, which could explain the inhibitory effects of twitch response still present but less evident in knockout strain and the lack of effect of the antagonist nor-BNI.

Idiopathic chronic constipation: tachykinins as cotransmitters in colonic contraction.

BACKGROUND: Tachykinins (TKs) have been shown to be involved in the excitatory enteric motor pathway. This study aimed to examine the direct and nerve-mediated effect of specific NK1, NK2 and NK3 receptor agonists and antagonists in colonic preparations from control subjects and patients with idiopathic chronic constipation (ICC). MATERIALS AND METHODS: Cumulative concentrations of Sar9Met(O2)11 substance P (selective NK1 receptor agonist), [Ala5,beta-Ala8]-neurokinin A (4-10) (selective NK2 receptor agonist) and [MePhe7]-neurokinin B (selective NK3 receptor agonist) were tested on colonic circular muscle strips to evaluate the direct drug effects. In addition, in the presence of atropine, the role of TKs in the off-contraction that follows the typical inhibitory response evoked by low frequencies of electrical field stimulation (0.5--10 Hz, 20 V, 1 ms pulse trains lasting 1 min) was investigated. RESULTS: In control preparations, the rank order of potency was: NK2 receptor-selective agonist > NK3 receptor-selective agonist > NK1 receptor-selective agonist. The off-contraction was found to be reduced by about 30--40% in colonic circular muscle from ICC patients with respect to controls. Incubation with the NK1 receptor agonist did not modify the off-contraction measurements in either control or ICC preparations. Conversely, both NK2 and NK3 receptor agonists significantly (P < 0.01) increased the off-contraction in ICC preparations only. This increased response was fully antagonized by MEN-10627, a NK2 and NK3 receptor antagonist depending on the dose. CONCLUSIONS: We may conclude that ICC is hyporesponsive to TKs and that the contractile reflex to distension is greatly reduced in ICC disease, but can be restored by incubation with NK2 and NK3 receptor agonists.

Endothelin-1-receptor-mediated responses in resistance vessels of young and adult spontaneously hypertensive rats.

OBJECTIVE: To assess whether primary changes in endothelin-1 (ET-1) receptor responsiveness or secondary vessel functional modifications could characterize the effects evoked by ET-1 in the mesenteric vascular bed (MVB) of prehypertensive 5-week-old and 12-week-old spontaneously hypertensive rats (SHRs). DESIGN AND METHODS: We used male 5-week-old and 12-week-old SHRs and sex- and age-matched Wistar-Kyoto (WKY) rats as controls. ET-1 receptor responsiveness was evaluated by ET-1 (0.04-2 micromol/l) concentration-response curves and repeated with indomethacin and BQ-123 (0.1-0.5 micromol/l), the latter a selective ETA receptor antagonist. ETB receptor responsiveness was tested by sarafotoxin S6c (1-100 nmol/l) and IRL-1620 (0.1-10 nmol/l) concentration-response curves, obtained in the noradrenaline-precontracted MVB. RESULTS: At 5 weeks of age, ET-1 induced a similar concentration-dependent contraction in SHRs and WKY rats, with an overlapping BQ-123 pA2 value (negative common logarithm of the antagonist that produces an agonist dose ratio of 2) in the two strains. Indomethacin was ineffective in both groups. Sarafotoxin S6c and IRL-1620 both evoked an ETB-mediated, significant relaxation, only in WKY rats. In 12-week-old SHRs, ET-1 evoked a markedly increased maximal effect compared with the response in WKY rats (P< 0.01); this was prevented by treatment with indomethacin. The BQ-123 pA2 value was higher in SHRs than in WKY rats (P< 0.01). Both sarafotoxin S6c and IRL-1620 evoked a significant concentration-dependent relaxation in WKY rats, which was not detected in SHR preparations. CONCLUSIONS: Our results could suggest that the different responses evoked by ET-1 in the MVB of SHRs during the onset of hypertension may be related partially to primary alterations in the ET-1 receptorial pattern and partially to the onset of high blood pressure, leading to an impairment in the haemodynamic balance.

Changes in the frequency of splenic immunocompetent cells in rats exposed to carbon monoxide during gestation.

The aim of the present study was to evaluate whether prenatal exposure to relatively low concentrations of carbon monoxide (CO) may alter the frequency of splenic cells either in young (15-21 days) or in aged rats (18 months). Wistar female rats were exposed to 75 and 150 ppm of CO from day 0 to day 20 of pregnancy, respectively. The results show that prenatal exposure to 150 ppm of CO significantly decreases the number of leucocyte common antigen (LCA+) cells in 21 day old male rats, whereas other cellular populations, such as macrophages, Major Histocompatibility (MHC) II cells, T and B lymphocytes display only a trend towards a reduction without achieving statistical significance. The alterations in LCA+ cell frequency produced by gestational exposure to CO were reversible. These data further extend previous findings showing that rats prenatally exposed to moderate concentrations of CO exhibit subtle immunological changes in the absence of overt signs of toxicity.

Behavioral and neurochemical changes produced in rats by developmental treatments with psychotropic drugs.

The timing of developmental administration of psychotropic drugs affecting dopaminergic and GABAergic neurotransmission is crucial for the induction of specific neurobehavioral and neurochemical changes in rodents. Compensatory mechanisms occurring in response to a prolonged treatment with some neuroleptic and anxiolytic agents during development seem to be markedly different from those occurring in response to a prolonged administration in adult animals.

Fibronectin levels in pregnancy and puerperium.

Fibronectin levels were serially assayed during the third trimester of pregnancy and puerperium in a group women with uncomplicated pregnancies, and two groups with mild/severe hypertensive disorders of pregnancy. The values were found increased in the complicated pregnancies, with extremely elevated levels in cases of severe preeclamptic fits.

Comparative evaluation of the effects of lidocaine (lignocaine) hydrochloride and salicylate on nervous and Purkinje fibres.

Lidocaine hydrochloride and lidocaine salicylate (lisacaine) have been tested on the frog node of Ranvier, on the sheep cardiac Purkinje fibres and rat phrenic nerve-diaphragm. On the node of Ranvier both drugs produced the same degree of reduction of peak INa and steady-state potassium current and the same degree of shift of the steady-state inactivation curve for INa to more negative potential. Lisacaine took less time to reach the steady-state effect. On the cardiac Purkinje fibres both drugs decreased the action potential duration without any detectable difference; but their effects on V max (i.e. the maximum rate of depolarization) were different that of lisacaine being faster. On the rat phrenic nerve-diaphragm both drugs produced the same percentage of reduction of the contractile response of diaphragm but, the action of lisacaine was faster. Therefore the lidocaine molecule with the salicylate anion while displaying the same anaesthetic effectiveness has a faster action than the hydrochloride.

[Anti-thirst action of propranolol]. / Azione antidipsica del propranololo.

A reduction of the thirst was observed one hour after intramuscolar injection of 0.3 mg/kg propranolol in the rat; this effect was not observed with higher doses. According to work hypotheses, small doses could act blocking renal beta-adrenergic receptors: the stopped renin emission reduces angiotensin production that is the basic factor of thirst. The AA hypothesize that the lack of the effect in response to higher doses of propranolol can be explained through a different action of this drug which antagonizes the first one.

Rifampicin induction of myopathy: lack of a direct effect on rat neuromuscular system.

The effect of acute administration of rifampicin on neuromuscular transmission was tested, in-vivo, in the rat. Rifampicin did not alter the strength of contraction of the muscle indirectly stimulated at various frequencies. Additional isoniazid pretreatment did not alter the absence of effect of rifampicin on neuromuscular action.

Effects of dibekacin, a new aminoglycoside antibiotic, on the rat sciatic nerve-gastrocnemius muscle preparation.

O-3-amino-3-deoxy-alpha-D-glucopyranosyl-(1----6)-O-[2,6-diamino-2,3,4,6 -tetradeoxy-alpha-D-erythro-hexopyrano-hexopyranosyl-(1----4 ) ]-2-deoxy-L- streptamine (dibekacin), like other known aminoglycoside antibiotics, possesses a dose-dependent neuromuscular blocking activity in vivo. d-Tubocurarine, at a dose which per se does not influence the contraction of gastrocnemius muscle elicited by sciatic nerve stimulation, significantly potentiates the neuromuscular blockade produced by dibekacin. Neostigmine methylsulfate is unable to reverse the neuromuscular blocking activity of dibekacin, whereas calcium chloride antagonizes the neuromuscular blockade produced by this antibiotic.

[Pharmacology of lycorine. 1) Effect on biliary secretion in the rat]. / Studi farmacologici sulla licorina. 1) Effetto sulla secrezione biliare nel ratto.

The Authors study pharmacological actions of lycorine, alkaloid of Lycoris radiata. On the basis that anti-inflammatory substances have a choleretic effect, the activity of lycorine on biliary secretion of rats has been investigated. Lycorine, at a dose of 1 mg/kg induces, in rats anaesthetized with urethane (1,2 g/kg i.m.), a marked choleretic effect. This experiment do not define the mechanism responsible for the observed choleresis.

Dantrolene sodium: stimulatory and depressant effects on the contractility of guinea-pig uterus in vitro.

The effects of dantrolene sodium on the spontaneous and oxytocin-induced contraction of guinea-pig uterus were studied in vitro. Dantrolene reversibly increased the spontaneous contraction frequency of guinea-pig uterus. The effect was not dose-related and was not antagonized by atropine, methysergide or indomethacin. Dantrolene dose dependently and reversibly reduced the contractile responses of guinea-pig uterus to oxytocin. The varying effects of dantrolene on the uterus probably involve inhibition of calcium movement at more than one site of the muscle.

[Effect of prostaglandin F2 alpha on biliary secretion in the rat]. / Effetto della prostaglandina F2 alpha sulla secrezione biliare di ratto.

The effects of PGF2 alpha on biliary secretion of rats have been investigated. PGF2 alpha' at the dose of 100 micrograms/kg, produces a choleretic activity during the first 20 min after the injection. The effects are discussed by comparison to those observed in dogs, where a mechanism involving the canicolar level has been hypothesized.

[Effect of indoprofen on biliary secretion in the rat]. / Effetto dell'indoprofene sulla secrezione biliare di ratto.

The activity of indoprophen on biliary secretion of rats has been investigated. Indoprophen, at a dose of 20 mg/kg induces a marked choleretic effect. It has been hypothesized that the choleretic action of indoprophen could be attributed to an inhibition of prostaglandin-synthetase and to an increase of cAMP which is the physiological factor responsible of ductal choleresis.

Effects of two new aminoglycoside antibiotics on the rat sciatic nerve-gastrocnemius muscle preparation.

2'-Amino-2'-deoxy-kanamycin (bekanamycin, Kanendomycin) and pentisomicin displayed a neuromuscular blocking activity on the rat sciatic nerve-gastrocnemius muscle preparation. Pentisomicin showed the highest neuromuscular blocking effect; the neuromuscular blocking potency of bekanamycin was similar to that of tobramycin, another new aminoglycoside. The neuromuscular block produced by these antibiotics was reversed by calcium chloride whereas it was not influenced by neostigmine methylsulfate.

Comparative evaluation of the neuromuscular blocking activity of three new aminoglycoside antibiotics in rats.

The effects of three aminoglycoside antibiotics on the rat isolated phrenic nerve-diaphragm preparation and on the sciatic nerve-gastrocnemius muscle preparation were investigated. Tobramycin, amikacin and ribostamycin produced dose-dependent neuromuscular blockade of the diaphragm twitches. Comparison of results showed that the neuromuscular blocking potency was as follows: tobramycin greater than amikacin greater than ribostamycin. The neuromuscular blockade produced gy these antibiotics was reversed by calcium chloride, whereas it was not influenced by neostigmine methylsulfate. Furthermore, the neuromuscular blocking potency in vitro of these three aminoglycosides was paralleled by their activity in vivo on the sciatic nerve-gastrocnemius muscle preparation.