Synergistic anti-inflammatory interaction between meloxicam and aminoguanidine hydrochloride in carrageenan-induced acute inflammation in rats

Interaction studies with inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) inhibitor have been conducted to assess the nature of interaction and the possible therapeutic advantage. The interaction between meloxicam--a selective COX-2 inhibitor--and aminoguanidine hydrochloride--a selective iNOS inhibitor-- was examined in carrageenan-induced paw edema in rats. Appropriate statistical method was applied to detect the nature of anti-inflammatory interaction. Different doses of meloxicam (1, 3, 10 and 30 mg/kg) or aminoguanidine hydrochloride (10, 30, 100 and 300 mg/kg) were administered orally to adult male albino rats. Higher doses of meloxicam (3, 10 and 30 mg/kg) showed statistically significant anti-inflammatory effect. However, aminoguanidine hydrochloride did not show any anti-inflammatory activity. Combination of sub-threshold dose of meloxicam (1 mg/kg) with increasing doses of aminoguanidine hydrochloride (30, 100 and 300 mg/kg) resulted in synergistic anti-inflammatory effect. Combined therapy with sub-threshold dose of aminoguanidine hydrochloride (30 mg/kg) with increasing doses of meloxicam (1, 3, 10 and 30 mg/kg) also resulted in synergistic anti-inflammatory effect. The possible mechanism of interaction could be the stimulation of COX-2 activity by nitric oxide (NO) by combining with heme component. These results suggest that co-administration of meloxicam and aminoguanidine hydrochloride may be an alternative in clinical control of inflammation.     

Nicotene-induced analgesia in rats: The role of calcium and the diversity of responders and nonresponders

Following a single dose of nicotine, (NIC, 1 mg/kg s.c.), 60% of tested rats revealed significant anticociception as measured by the tail-flick (TF) test, and were classified as responders, with those in which TF latencies did not change, nonresponders. The following experiments were carried out one week later. In nonresponders, pretreatment with ethylenediaminetetraacetic acid (EDTA, 250 μM/kg s.c. four times every 15 min) followed by 1 mg NIC, produced significant analgesia in 50% of rats, to the same magnitude as did nicotene alone (1 mg) in responders. The other 50% of rats which failed to respond to EDTA pretreatment, all revealed similar analgesia following the higher dose of NIC (1.5 mg/kg s.c.), with similar side effects, as generally observed in responders. In responders, pretreatment with CaCl₂ (1.5 mM/kg s.c.) completely abolished NIC (1 mg/kg s.c.) - induced analgesia in all rats. Our data provide stronger evidence and a further verification that EDTA potentiates, whereas CaCl₂ completely abolishes, nicotene-induced analgesia in rats; supporting our hypothesis of the involvement of calcium ions in this effect.     

Antihypertensive effect of total flavonoid fraction of Astragalus complanatus in hypertensive rats

The purpose of the present study was to quantify the antihypertensive effect of the total flavonoid (TF), extracted from the seed of Astragalus complanatus R. Brown, and to observe its effect on the renin-angiotensin system (RAS) in both renal hypertensive rats (RHR) and spontaneously hypertensive rats (SHR). RHR were created by the two-kidney one clip (2K1C) method. Systolic blood pressure was measured in conscious rats by the tail-cuff method. Plasma angiotensin II (AngII) and plasma renin activity (PRA) were measured with radioimmunoassay at 60 min after drug administration. The effects of TF on cardiac hemodynamics were also recorded in anesthetized RHR and SHR. TF was given by oral administration in low dose (100 mg/kg) and high dose (200 mg/kg) respectively. Compared to pre-administration control, TF induced an obvious decrease in systolic blood pressure in conscious normotensive Wistar rat, RHR and SHR. In the three groups the systolic blood pressure reached the lowest value at 60 min after TF. TF also induced a significant decrease in blood pressure in anesthetized RHR and SHR. At 60 min after treatment of TF, mean arterial pressure in high dose group (200 mg/kg) was decreased by 17% in RHR and by 17% in SHR respectively (P < 0.01). The depressor effect of TF lasted for at least 60 min. Cardiac output, heart rate and +/- dp/dtmax did not change. Conversely, total peripheral resistance was significantly decreased. The decrease in plasma AngII was found in both RHR and SHR. On the contrary, PRA increased at the same time. These findings suggested that TF is effective in reducing blood pressure in both RHR and SHR. The antihypertensive action of TF was attributed to a decrease in TPR secondary to a decrease in plasma concentration of AngII caused by TF.     

Study of the in-vivo antioestrogenic action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE), a novel intracellular histamine antagonist and antioestrogen binding site ligand

N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE) binds with high affinity to the antioestrogen binding site (AEBS), but not to the oestrogen receptor. There is an association of AEBS with a novel intracellular histamine receptor (H1C) of micromolar affinity through which histamine acts as a second messenger. An optimal dose of 4 mg DPPE/kg antagonized the uterine growth-stimulating effects of oestradiol in immature oophorectomized rats. Unlike tamoxifen, DPPE alone was not a partial agonist, but decreased uterine size and weight below control values at concentrations between 0.1 and 75 mg/kg. DPPE also antagonized oestradiol-stimulated uterine growth at 72 h; the inhibition observed was not significantly different from that seen with tamoxifen. Oestradiol-treated animals receiving the combination of DPPE (4 mg/kg) + low dose tamoxifen (0.04 mg/kg) for 72 h had significantly smaller uteri than did those receiving the same dose of DPPE or tamoxifen alone. Histologically, either DPPE or tamoxifen antagonized oestradiol stimulation of eosinophil migration and glandular epithelial proliferation; the latter inhibition was significantly greater for DPPE + tamoxifen (0.04 mg/kg) than for the same dose of DPPE or tamoxifen alone. Unlike tamoxifen, DPPE did not antagonize oestradiol stimulation of luminal epithelial proliferation, but in the presence of oestradiol, DPPE significantly decreased tamoxifen (0.65 mg/kg)-induced hypertrophy of the luminal epithelium. Based on these findings, we suggest that binding to the AEBS/intracellular histamine receptor is important to the action of antioestrogens.     

Biphasic effects of yohimbine on the ejaculatory response in the dog

The effects of various doses (0.01-1.00 mg/kg) of yohimbine, an alpha-2 adrenoceptor antagonist, on the erectile and ejaculatory response elicited by manual penile stimulation were investigated in male dogs. Systemic administration of yohimbine caused a biphasic effect on ejaculatory response; the amount of ejaculate produced by the genital stimulation (for 5 min) was dose-dependently increased by low doses (0.01-0.10 mg/kg) of yohimbine, whereas it was decreased by the highest dose (1.00 mg/kg) of yohimbine. The erectile potency was attenuated only, by the highest dose of yohimbine. The most effective dose (0.10 mg/kg) of yohimbine on ejaculation did not affect the duration of penile erection after removing the genital stimulation. In a stereoisomer's testing, the stimulatory effect on ejaculation was also observed by rauwolscine, an alpha-2 adrenoceptor antagonist (0.03 and 0.10 mg/kg), but not by corynanthine, an alpha-1 adrenoceptor antagonist (0.10 and 0.30 mg/kg). These results suggest that yohimbine at low doses specifically facilitate the ejaculatory response through the blockade of the alpha-2 adrenoceptors. This study also indicates that the effects of yohimbine on male genital responses vary with its dosage used.     

Effects of sodium and potassium channel blockers on hyperinflation-induced slowly adapting pulmonary stretch receptor stimulation in the rat

The excitatory responses of slowly adapting pulmonary stretch receptor (SAR) activity to hyperinflation (inflation volume = 3 tidal volumes) for approximately 10 respiratory cycles were examined before and after administration of flecainide, a Na+ channel blocker, and 4-aminoprydine (4-AP), a K+ channel blocker. The experiments were performed in anesthetized, artificially ventilated rats after unilateral vagotomy. During hyperinflation the SARs increased their activity during inflation and decreased their discharge during deflation. The magnitude of increased SAR activity during inflation became more prominent as compared to that of decreased receptor activity during deflation. Flecainide treatment (6 mg/kg) that was sufficient to block veratridine (50 microg/kg)-induced SAR stimulation did not significantly alter the excitatory response of SAR activity to hyperinflation. Subsequent administration of 3 mg/kg flecainide (a total dose, 9 mg/kg) resulted in a greater inhibition of hyperinflation-induced SAR stimulation. Although administration of 4-AP (2 mg/kg) usually stimulated SAR activity, particularly in the deflation phase, in the control ventilation, 4-AP treatment had no significant effect on hyperinflation-induced SAR stimulation. These results suggest that the excitatory effect of hyperinflation on SAR activity may not be involved in the activation of either flecainide-sensitive Na+ channels or 4-AP-sensitive K+ channels.     

Interaction of apolipoprotein AIV with cholecystokinin on the control of food intake

Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are peptides that act both peripherally and centrally to reduce food intake by decreasing meal size. The present study examined the effects of intraperitoneally administered bolus doses of recombinant apo AIV, CCK-8, and a combination of subthreshold doses of apo AIV and CCK on 4-h food intake in rats that were fasted overnight. Apo AIV at 100 microg/kg reduced food intake significantly relative to the saline control for 1 h, as did doses of CCK-8 at or above 0.125 microg/kg. Doses of apo AIV (50 microg/kg) or CCK (0.06 microg/kg) alone had no effect on food intake. However, when these subthreshold doses of apo AIV and CCK were administered together, the combination produced a significant inhibition of food intake relative to saline controls (P < 0.001), and the duration of the effect was longer than that caused by the administration of either apo AIV or CCK alone. The satiation effect produced by CCK-8 + apo AIV was attenuated by lorglumide, a CCK1 receptor antagonist. We conclude that, whereas the intraperitoneal administration of doses of either recombinant apo AIV or CCK at or above threshold levels reduces food intake, the coadministration of subthreshold doses of the two peptides is highly satiating and works via CCK1 receptor.     

Cloning and functional characterization of Neisseria gonorrhoeae tonB, exbB and exbD genes

Neisseria gonorrhoeae is able to utilize iron (Fe) from a variety of sources including transferrin (TF) and lactoferrin (LF). To gain insight into the molecular mechanisms used by gonococci to scavenge Fe from TF and LF, we cloned a 3.5 kb segment of wild-type DNA that repaired the defect in tlu mutants, which are unable to take up Fe from either TF or LF despite exhibiting apparently normal ligand binding to the receptor. Nucleotide sequence determination identified three open reading frames (ORFs), designated ORF1, ORF2, and ORF3, which were arranged in tandem. The deduced amino acid sequence of the 852 bp ORF1 encoded a 28 kDa protein that exhibited 26–32% identity with TonB proteins of nine other bacteria. The 663 bp ORF2 predicted a 24 kDa protein and the 435 bp long ORF3 predicted a 15 kDa protein. These predicted protein sequences exhibited 32–38% and 24–36% identity, respectively, with ExbB and ExbD proteins of three other bacteria. Thus, the sequence comparison identified the ORF1, ORF2 and ORF3 as gonococcal homologues of the E. coli tonB , exbB and exbD genes. An insertional mutation in the tonB homologue resulted in the failure of gonococci to grow with TF, LF or human haemoglobin (HB) as sole Fe sources and in the inability to take up ⁵⁵Fe from TF and LF. The tonB mutation did not prevent the utilization of Fe from citrate (CT) or haemin (HM). Binding of TF, LF and HB to whole cells in a solid-phase binding assay was largely unaffected by the tonB mutation. We conclude that the pathways for utilization of Fe bound to TF, LF and HB but not to HM or CT were dependent on the TonB system.     

Stimulation of pancreatic secretory process in the rat by low-molecular weight proteinase inhibitor

Summary Application of a single dose of a new type of proteinase inhibitor camostate (FOY-305) via orogastric tube was used in rats to study the dose-response relationship of resulting pancreatic stimulation. Doses up to 10 mg/ kg failed to elicit any response, while significant decrease in enzyme content and increase in serum CCK-levels were observed with doses ranging from 25 to 400 mg/kg. A single dose of 100 mg/kg was selected for a time-sequence analysis, which revealed a 60 to 70% depletion of enzyme stores persisting over 6 h and reverting to control levels by 12 h. Peak increases in serum CCK-levels (15-fold above the elevation observed after regular food intake) were found after 30 min and persisted as an 8-to 10-fold elevation for at least 3 h, then declined to control levels by 9 h. This prolonged endogenous hormone release and resulting pancreatic stimulation were also verified in a separate group of animals in which volume, protein, and enzyme output were measured after cannulation of the pancreatic duct. While volume secretion was not altered by feeding a single dose of 100 mg/kg FOY-305, protein and enzyme output increased 2-to 3-fold over a period of 7 h. Fine-structural analysis of the pancreas demonstrated efficient depletion of zymogen granules from acinar cells with all doses between 50 and 400 mg/kg, accompanied by the appearance of membrane material in the acinar lumina at 3 and 6 h. The same transient increase in the number of lysosomal bodies predominantly containing mitochondria with all doses above 50 mg/kg was interpreted as increased organelle turnover due to persisting hormonal stimulation.Supported by a grant from the Deutsche Forschungsgemeinschaft (Ke 113/15-1/2)     

A1 and A2 adenosine receptor regulation of erythropoietin production

The effects of adenosine (ADE) and ADE agonists on erythropoietin (Ep) production were determined using percent (%) 59Fe incorporation in red cells of exhypoxic polycythemic mice. The hemisulfate salt of ADE produced a significant increase in % 59Fe incorporation in response to hypoxia in concentrations of 400 to 1600 nmol/kg/day (i.v.). 5'-N-ethyl-carboxamideadenosine (NECA), a selective A2 receptor agonist, increased radioiron incorporation in a dose-dependent manner (10-100 nmol/kg/day, i.v.). In contrast, N6-cyclohexyladenosine (CHA), a selective A1 receptor agonist, did not affect radioiron incorporation in concentrations up to 1600 nmol/kg/day (i.v.). Albuterol, a beta 2-adrenergic agonist, enhanced % 59Fe incorporation in polycythemic mice and low doses of CHA (50 and 100 nmol/kg/day), which were not effective alone on % 59Fe incorporation in polycythemic mice exposed to hypoxia, inhibited the enhancement in radioiron induced by albuterol (25 and 100 micrograms/kg/day, i.p.) plus hypoxia. Theophylline (20 and 80 mg/kg/day, i.p.), a well-known antagonist of ADE receptors, blocked the ADE and NECA enhancement in radioiron incorporation at a dose of theophylline alone which produced only a slight enhancement of % 59Fe incorporation. These results suggest that ADE may both inhibit through A1 receptor activation and increase via A2 receptor stimulation the production of Ep.     

Global inhibition of reactive oxygen species (ROS) inhibits paclitaxel-induced painful peripheral neuropathy

Paclitaxel (Taxol?) is a widely used chemotherapeutic agent that has a major dose limiting side-effect of painful peripheral neuropathy. Currently there is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathies. Evidence for mitochondrial dysfunction during paclitaxel-induced pain was previously indicated with the presence of swollen and vacuolated neuronal mitochondria. As mitochondria are a major source of reactive oxygen species (ROS), the aim of this study was to examine whether pharmacological inhibition of ROS could reverse established paclitaxel-induced pain or prevent the development of paclitaxel-induced pain. Using a rat model of paclitaxel-induced pain (intraperitoneal 2 mg/kg paclitaxel on days 0, 2, 4 & 6), the effects of a non-specific ROS scavenger, N-tert-Butyl-α-phenylnitrone (PBN) and a superoxide selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were compared. Systemic 100 mg/kg PBN administration markedly inhibited established paclitaxel-induced mechanical hypersensitivity to von Frey 8 g and 15 g stimulation and cold hypersensitivity to plantar acetone application. Daily systemic administration of 50 mg/kg PBN (days -1 to 13) completely prevented mechanical hypersensitivity to von Frey 4 g and 8 g stimulation and significantly attenuated mechanical hypersensitivity to von Frey 15 g. Systemic 100 mg/kg TEMPOL had no effect on established paclitaxel-induced mechanical or cold hypersensitivity. High dose (250 mg/kg) systemic TEMPOL significantly inhibited mechanical hypersensitivity to von Frey 8 g & 15 g, but to a lesser extent than PBN. Daily systemic administration of 100 mg/kg TEMPOL (day -1 to 12) did not affect the development of paclitaxel-induced mechanical hypersensitivity. These data suggest that ROS play a causal role in the development and maintenance of paclitaxel-induced pain, but such effects cannot be attributed to superoxide radicals alone.     

Ibogaine reduces amphetamine-induced locomotor stimulation in C57BL/6By mice, but stimulates locomotor activity in rats.

The effect of ibogaine hydrochloride on locomotor stimulation induced by d-amphetamine sulfate was tested in male C57BL/6By mice and in female Sprague-Dawley rats. In mice, locomotor stimulation induced by d-amphetamine at 1 or 5 mg/kg s.c. was reduced by prior administration of one or two injections of ibogaine (40 mg/kg), given 2 or 18 hours earlier. This reduction in locomotor activity persisted for two days. Locomotor stimulation induced by a higher dose (10 mg/kg) of d-amphetamine was not reduced by such prior administration of ibogaine. A lower dose of ibogaine (20 mg/kg) did not reduce the subsequent locomotor activity induced by d-amphetamine. Ibogaine decreased striatal dopamine levels, while d-amphetamine increased them. Ibogaine treatment (2 x 40 mg/kg, 18 hours apart) induced a decrease by 30% in the level of striatal dopamine and its metabolites measured in tissue extracts 3 hours after the second ibogaine injection. One hour after d-amphetamine (5 mg/kg) administration, the level of striatal dopamine increased by 26%. Although the level of striatal dopamine was initially lower in the ibogaine-pretreated mice, d-amphetamine (5 mg/kg) administration induced an increase in striatal dopamine and its metabolites. The effect of ibogaine seems to be species specific, since in rats pretreated with ibogaine 18 hours before d-amphetamine, locomotor stimulation induced by d-amphetamine was further increased. In addition, the in vitro electrical-evoked release of [3H]dopamine from striatal tissue was either unchanged or inhibited in the presence of d-amphetamine, and after ibogaine pretreatment in vivo, the release of tritium in the presence of d-amphetamine was inhibited or stimulated in mice and rats, respectively.     

Effects of L-arginine on prevention and treatment of lithium-pilocarpine-induced status epilepticus

The effects of various doses of L-arginine, a nitric oxide substrate, on lithium-pilocarpine-induced seizures were studied in rats. Rats were implanted with chronic, stainless steel screw electrodes epidurally for electrocortical recordings. A control group received 3 mEq/kg LiCl (i.p.) and 24 h later 45 mg/kg pilocarpine HCl (i.p.). Two different experimental procedures were followed: (1) L-arginine was applied in doses of 100 mg/kg, 300 mg/kg or 500 mg/kg (i.p.), 30 min before pilocarpine injection; (2) 300 mg/kg, 500 mg/kg or 1000 mg/kg (i.p.) L-arginine was injected either 5 min or 30 min after the onset of status epilepticus (SE). L-arginine (300 mg/kg) injected 30 min before pilocarpine significantly reduced the percentage of SE, but did not change the latency to SE or 24-hour survival. These parameters were not significantly affected by the 100 mg/kg or 500 mg/kg dose of L-arginine. On the other hand, no dose of L-arginine that was applied after SE had begun, had any significant influence on the seizures. We concluded that L-arginine may prevent seizure activity in some but not all doses, and does not have any effect on the ongoing seizure activity.     

Effect of angiotensin AT2 receptor stimulation on vascular cyclic GMP production in normotensive Wistar Kyoto rats

In the present study in normotensive Wistar Kyoto rats (WKY), we investigated whether any angiotensin II (ANG II) increases in vascular cyclic GMP production were via stimulation of AT(2) receptors. Adult WKY were infused for 4h with ANG II (30 ng/kg per min, i.v.) or vehicle (0.9% NaCl, i.v.) after pretreatment with (1) vehicle, (2) losartan (100 mg/kg p.o.), (3) PD 123319 (30 mg/kg i.v.), (4) losartan+PD 123319, (5) icatibant (500 microg/kg i.v.), (6) L-NAME (1 mg/kg i.v.), (7) minoxidil (3 mg/kg i.v.). Mean arterial blood pressure (MAP) was continuously monitored, and plasma ANG II and aortic cyclic GMP were measured at the end of the study. ANG II infusion over 4h raised MAP by a mean of 13 mmHg. This effect was completely prevented by AT(1) receptor blockade. PD 123319 slightly attenuated the pressor effect induced by ANG II alone (123.4+/-0.8 versus 130.6+/-0.6) but did not alter MAP in rats treated simultaneously with ANG II + losartan (113+/-0.6 versus 114.3+/-0.8). Plasma levels of ANG II were increased 2.2-3.7-fold by ANG II infusion alone or ANG II in combination with the various drugs. The increase in plasma ANG II levels was most pronounced after ANG II+losartan treatment but absent in rats treated with losartan alone. Aortic cyclic GMP levels were not significantly changed by either treatment. Our results demonstrate that the AT(2) receptor did not contribute to the cyclic GMP production in the vascular wall of normotensive WKY.     

Aspirin before reperfusion blunts the infarct size limiting effect of atorvastatin

We assessed whether aspirin (acetylsalicylic acid, ASA), administered before reperfusion, abrogates the infarct size (IS)-limiting effect of atorvastatin (ATV). Statins reduce IS. This dose-dependent effect is mediated by upregulation of cycloxygenase-2 (COX2) and PGI(2) production. Administration of selective COX2-inhibitors either with ATV for 3 days or immediately before coronary occlusion blocks the IS-limiting effect of ATV. Sprague-Dawley rats received 3-day ATV (10 mg x kg(-1) x day(-1)) or water alone. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion (IS protocol, n=8 in each group), or rats underwent 30 min coronary artery occlusion and 10 min reperfusion (enzyme expression and activity protocol, n=4 in each group). Immediately before reperfusion rats received intravenous ASA (5, 10, or 20 mg/kg) or saline. Area-at-risk (AR) was assessed by blue dye and IS by triphenyltetrazolium chloride. ATV reduced IS (10.1 +/- 1.4% of the AR) compared with controls (31.0 +/- 2.2%). Intravenous ASA alone did not affect IS (29.0 +/- 2.6%); however, ASA dose dependently (5, 10, and 20 mg/kg) attenuated the protective effect of ATV on IS (15.8 +/- 0.9%, 22.0 +/- 1.6%, and 23.7 +/- 3.8%, respectively). ASA dose dependently blocked the upregulation of COX2 by ATV. COX2 activity was as follows: control, 8.93 +/- 0.90 pg/mg; ATV, 75.85 +/- 1.08 pg/mg; ATV + ASA5, 34.39 +/- 1.48 pg/mg; ATV + ASA10, 19.87 +/- 1.10 pg/mg; and ATV + ASA20, 9.36 +/- 0.94 pg/mg. ASA, administered before reperfusion in doses comparable to those used in the clinical setting, abrogates the IS-limiting effect of ATV in a model with mechanical occlusion of the coronary artery. This potential adverse interaction should be further investigated in the clinical setting of acute coronary syndromes.     

Effect of mifepristone on pregnancy,pregnancy-specific protein B (PSPB), progesterone,estradiol-17beta,prostaglandin F2alpha (PGF2alpha) and prostaglandin E (PGE) in ovariectomized 90-day pregnant ewes

The objective of this experiment was to determine the effect of mifepristone, a progesterone receptor antagonist, on pregnancy and secretion of steroids, pregnancy-specific protein B (PSPB) and prostaglandins at mid-pregnancy in ewes. Ninety-day pregnant ewes were ovariectomized (OVX) and treatments were initiated 72 h post-OVX. Ewes received (1) vehicle, (2) prostaglandin F2alpha (PGF2alpha, 8 mg/58 kg/bw, i.m.) 84 h post-OVX, (3) mifepristone (50 mg intrajugular at 72, 84, 96, and 108 h post-OVX), (4) mifepristone (50mg) + PGF2alpha, (5) mifepristone (100 mg intrajugular at 72, 84, 96, and 108 h), and (6) mifepristone (100 mg) + PGF2alpha. Ewes treated with vehicle or PGF2alpha alone did not abort (P > or = 0.05). But, 60, 80, 60, and 100% of ewes treated with mifepristone (50 mg), mifepristone (50 mg) + PGF2alpha, mifepristone (100 mg), and mifepristone (100 mg) + PGF2alpha, respectively, aborted (P < or = 0.05). Profiles of progesterone, estradiol-17beta, prostaglandin E (PGE), or PSPB did not differ (P > or = 0.05) among treatment groups. Profiles of PGF2alpha of treatment groups receiving mifepristone with or without PGF2alpha differed (P < 0.05) from vehicle or PGF2alpha alone-treated ewes. It is concluded that progesterone actions are necessary to suppress uterine/placental secretion of PGF2alpha and that maintenance of critical progesterone: estradiol-17beta and PGE:PGF2alpha ratios are necessary for maintenance of pregnancy.     

Involvement of some 5-HT receptors in methamphetamine-induced locomotor activity in mice.

Effects of some selective 5-HT antagonists on methamphetamine-induced locomotor activity were investigated in male mice in order to study whether this effect of methamphetamine is selectively or at least partially, induced through stimulation of a specific serotonin receptor subtype. Methamphetamine (1.5 mg/kg, IP) produced a significant increase in locomotor activity. Methamphetamine-induced hyperactivity by the above mentioned dose was significantly antagonized by NAN-190 ( 5-HT(1A) antagonist) at a dose of 4 mg/kg, IP, methiothepin (5-HT(1B/1D) antagonist) at a dose of 0.1mg/kg, IP or mianserin ( 5-HT(2C) antagonist) at a dose of 8 mg/kg, IP. On the other hand, methysergide ( 5-HT(2A/2B) antagonist) at a dose of 1mg/kg, IP or ondansetron ( 5-HT(3) antagonist) at a dose of 0.5mg/kg, IP potentiated the methamphetamine-induced hyperactivity. None of the above mentioned doses of 5-HT antagonists altered the spontaneous activity of mice when administered alone. The results of the present study indicate a possible role for serotonergic mechanisms, in addition to the catecholaminergic systems, in the locomotor stimulant activity of methamphetamine in mice. This role is possibly mediated through direct stimulation of some 5-HT receptor subtypes. Stimulation by methamphetamine of 5-HT(1A), 5-HT(1B/1D) and/or 5-HT(2C) receptor subtypes may result in hyperactivity, whereas stimulation by methamphetamine of 5-HT(2A/2B) and/or 5-HT(3) receptor subtypes may result in decreased activity.     

Exposure of the pregnant rat to warfarin and vitamin K1: an animal model of intraventricular hemorrhage in the fetus

Pregnant Sprague-Dawley rats were given daily oral doses of sodium warfarin (100 mg/kg) and concurrent intramuscular injections of vitamin K1 (10 mg/kg). This dosing regimen did not have any apparent deleterious effect on the dams and did not affect the fetuses when administered from day 1 to day 12 of pregnancy. However, similar treatment from day 9 to 20 caused hemorrhage in the fetuses examined on day 21 of gestation. There were no hemorrhages in the control fetuses from dams receiving vitamin K1 only. The lowest effective dose of warfarin, in conjunction with daily doses of vitamin K1, was 3 mg/kg. This dose caused hemorrhage in 28% of fetuses; the incidence of affected fetuses was not further increased by doses of warfarin up to 100 mg/kg. Hemorrhages affected the fetal brain, face, eyes, and ear and occasionally the limbs. Brain hemorrhages were frequently intraventricular and caused various degrees of hydrocephaly. Bony defects were not a feature of prenatal exposure to warfarin. These results show that prenatal exposure of the rat to warfarin and vitamin K duplicates the hemorrhagic abnormalities and pathology associated with prenatal exposure to warfarin in the human. It did not induce bony or facial defects probably because the vitamin K-dependent components of bone development occur postnatally in the rat. This model should allow detailed determination of the role of vitamin K-dependent proteins in development.     

An antinociceptive effect of the intraperitoneal injection of nifedipine in rats,measured by tail-flick test

The tail-flick (TF) technique was used to assess the antinociceptive properties of nifedipine (NIF) given intraperitoneally (i.p.). First, the most suitable intensity of the noxious stimulus (temperature of the bulb) has been ascertained and used in the main study. Male Sprague-Dawley rats received NIF, dissolved in dimethyl sulfoxide (DMSO) at the doses of 0.0, 0.5, 2, 5, 10 and 15 mg/kg, or control with no injection. For the main study, the noxious stimulus was limited to 15 sec (cut-off time) and TF latencies were recorded up to 120 min. The antinociceptive response was expressed as the area under the curve for each rat and analyzed by one-way ANOVA. The antinociceptive response to the lower doses of NIF (0.5 and 2 mg/kg) did not differ from control (no injection) and DMSO alone. Significance was found at 5, 10 and 15 mg NIF with no difference among the doses. However, there was an increasing tendency of the mean values from 0.5 to 15mg NIF resulting in a positive correlation. The correlation coefficient was 0.32483 (p=0.015) and regression equation Y=(19.37) × dose + 1320. Our data suggest that spinal mechanisms are involved in NIF-induced antinociception.     

Repeated treatment with imipramine, fluvoxamine and tranylcypromine decreases the number of escape failures by activating dopaminergic systems in a rat learned helplessness test.

Chronic administration of antidepressants has been shown to reduce the number of escape failures in the rat learned helplessness test (LH). In the present study we investigated the role of D1, D2 and D3 receptors in mediating this effect. In our first series of experiments, we demonstrated that SKF38393, D1 receptor agonist, in a dose of 2.5 mg/kg (i.p.) and quinpirole, D2 receptor agonist in a dose of 0.5 mg/kg (i.p.), significantly decreased the number of escape failures in LH, and these were reversed by SCH23390 (0.015 mg/kg), D1 receptor antagonist, and by sulpiride (25 mg/kg), D2 receptor antagonist, respectively. In contrast, 7-OH-DPAT, a D3 receptor agonist, in a dose of 10 mg/kg (i.p.) did not affect the number of escape failures in LH. In a second series of experiments, we showed that eight days of repeated treatment with imipramine (10 mg/kg, p.o.), fluvoxamine (1.25 mg/kg, p.o.) and tranylcypromine (1.25 mg/kg, p.o.) significantly decreased the number of escape failures in LH. The decrease in escape failures seen with use of imipramine and tranylcypromine was reversed by sulpiride in LH, but not by SCH23390. On the other hand, the effect of fluvoxamine was reversed by both SCH23390 and sulpiride. These findings indicate that stimulation of D1 and D2 receptors decreased the number of escape failures in LH, respectively. Thus, D2 and/or D1 receptors are probably involved in the decreased number of escape failures in case of repeated treatment with antidepressants in LH.