Attenuation of stress-induced gastric lesions by lansoprazole, PD-136450 and ranitidine in rats.

Combining restraint with cold temperature (4°C) consistently induces gastric ulceration in rats after 3.5 h. The cold restraint-stress (CRS) method provides a suitable model for acute ulcer investigations. This study compares the antiulcer activities of lansoprazole (a proton pump inhibitor), PD-136450 (CCK(2)/gastrin receptor antagonist) and ranitidine (histamine H(2) receptor antagonist) on CRS-induced gastric ulcers in rats. The results have shown that lansoprazole, which is a potent anti-secretory agent, provides complete protection in this model of ulcer formation. The use of indomethacin pretreatment to inhibit the prostaglandin (PG) synthesis and N(G)-nitro L-arginine methyl ester (L-NAME) pretreatment to inhibit nitric oxide synthase did not alter the lansoprazole-induced inhibition of ulcer index obtained in the untreated Wistar rats indicating that these two systems were not involved in the activation of lansoprazole. PD-136450, an effective anti-secretory agent against gastrin- but not dimaprit-induced stimulation, evoked a dose-dependent inhibition of CRS-induced gastric ulcers. The results show that both PG and nitric oxide pathways can influence the inhibitory effect of PD-136450 against CRS-induced gastric ulcer. The antiulcer activities of both lansoprazole and PD-136450 were compared to that of ranitidine. The results showed that ranitidine was more potent than lansoprazole and PD-136450 in inhibiting CRS-induced gastric ulcers and its effect was shown to be influenced by PG as well as nitric oxide synthase. The results of this study have demonstrated that although lansoprazole, PD-136450 and ranitidine were protective against CRS-induced gastric ulcers, the antiulcer activities of PD-136450 and ranitidine involved both PG and nitric oxide pathways, while lansoprazole acted independently of these two systems during CRS.

Distribution of neuroendocrine cells in the small and large intestines of the one-humped camel (Camelus dromedarius).

The distribution and relative frequency of neuroendocrine cells in the small and large intestines of one-humped camel were studied using antisera against 5-hydroxytryptamine (5-HT), cholecystokinin (CCK-8), somatostatin (SOM), peptide tyrosine tyrosine (PYY), gastric inhibitory polypeptide (GIP), neuronal nitric oxide synthase (nNOS), gastrin releasing peptide (GRP), substance P (SP), and neurokinin A (NKA). Among these cell types, CCK-8 immunoreactive (IR) cells were uniformly distributed in the mucosa, while others showed varied distribution in the villi or crypts of the small intestine. Immunoreactive cells like 5HT, CCK-8, and SOM showed peak density in the villi and crypts of the small intestine and in the colonic glands of the large intestine, while cells containing SP were discerned predominately in the crypts. 5-HT, CCK-8 and SOM cells were mainly flask-shaped and of the open-variety, while PYY and SP immunoreactive cells were mainly rounded or basket-shaped and of the closed variety. Basically the distribution pattern of the endocrine cells in the duodenum, jejunum and colon of the one-humped camel is similar to that of other mammals. Finally, the distribution of these bioactive agents may give clues as to how these agents aid in the function of the intestinal tract of this desert animal.

Effects of brain natriuretic peptide on contraction and intracellular Ca2+ in ventricular myocytes from the streptozotocin-induced diabetic rat.

The streptozotocin (STZ)-treated rat is a widely studied experimental model of diabetes mellitus (DM). Its pathophysiology includes hypoinsulinemia, hyperglycemia, cardiac hypertrophy, and a cardiomyopathy that is characterized by the presence of diastolic and/or systolic contractile dysfunction. As part of their endocrine function cardiomyocytes in the heart produce and secrete a family of related peptide hormones called the natriuretic peptides that include A-type natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). ANP and BNP levels are variously augmented in patients with hypertension, cardiac overload, in the ventricles of failing or hypertrophied heart, in cardiac heart failure, in acute myocardial infarction (MI), and in some circumstances in DM. In this article, the effects of BNP on ventricular myocyte contraction and Ca2+ transport in STZ-induced diabetic rats have been investigated. BNP concentration was significantly increased in blood plasma and in atrial muscle in STZ-induced diabetic rats compared to age-matched controls. BNP was 11.9 +/- 0.9 ng/mL in plasma from diabetic rats compared to 6.7 +/- 1.6 ng/mL in controls and 15.8 +/- 2.0 ng/mg protein in diabetic atrial muscle compared to 8.5 +/- 1.0 ng/mg protein in controls. The heart weight to body weight ratio, an indicator of hypertrophy, was significantly increased in diabetic rat heart (4.3 +/- 0.1 mg/g) compared to controls (3.7 +/- 0.04 mg/g). The amplitude of shortening was not significantly altered in diabetic myocytes (10.3 +/- 0.4%) compared to controls (10.9 +/- 0.4%). BNP reduced the amplitude of shortening to a greater extent in diabetic myocytes (8.1 +/- 0.6%) compared to controls (10.1 +/- 0.4%). The time to peak (TPK) shortening was significantly prolonged in diabetic myocytes (254 +/- 8 ms) compared to controls (212 +/- 5 ms) and was not additionally altered by BNP. The time to half relaxation of shortening was also significantly prolonged in diabetic myocytes (131 +/- 8 ms) compared to controls (111 +/- 5 ms). BNP (10(-8) to 10(-6) M) normalized the time to half relaxation of shortening in diabetic myocytes to that of controls. Time to peak (TPK) shortening of Ca2+ was not different between diabetic and control rats. However, BNP (10(-7) M) increases TPK of Ca2+ significantly. The amplitude of the Ca2+ transient was significantly increased in diabetic myocytes (0.42 +/- 0.02 Ratio units [RU]) compared to controls (0.36 +/- 0.02 RU) and was not additionally altered by BNP. BNP may have a protective role in STZ-induced diabetic rat heart.

Effect of high-calorie diet on the prevalence of diabetes mellitus in the one-humped camel (Camelus dromedarius).

The one-humped camel is a typical desert animal. It has the capability of withstanding the harsh climatic changes and the scarcity of food and water, in addition to the high-ambient temperature. The prevalence of diabetes mellitus in two different groups of the one-humped camel, group (A) control (n = 102) camels and group (B) high-calorie diet-fed camels (n = 103), in Al-Ain region (UAE) was studied using biochemical and radioimmunoassay techniques. In this article, 7% of the control camels have diabetes mellitus (blood glucose level: > or =140 mg/dL) compared to 21% of the high-calorie-fed camels. Plasma insulin level was significantly (P < 0.05) lower in group B compared to group A. The low insulin level in camels consuming high-caloric diet could be a sign of exhaustion of pancreatic beta cells. The hematological parameters were nearly similar in both groups and no significant differences were seen. Liver and kidney enzymes were normal in both groups. Iron and copper were significantly (P < 0.005) higher in the high-calorie-fed camels compared with the control. Our study indicates that high-caloric feed consumption in camels is associated with the development of disorders in glucose metabolism leading to diabetes mellitus.

PD-136,450: a CCK2 (gastrin) receptor antagonist with antisecretory, anxiolytic and antiulcer activity.

This study investigated the effects of PD-136,450 (PD), a highly selective ligand for the CCK2 receptor, on gastric acid and pancreatic secretions, gastric cytoprotection and anxious behaviour in the rat and rabbit. PD inhibited gastrin (but not dimaprit) stimulated acid secretion in anaesthetized and conscious rats (IC50 of 1 mg kg(-1) sc) and inhibited 14C-aminopyrine uptake in isolated gastric glands from rabbits. In addition, PD decreased dose-dependently gastric haemorrhagic lesions in rats treated orally with acidified ethanol. Both, the antisecretory effects on gastric acid secretion and the gastric cytoprotective effects were less potent compared with the proton pump inhibitor omeprazole. PD strongly increased pancreatic secretion, which was substantially inhibited by the CCK1 antagonist L-364,718 (but not by the CCK2 antagonist L-365,260). PD also showed significant anxiolytic activity as assessed by a black and white box two-compartment activity assay. Both, time spent in the dark compartment and latency for movement from the light to the dark compartment was increased by PD (similarly with 5 mg kg(-1) diazepam). In conclusion, PD inhibited gastrin-stimulated gastric acid secretion, decreased ethanol-induced damage to the gastric mucosa, stimulated pancreatic secretion (via CCK1 receptors) and displayed anxiolytic activity. Thus, PD may have utility as an adjunct therapy in peptic ulcer disease by countering the actions of gastrin and increasing acid neutralization and mucosal protection.

Distribution of insulin like growth factor-1 (IGF-1) and its receptor in the intestines of the one-humped camel (Camelus dromedarius).

The distribution of insulin-like growth factor-1 (IGF-1) and its receptor in the gut of the one-humped camel (Camelus dromedarius) were studied by immunohistochemistry and quantitative receptor autoradiography. IGF-1-IR cells occurred mainly in the lamina propria and epithelium of the small intestine, while in the large intestine positive cells were seen in the columnar cells of the epithelial layer of colonic glands. IGF-I was also discernible in the muscularis externa of the intestines. Autoradiography revealed a higher concentration of receptors in the mucosa compared to the muscular layer. With regard to the mucosa, the highest density of receptors was discernible in the duodenum. Immunohistochemistry revealed the main sites of the receptors to be the lamina propria, epithelia of the crypts and the villi of intestines. Double immunofluorescence studies with combined antisera to IGF-I and its receptor showed that the ligand and its receptor usually occurred within the same cell in the mucosa. A few cells with varied profiles immunoreacted to either the ligand or the receptor but not to both. Cells with varied profiles immunoreacted to antiserum of the receptors but not to the ligand in the muscle layer. Thus IGF-1 might be acting on its receptor via both an autocrine and paracrine modes in the camel mucosa. In the muscularis layer, IGF-1 may be acting by different mechanisms. Our data demonstrate that unlike all other mammals studied, the camel contains a high concentration of IGF-1 receptors in the duodenal mucosa compared to other parts of the camel gut. It also possesses a higher concentration of the receptor in its mucosa compared to the muscle layer. We speculate that this might be a significant feature necessary for the regenerative ability of the duodenal mucosa in the one-humped camel.

Experimental studies on reproductive toxicologic effects of lamotrigine in mice.

BACKGROUND: Virtually all antiepileptic drugs (AED) tested so far have been found to be teratogenic. The second generation AED possess a number of therapeutic advantages over the older ones. There are, however, very little data on their effects on embryonic development. A recent report suggests that lamotrigine (LTG) can be teratogenic to human fetuses. With only a few cases of prenatal exposure to LTG in the record, however, it has not been possible to establish a recognizable pattern of malformations in the infants of LTG-treated mothers. OBJECTIVES: The objectives of the present study were to evaluate the reproductive toxic effects of LTG . RESULTS: Single (50-200 mg/kg) or multiple doses (25, 50, 75 mg/kg) of LTG were administered by intraperitoneal (i.p.) injection (note that the therapeutic administration is oral) to groups of TO mice on gestation day (GD) 7 or 8. Fetuses were collected on GD 18. Maternal toxic effects including a dose-related mortality, a high incidence of abortion, embryo lethality, congenital malformations and intrauterine growth retardation (IUGR) were observed in the LTG-treated group. Administration of LTG in multiple low doses resulted in a better maternal survival and increased incidence of embryonic resorption and malformations with increasing dose; IUGR was significant but not dose-dependent. The malformations characteristic of the LTG multiple low dose group fetuses included maxillary-mandibular hypoplasia, exencephaly, cleft palate, median facial cleft, urogenital anomalies and varying degrees of caudal regression. Skeletal malformations and developmental delay of the skeleton were observed both in single and multiple dose groups. CONCLUSIONS: The results of this study indicate that LTG administered i.p. at high doses can induce intrauterine growth retardation and at low multiple doses causes a dose-dependent increase in embryonic resorption, craniofacial and caudal malformations as well as maternal toxicity in the mouse. Previous studies in other laboratories have used oral route of exposure and concluded that there are no teratogenic effects of LTG at dose levels that are not maternally toxic.

Comparison of the antisecretory and antiulcer activity of epidermal growth factor, urogastrone and transforming growth factor alpha and its derivative in rodents in vivo.

This study investigates the effects of epidermal growth factor (EGF), urogastrone (UG) and transforming growth factor-alpha (TGFalpha) and its derivative on dimaprit- and pentagastrin-induced gastric acid secretion and on acidified ethanol (AE)-evoked ulcer formation in anaesthetized rats. EGF, TGFalpha and UG administered subcutaneously (s.c.) 30 min before dimaprit inhibited gastric acid secretion. Against pentagastrin-stimulated secretion, TGFalpha inhibited, while EGF and UG potentiated, acid secretion dose-dependently. Intraduodenal (i.d.) administration of TGFalpha and UG had no effect, while EGF potentiated, both secretagogue-induced acid secretion in the same dosage schedule. Administration of either EGF, UG or TGFalpha i.v. bolus, in response to continuous infusion of dimaprit resulted in a significant (p < 0.05-p < 0.001) inhibition of acid secretion which was transient and returned to normal within 30-45 min for UG while it slowly returned to normal for EGF and TGFalpha. The truncated form of TGFa (amino acids 34-43) did not show any antisecretory effect when administered parenterally. Acidified ethanol produced gastric haemorrhagic lesions in the rat 1 h after oral administration. The gastric mucosal protective effects of TGFalpha, EGF and UG administered either orally or s.c. 30 min before the administration of AE were dose-dependent against this model of ulcer induction. Indomethacin (Indo), administered 15 min before AE to inhibit prostanoids biosynthesis, significantly (p < 0.001) reduced the cytoprotective effects of TGFalpha, EGF and UG and aggravated the ulcer index when administered s.c. The results show that PGs may be involved in mediating the protective effects of the three growth factors. Administration of NG-nitro-L argininemethylester (L-NAME) 15 min prior to TGFa, EGF and UG s.c. or orally, significantly (p < 0.001) decreased the degree of ulcer indices and was able to reduce the protective effects of TGFalpha, EGF and UG, thus including the role of NO in mediating the protective effects of these growth factors. In conclusion, these results have demonstrated that EGF, UG and TGFalpha have a short and reversible inhibitory effect on dimaprit-stimulated gastric acid secretion and each is effective parenterally but not orally. UG and EGF potentiated, while, TGFa inhibited pentagastrin-stimulated acid secretion. In addition, TGFalpha seems to lose its activity when it is truncated from the C terminus. The present study also suggests that EGF, UG and TGFalpha are equally effective against AE-induced gastric ulcer and bring about their cytoprotective action through their reduction of acid secretion and through PG and NO pathways.

A comparative study on the activity of lansoprazole, omeprazole and PD-136450 on acidified ethanol- and indomethacin-induced gastric lesions in the rat.

1. The proton pump inhibitors lansoprazole (LP) and omeprazole (OP) and the cholecystokinin (CCK)-receptor antagonist PD-136450 (PD) provide a broad spectrum of activities in their ability to inhibit gastric acid secretion and protect the stomach against ulcerogens. In the present study, we investigated the protective effects of these compounds against gastric ulcers induced by acidified ethanol (AE) and indomethacin. 2. Both AE (60% ethanol in 150 mmol/L HCl, 1 mL/rat) and indomethacin (30 mg/kg) produced gastric haemorrhagic lesions in the rat 1 and 6 h after oral administration, respectively. 3. The gastric mucosal protective effects of LP (1-20 mg/kg), OP (0.5-10 mg/kg) and PD (1-20 mg/kg), administered either orally or subcutaneously (s.c.) 30 min before the administration of AE or indomethacin, were dose dependent against both models of ulcer induction. 4. To determine whether the cytoprotective effect of LP, OP and PD (each 10 mg/kg) was mediated by endogenous prostaglandins (PG), indomethacin (10 mg/kg, s.c.) was administered 15 min before AE to inhibit prostanoids biosynthesis. Indomethacin reduced the cytoprotective effects of OP, but not LP, administered either orally or s.c. Indomethacin reduced the cytoprotective effect of PD administered orally, although the effect was much less significant than when PD was administered s.c. The results exclude the role of PG in mediating the protective effects of LP, whereas the possibility exists for PG to have a role in mediating the protective effects of OP and PD. 5. To investigate the possible involvement of endogenous nitric oxide (NO) in the cytoprotective action of LP, OP and PD, we treated rats with a selective inhibitor of NO synthesis, namely NG-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg, s.c.). Administration of L-NAME 15 min prior to LP, OP or PD (each 10 mg/kg) orally or s.c. and challenge with AE or indomethacin did not significantly increase the degree of the ulcer index and L-NAME was not able to antagonize the protective effects of LP, OP and PD, thus excluding the role of NO in mediating the protective effects of these drugs. However, the effects of PD in reducing the indomethacin-induced ulcer index were less significant in the presence than the absence of L-NAME (P < 0.05 vs P < 0.001, respectively), suggesting a role for NO. 6. In conclusion, the results of the present study suggest that LP and OP are equally effective against AE- as well as indomethacin-induced gastric ulcers and were more potent than PD in protecting the stomach against ulcer formation. Lansoprazole, OP and PD bring about their cytoprotective action through the reduction of acid secretion and some other unknown mechanisms. However, OP and PD may exert their cytoprotective action through PG and NO pathways.

Loss of kidney IGF-1 receptors in experimental long-term diabetic rats.

The present study was undertaken to assess the long-term effects of streptozotocin-induced diabetes mellitus on insulin-like growth factor-1 (IGF-1) receptors in rat kidneys. Morphological changes were also evaluated using light and electron microscopy. Using receptor autoradiography the levels of IGF-1 were investigated in rat kidneys diabetic for eight months and controls. Sections from both diabetic and control rats were stained with haematoxylin and eosin for morphological studies. Ultra-thin kidney sections were examined using a transmission electron microscope. IGF-1 receptors were significantly lower in the cortex and the medulla of the diabetic rats compared with controls. Morphological differences between normal and diabetic kidneys were observed in both the cortex and medulla. Glomerular changes and necrosis of the renal cortical and medullary parenchyma were demonstrated in the diabetic rats. Necrosis of cells of the collecting ducts and loops of Henle could explain the loss of IGF-1 receptor concentration in the medulla. Shrinkage of glomeruli and normal proximal convoluted tubules of diabetic kidneys were also observed. Our results also revealed extensive damage to the distal convoluted tubules that have not been reported to possess any insulin-like growth factor-1 receptors. Our results demonstrate a reduction of kidney IGF-1 receptors after long-term diabetes mellitus possibly because of the extensive morphological loss of renal tissue. It could be speculated that early administration of IGF-1 might be useful in longterm diabetes mellitus to prevent the degeneration and/or help regeneration of damaged renal tissue.

Morphological changes in the rat kidney following long-term diabetes.

The morphological basis of diabetic nephropathy has been studied using light and electron microscopy. Kidneys of streptozotocin-induced diabetic rats were examined on the light microscope at 4 weeks and 8 months after induction of diabetes mellitus. In addition, the 8-month diabetic kidneys were examined with the electron microscope. Renal hypertrophy was evidenced by the increase in the weight of kidneys of diabetic rats. Whilst the diabetic kidneys were approximately twice as large after 4 weeks they were only 30% larger compared to age-matched controls after 8 months of induction of diabetes. After 4 weeks, light microscopy revealed dilated tubules within the cortex of the diabetic kidneys. Light microscopy showed a significant amount of destruction of the distal convoluted tubules while electron microscopy revealed a spectrum of damage that included basement membrane thickening, loss of podocytic foot processes, disruption of tubular basal infoldings and their related mitochondria and fibrosis of the tubules 8 months after induction of diabetes. It is concluded that renal hypertrophy persists after a prolonged occurrence of diabetes but the extensive damage and loss of renal tissue including the loss of the foot processes of podocytes might be partly responsible for the clinical presentation of diabetic nephropathy.

In vitro administration of 17 beta-estradiol inhibits drug-induced contractions of the rat isolated seminal vesicle.

1. The rat isolated seminal vesicle responded to noradrenaline (NA), acetylcholine (ACh), potassium chloride (KCl) and barium chloride (BaCl2) with reproducible contractions. 2. 17 beta-estradiol (17 beta E) cumulatively added in the isolated organ bath reduced the number of contractions with all agonists used in the rank order of potency: BaCl2 > or = KCl > ACh > NA. The dose-response curves constructed in the presence of 17 beta E (2 x 10(-5) mol/l) produced a rightward shift and a reduction in the maximum response showing inhibitory activity. 3. When the calcium content in the normal Krebs medium (2.5 mmol/l) was reduced to half, the inhibitory activity of 17 beta E was potentiated. The maximum inhibition rates to KCl (phasic and tonic), BaCl2 and ACh were significantly (P < 0.05) different from each other. 4. The inhibitory effects of 17 beta E against all agonists tested were found to be similar in their responses to verapamil, but were much lower in potency. 5. The inhibitory effects of 17 beta E was seen only when the hormone was present in the tissue environment and was readily reversible as soon as the tissue was washed with the Krebs medium, suggesting that the effect of 17 beta E is localized. 6. It is suggested that the in vitro application of 17 beta E on the rat isolated seminal vesicle interferes with the process of translocation of calcium ions from the extracellular medium.

Functional responses of the rat isolated seminal vesicle to electrical field stimulation: a pharmacological analysis.

1. Electrical field stimulation (EFS) of the rat isolated seminal vesicle elicited frequency-dependent and tetrodotoxin sensitive contractions which were unaltered by hexamethonium or mecamylamine. 2. Prazosin alone was not sufficient to abolish these responses, but a combination of atropine and prazosin was fully effective, indicating involvement of both noradrenergic and cholinergic mechanisms. 3. Responses were predominantly cholinergic (blocked by atropine, potentiated by ecothiopate but not significantly altered by prazosin or guanethidine) at 1-8 Hz but became increasingly noradrenergic (blocked by prazosin or guanethidine but relatively unaltered by atropine or ecothiopate) with increasing frequencies of stimulation. 4. Electrical field stimulation of seminal vesicles removed from reserpine or 6-hydroxydopamine (6-OHDA)-pretreated rats produced contractions that were clearly cholinergic in nature. 5. After exposing the seminal vesicles to guanethidine, or after pretreatment of rats with 6-OHDA, responses to EFS remained, indicating that activation of discrete cholinergic and noradrenergic innervations seem to underlie the contractile responses observed. 6. Yohimbine and prazosin potentiated the predominantly cholinergic responses at 1, 2 and 4 Hz in tissues from untreated rats, but not in those from animals pretreated with reserpine or 6-OHDA, indicating the possibility of an interaction between the two innervations. 7. No inhibitory responses to EFS could be demonstrated in tissues precontracted with KCl in the presence of a combination of atropine and prazosin suggesting the absence of a nonadrenergic, noncholinergic inhibitory innervation.

Pharmacological characterization of the postjunctional alpha-adrenoceptors of the rat isolated seminal vesicle.

In an attempt to define the pharmacological characteristics of the postjunctional alpha-adrenoceptors of the rat seminal vesicle, responses to certain phenylethanolamine and imidazoline agonists were investigated, in vitro, under experimental conditions outlined by Furchgott (1972), using alpha 1-selective, non-selective and alpha 2-selective adrenoceptor antagonists. Adrenaline (ADR), noradrenaline (NA) and phenylephrine (PE) produced concentration-dependent contractions. In many experiments the concentration-response (C-R) curves had a distinct "shoulder" at the level of 60-80% of the maximum response (Emax), a situation reminiscent of the rat anococcygeus muscle and the rat basilar artery. The relative potencies of ADR:NA:PE, derived from their EC50 values, were 4.07:1:0.26. In contrast clonidine, oxymetazoline and naphazoline failed to contract the tissue even in concentrations up to 1 X 10(-3) M. In fact the imidazoline derivatives prevented responses to the phenylethanolamines. The antagonist action of clonidine, against phenylephrine, was studied in detail. Prazosin, phentolamine, yohimbine, corynanthine and clonidine all caused a rightward displacement of the C-R curves for NA without depressing Emax. The Arunlakshana and Schild plots of the data were linear and had slopes not significantly different from unity. The pA2 estimates obtained were 9.17 (9.13-9.21) for prazosin, 8.58 (8.07-9.09) for phentolamine, 6.70 (6.44-6.98) for yohimbine and 7.05 (6.81-7.30) for corynanthine. Clonidine had a pA2 value of 6.60 (6.55-6.67) against phenylephrine. On the basis of results obtained with antagonists, the postjunctional alpha-adrenoceptors of the rat seminal vesicle could be firmly placed in the gross category of "alpha 1".(ABSTRACT TRUNCATED AT 250 WORDS)