Gastric antisecretory effects of esaprazole in rats.

The effects of esaprazole on gastric secretion (volume, pepsin and acid output) were investigated on animal models, both in vivo and in vitro. In conscious rats whose vagal activity was stimulated by pylorus ligation, esaprazole decreased volume, acid output and pepsin secretion. In anaesthetized stomach-perfused rats, esaprazole inhibited gastric acid secretion evoked by both vagus nerve stimulation or bethanechol infusion. By contrast, on isolated guinea-pig gastric fundus, esaprazole failed to counteract the acid output stimulated by histamine, bethanechol or pentagastrin. In addition to this, phasic contractions evoked by acetylcholine on isolated guinea-pig ileum were antagonized by esaprazole only at high concentrations. The present results suggest that the inhibitory actions of esaprazole on secretory parameters involve the cholinergic parasympathetic pathway, probably through both direct and indirect mechanisms.     

Gastric antisecretory and antiulcer effects of simvastatin in rats

BACKGROUND AND AIM: Recently, statins have appeared to have additional benefits beyond their lipid lowering effects, which has led to the interest in the use of this class of drugs outside the realm of cardiovascular disease. Simvastatin (SIM) is a commonly prescribed statin with anti-inflammatory and antioxidant properties. Excessive generation of oxygen-derived free radicals (ODFR) and proinflammatory mediators has been implicated in the pathogenesis of gastric ulcers. This investigation aimed to study the effect of SIM on experimentally induced gastric acid secretion and ulcer formation. METHODS: Adult Wistar rats were divided into experimental groups containing six animals. Acid secretion studies were undertaken using pylorus-ligated rats pretreated with SIM (20, 40, and 60 mg/kg). The effect of orally administered SIM was also studied on indomethacin- and ethanol-induced gastric ulcers. The levels of myeloperoxidase (MPO), non-protein sulfhydryls (NP-SH), nitric oxide (NO), antioxidant enzymes, and gastric wall mucus were measured in the glandular stomach of rats following ethanol-induced gastric lesions. RESULTS: Administration of SIM significantly and dose-dependently inhibited the volume of gastric secretion and the acidity. Pretreatment with SIM significantly reduced the formation of indomethacin- and ethanol-induced gastric lesions. The antiulcer activity of SIM was associated with significant attenuation of adverse effects of ethanol on gastric wall mucus, NP-SH and MPO. SIM modified the gastric NO levels and reversed the ethanol-induced decrease in glutathione-S-transferase and increase in superoxide dismutase and catalase. CONCLUSIONS: These findings clearly suggest the involvement of proinflammatory agents and ODFR in the pathogenesis of gastric lesions. The gastroprotective effects of SIM are mediated by inhibition of neutrophils activity, reduction of oxidative stress, and maintenance of vascular integrity. This study was conducted in rats; its relevance to human gastric ulcers is not known and warrants further study.     

Localization of central prostaglandin E2 antisecretory effects

Intracerebroventricular prostaglandin E2 (PGE2) inhibits stimulated gastric acid secretion; however, the central site of action is unknown. Specific PGE2 binding sites have been localized to the ventromedial hypothalamic nucleus and central amygdala (A). The nuclear accumbens has been shown to play a role in central neurotensin-induced antisecretory effects. These studies tested the hypothesis that microinjections of PGE2 into the ventromedial hypothalamic nucleus, central amygdala, and nuclear accumbens inhibit stimulated gastric acid secretion. The hippocampus served as a cerebral control region. Two days before the experiments, metal cannulas were stereotaxically positioned bilaterally into specific areas of the brain, and metal gastric cannulas were operatively implanted, under nembutal anesthesia, in male 250-g Sprague-Dawley rats. On the experimental day, the rats, fasted for 14 hours, were given saline or PGE2 (0.1-1.0 micrograms in 0.2 microL/side) through the central cannulas 10 minutes before administering pentagastrin (40 micrograms/kg SC). Gastric secretion was measured at 30-minute intervals and expressed as acid output, micromoles per hour. Acid output (mean +/- SE) in control animals was 161 +/- 14 mumol/h. Prostaglandin E2 administration at doses of 0.10, 0.50, and 1.0 micrograms/side (a) into ventromedial hypothalamic nucleus reduced acid output to 53 +/- 11,* 36 +/- 10,* and 27 +/- 11* mumol/h regularly; (b) into NACB reduced acid output to 157 +/- 36, 60 +/- 12,* and 38 +/- 12* mumol/h; and (c) into A reduced acid output to 144 +/- 31, 141 +/- 26, and 90 +/- 19* mumol/h, respectively (*P less than 0.05 by Neuman-Keuls test). Prostaglandin E2 (0.50 micrograms/side) administration into hippocampus had no significant effect on acid output (134 +/- 28 mumol/h). Although central PGE2 administration was associated with hyperthermia, this occurred at lower doses than those required to inhibit acid secretion. Prostaglandin E2 administration into specific brain areas known to have PGE2 receptors, the central amygdala and ventromedial hypothalamic nucleus, and into nuclear accumbens inhibits stimulated gastric acid secretion. These observations suggest that PGE2 may have a physiological role in the central control of gastric acid secretion.     

Skeletal effects of long-term caloric restriction in rhesus monkeys

Age-related bone loss is well established in humans and is known to occur in nonhuman primates. There is little information, however, on the effect of dietary interventions, such as caloric restriction (CR), on age-related bone loss. This study examined the effects of long-term, moderate CR on skeletal parameters in rhesus monkeys. Thirty adult male rhesus monkeys were subjected to either a restricted (R, n = 15) or control (C, n = 15) diet for 20 years and examined throughout for body composition and biochemical markers of bone turnover. Total body, spine, and radius bone mass and density were assessed by dual-energy X-ray absorptiometry. Assessment of biochemical markers of bone turnover included circulating serum levels of osteocalcin, carboxyterminal telopeptide of type I collagen, cross-linked aminoterminal telopeptide of type I collagen, parathyroid hormone, and 25(OH)vitamin D. Overall, we found that bone mass and density declined over time with generally higher levels in C compared to R animals. Circulating serum markers of bone turnover were not different between C and R with nonsignficant diet-by-time interactions. We believe the lower bone mass in R animals reflects the smaller body size and not pathological osteopenia.     

Apo E levels and distribution in rhesus monkeys consuming an atherogenic diet

The effect of an atherogenic diet on serum apo E levels and distribution among the lipoproteins of rhesus monkeys was studied. Animals able to maintain their serum cholesterol levels below 250 mg/dl (hyporesponders) showed no significant change in their serum apo E levels; however, in monkeys whose serum cholesterol concentrations ranged from 250 to 850 mg/dl, serum apo E levels appeared to have increased in direct proportion to plasma cholesterol concentration (r2 = 0.92) such that in monkeys whose serum cholesterol concentration exceeded 650 mg/dl (hyperresponders), the apo E levels had increased 5-6-fold. The majority of the apo E (60%) in hyporesponders consuming the atherogenic diet was associated with HDL, whereas only 10% of the serum apo E was associated with HDL in hypercholesterolemic hyperresponders. Nonetheless, the absolute amount of HDL-associated apo E was the same in both phenotypes. Thus, essentially all of the increase in serum apo E levels in hyperresponders was due to an increase in non-HDL-associated apo E. The mean density of the fraction showing the greatest increase in apo E, and accounting for the majority of the d less than 1.063 g/ml apo E in hyperresponders, was 1.010 g/ml. That fraction was distinct from the lipoproteins principally responsible for the increase in apo B and cholesterol levels in those animals. The latter were smaller in size and higher in density than the major apo E-rich fraction. Nonetheless, the d less than 1.063 g/ml apo E apparently circulates on apo B-containing particles, since it was retained on an anti-apo B immunoaffinity column. These data show that a diet-induced hypercholesterolemia is accompanied by a marked increase in serum apo E levels in rhesus monkeys, but that the lipoproteins principally responsible for the increase in apo E levels are distinct from those mainly responsible for the hypercholesterolemia. They also suggest that the levels of apo E-containing HDL in hypercholesterolemic hyperresponders are not significantly lowered by the diet, even though those animals' apo A-I levels were severely reduced. Thus, both the LDL and the HDL of the hypercholesterolemic primate contain apo E-rich subfractions which are metabolically distinct from the principal lipoprotein family in each fraction.     

Calorie restriction in rhesus monkeys

Calorie restriction (CR) extends lifespan and reduces the incidence and age of onset of age-related disease in several animal models. To determine if this nutritional intervention has similar actions in a long-lived primate species, the National Institute on Aging (NIA) initiated a study in 1987 to investigate the effects of a 30% CR in male and female rhesus macaques (Macaca mulatta) of a broad age range. We have observed physiological effects of CR that parallel rodent studies and may be predictive of an increased lifespan. Specifically, results from the NIA study have demonstrated that CR decreases body weight and fat mass, improves glucoregulatory function, decreases blood pressure and blood lipids, and decreases body temperature. Juvenile males exhibited delayed skeletal and sexual maturation. Adult bone mass was not affected by CR in females nor were several reproductive hormones or menstrual cycling. CR attenuated the age-associated decline in both dehydroepiandrosterone (DHEA) and melatonin in males. Although 81% of the monkeys in the study are still alive, preliminary evidence suggests that CR will have beneficial effects on morbidity and mortality. We are now preparing a battery of measures to provide a thorough and relevant analysis of the effectiveness of CR at delaying the onset of age-related disease and maintaining function later into life.     

Accommodative function in rhesus monkeys: effects of aging and calorie restriction

Numerous degenerative changes in the visual system occur with age, including a loss of accommodative function possibly related to hardening of the lens or loss of ciliary muscle mobility. The rhesus monkey is a reliable animal model for studying age-related changes in ocular function, including loss of accommodation. Calorie restriction (CR) is the only consistent intervention to slow aging and extend lifespan in rodents, and more recently the beneficial effects of CR have been reported in nonhuman primates. The goal of the present study was to evaluate age-related changes in ocular accommodation and the potential effect of long-term (>8 years) CR on accommodation in male and female rhesus monkeys. Refraction, accommodation (Hartinger coincidence refractometer), and lens thickness (A-scan ultrasound) were measured in 97 male and female rhesus monkeys age 8–36 years under Telazol/acepromazine anesthesia. Refraction and accommodation measurements were taken before and after 40% carbachol corneal iontophoresis to induce maximum accommodation. Half the animals were in the control (CON) group and were fed ad libitum. The CR group received 30% fewer calories than age- and weight-matched controls. Males were on CR for 12 years and females for eight years. With increasing age, accommodative ability declined in both CON and CR monkeys by 1.03 ± 0.12 (P = 0.001) and 1.18 ± 0.12 (P = 0.001) diopters/year, respectively. The age-related decline did not differ significantly between the groups (P = 0.374). Baseline lens thickness increased with age in both groups by 0.03 ± 0.005 mm/year (P = 0.001) and 0.02 ± 0.005 mm/year (P = 0.001) for the CON and CR groups, respectively. The tendency for the for the lens to thicken with age occurred at a slower rate in the CR group vs. the CON group but the difference was not statistically significant (P = 0.086). Baseline refraction was –2.8 ± 0.55 and –3.0 ± 0.62 diopters for CON and CR, respectively. Baseline refraction tended to become slightly more negative with age (P = 0.070), but this trend did not differ significantly between the groups (P = 0.587). In summary, there was no difference in the slope of the age-related changes in accommodation, lens thickness, or refraction in the carbachol-treated eyes due to diet. These data are consistent with previous findings of decreased accommodative ability in aging rhesus monkeys, comparable to the age-dependent decrease in accommodative ability in humans. This study is the first to indicate that the accommodative system may not benefit from calorie restriction.     

Gastric antisecretory and antiulcer activity of bovine hemoglobin

AIM: To investigate gastric antisecretory and gastro- protective activity of bovine hemoglobin (B-Hb) in rats. METHODS: Adult Albino-Wistar rats were divided into groups of 6 animals each. B-Hb in doses of 100, 300 and 900 mg/kg body weight was tested for gastric acid secretion and antiulcer activity. Gastric secretions were measured 6 h after pylorus ligation in rats pretreated with B-Hb. The acidity was measured by titrating gastric contents against 0.01 mol/L NaOH to pH 7. Indomethacin ulcers were produced by oral administration of 30 mg/kg bw in the rats pretreated with B-Hb one hour before indomethacin. Six hours after indomethacin stomach removed and ulcer index was recorded. Ethanol ulcer were produced by 1 mL of ethanol in the rats pretreated with B-Hb 30 min before the ethanol.One hour after ethanol stomach were cut open to score ulcers. Histological examination and analysis of gastric wall mucus, non-protein sulfhydryl groups (NP-SH), and myeloperoxidase (MPO) were carried in gastric tissue following ethanol administration. RESULTS: In control rats pylorus ligation for 6 h resulted in the accumulation of 8.1 ± 0.61 mL of gastric secretion. The treatment of the rats with 100, 300 and 900 mg/kg of B-Hb produced a significant decrease in the volume of gastric secretion 5.6 ± 0.63, 5.5 ± 0.75 and 4.7 ± 0.58 mL respectively as compared to the control group [analysis of variance (ANOVA) F = 4.77, P < 0.05]. The lesion area in the control group was found to be 22.4 ± 3.2 mm2 six hours after the administration of indomethacin. Treatment of rats with B-Hb at doses of 100 mg/kg (24.3 ± 3.29 mm2), 300 mg/kg (16.2 ± 1.45 mm2) and 900 mg/kg (12.6 ± 1.85 mm2) produced a dose dependent decreased the lesion scores (ANOVA F = 4.50, P < 0.05). The ulcer index following one hour after 1 mL ethanol was 7.1 ± 0.31. Pretreatment of rats with B-Hb at the doses of 100 mg/kg (2.5 ± 0.42), 300 mg/kg (2.1 ± 0.4) and 900 mg/kg (0.7 ± 0.21) significantly inhibited the formation of gastric lesions (ANOVA F = 63.26     

The lepromin test in rhesus monkeys

The lepromin test was studied in rhesus monkeys. Six control monkeys which had not been inoculated with Mycobacterium leprae, six monkeys with experimentally induced leprosy, and nine monkeys which had been inoculated with M. leprae but had not developed leprosy were evaluated with 1X, 10X, and 15X lepromin A, with 1X and 10X lepromin M (mangabey monkey derived), with 1X and 25X purified inactivated M. leprae, and with an armadillo mock lepromin. We found that the lepromin test is useful in rhesus monkeys, but that a higher concentration of antigen than is used in humans is required to induce a response in monkeys. Control monkeys appear to be lepromin negative. Animals which have been inoculated and which develop lepromatous leprosy are also negative. Monkeys which are experimentally inoculated with M. leprae and do not develop leprosy become lepromin positive. Monkeys with indeterminate leprosy have reactions intermediate between lepromatous and resistant animals. No monkeys reacted to armadillo tissue. Our results indicate that 10X lepromin A is a useful preparation for the lepromin testing of rhesus monkeys.     

Auditory looming perception in rhesus monkeys

The detection of approaching objects can be crucial to the survival of an organism. The perception of looming has been studied extensively in the visual system, but remains largely unexplored in audition. Here we show a behavioral bias in rhesus monkeys orienting to "looming" sounds. As in humans, the bias occurred for harmonic tones (which can reliably indicate single sources), but not for broadband noise. These response biases to looming sounds are consistent with an evolved neural mechanism that processes approaching objects with priority.     

Conditioned effects produced by naltrexone doses that reduce ethanol-reinforced responding in rhesus monkeys

Clinical trials have shown that naltrexone is effective in treating alcohol dependence; nausea and dysphoria have been reported as "side effects" in many of these studies. In primates, naltrexone reduces reinforced responding for oral ethanol, sucrose, and phencyclidine. This study was designed to determine if naltrexone reduces reinforced responding for various solutions by producing an interoceptive stimulus that may result in a conditioned taste aversion. Four opioid antagonist-naive rhesus monkeys responded for solutions from a two-spout operant panel for 30 min per day. During a conditioning phase, the monkeys received novel Kool-Aid solutions paired with either saline or naltrexone (0.32 mg/kg) given 30 min before the session. The monkeys then had seven choice sessions between the saline-paired solution or the naltrexone-paired solution. During the conditioning phase, the naltrexone reduced responding after five naltrexone/solution pairings. In addition, a conditioned taste aversion was produced; the naltrexone-paired solution maintained significantly less responding than did the saline-paired solution during the choice phase. In the next phase, the saline and naltrexone were given "unpaired" from any distinct part of the operant session, and another seven choice sessions followed. Naltrexone had no effect when given "unpaired" from the operant session. Then, another conditioning phase was undertaken followed by another series of choice sessions. During the replication of the conditioning, naltrexone reduced responding by the second pairing, although no conditioned aversion was observed in the subsequent choice sessions. Thus, given in the same manner (dose, route, and pretreatment time) as situations in which naltrexone reduces oral ethanol-, sucrose-, and phencyclidine-reinforced responding, naltrexone produced a conditioned taste aversion. These results suggest that naltrexone-induced nausea and its conditioned effects should be considered in naltrexone's effect in alcoholics.     

Locomotor activity in female rhesus monkeys: assessment of age and calorie restriction effects

As a component of a long-term, longitudinal study of aging in this primate model, the objective of the current experiment was to assess age and diet effects on locomotor activity in a cross-sectional analysis. By attaching a motion detection device to the home cage, locomotor activity was monitored over a week in a group (N = 47) of female rhesus monkeys (Macaca mulatta) 6-26 yrs of age. About half these monkeys composed a control group fed a nutritionally fortified diet near ad libitum levels, whereas an experimental group had been fed the same diet at levels 30% less than comparable control levels for approximately 5 yrs prior to testing. Among control monkeys, a marked age-related decline in activity was noted when total activity was considered and also when diurnal and nocturnal periods of activity were analyzed separately. When comparing activity levels between control and experimental groups, only one significant diet effect was noted, which was in the youngest group of monkeys (6-8 yrs of age) during the diurnal period. Monkeys in the experimental group exhibited reduced activity compared to controls. Body weight was not consistently correlated to activity levels. In some older groups, heavier monkeys tended to show greater activity, but in younger groups the opposite pattern was observed.     

Oral antisecretory activity of prostaglandin E2 in man

We studied the oral gastric antisecretory activity of prostaglandin E₂ in three groups of six normal volunteers. Each volunteer was studied twice, once after receiving prostaglandin E₂ (0.5, 1.0, or 2.0 mg) and the other time after receiving placebo administered in a double-blind, randomized fashion. Gastric acid secretion was stimulated with a liquid protein meal from 1/2 to 1 1/2hr after drug administration. Acid secretion was quantitated using the technique of intragastric titration. Acid secretion after 0.5 mg of prostaglandin E₂ was no different than after placebo administration, but 1.0 mg and 2.0 mg of prostaglandin E₂ inhibited 58% (6.68±7.64 meq vs 14.67±6.75 meq, P<0.02) and 76% (2.38±2.38 meq vs 11.50±3.51, P<0.01) respectively, of gastric acid production compared to placebo therapy. After oral administration, prostaglandin E₂ in man is antisecretory with an ED₅₀ of 1.1 mg.     

Effect of indomethacin on serum lipids, lipoproteins, prostaglandins and the extent and severity of atherosclerosis in rhesus monkeys.

The present study evaluated indomethacin therapy--a nonsteroidal anti-inflammatory drug--on experimental hyperlipidemia and atherosclerosis in Rhesus monkeys. Twenty-four monkeys were divided randomly into four groups of six. Two groups received stock pellet diet and two were given an atherogenic diet for six months. After this period, one stock diet-fed group and one atherogenic diet-fed group were treated with oral indomethacin (2.5 mg) on alternate days for a further six months. Serum lipids and lipoproteins were markedly elevated in atherogenic diet-fed monkeys. Generally, indomethacin did not exert a hypocholesterolemic effect; however, liver cholesterol was decreased (P less than 0.05) in atherogenic diet-fed monkeys treated with indomethacin. High density lipoprotein cholesterol was increased in stock diet-fed, indomethacin-treated monkeys but not in atherogenic diet-fed, indomethacin-treated monkeys. Apoprotein A-I was not affected by indomethacin in either stock or atherogenic diet-fed monkeys; however, the drug produced a significant (P less than 0.01) reduction of serum thromboxane B2 in stock diet-fed monkeys, without restoring the 6-keto-prostaglandin F1 alpha to pretreatment levels. A protective role of the drug was noted on both the extent and severity of aortic and coronary atherosclerosis.     

Reproductive endocrine effects of intranasal administration of progesterone to adult female rhesus monkeys

Adult female rhesus monkeys exhibiting normal ovulatory menstrual cycles were treated with progesterone nasal sprays. Animals in group A (n = 9) were treated with the solvent only (controls). Animals in groups B (n = 6), C (n = 17) and D (n = 7), respectively, were treated with a daily dose of 0.4, 2 and 10 micrograms of progesterone and the spraying was done between days 5-14 of the cycle. Ovulation was monitored by laparoscopy on day 20. The serum endocrine profile throughout the treated menstrual cycle was studied with respect to oestradiol and progesterone. Bioactive luteinizing hormone (bLH) was studied in blood samples taken on the day of the mid-cycle oestradiol peak, 2 days before, and 2 days after. The menstrual cycle was divided into two phases with respect to the mid-cycle oestradiol peak: phase I was taken to include day 1 of the cycle to the day of the oestradiol peak, and the remaining part of the menstrual cycle was considered to be phase II. The serum-endocrine profile in the controls was similar to that observed in normal ovulatory menstrual cycles. However, in the progesterone-treated groups three types of menstrual cycles were discernable on the basis of the serum endocrine profile. In the type I menstrual cycle, observed only in group C (n = 10), the mid-cycle bLH peak was abolished and the progesterone levels remained low throughout the cycle. Laparoscopy revealed these to be anovulatory cycles.(ABSTRACT TRUNCATED AT 250 WORDS)