Atropine, diazepam, and physostigmine: thermoregulatory effects in the heat-stressed rat

We have previously reported that administration of atropine (A) to unrestrained, sedentary, heat-stressed rats resulted in a dose-dependent increase in heating rate (rate of rise of core temperature, degree C/min). Additionally, we have demonstrated that the decrements in treadmill endurance and increments in heating rate of physostigmine (PH)-treated running rats can both be restored to control levels by pretreating the animals with A and diazepam (D). Our objective in the present work was to determine if the administration of D + PH to A-treated unrestrained, sedentary, heat-stressed rats (N = 16/group, 510-530 g) could improve their thermal tolerance. The following drugs were administered singly (at 10 min intervals) via lateral tail vein: vehicle-control (C), A (200 micrograms/kg), D (500 micrograms/kg), and PH (200 micrograms/kg). After drug administration, the rats were heat-stressed (Tamb = 41.5 degrees C) until a core temperature of 42.6 degrees C was attained when they were removed to a 26 degrees C chamber. The heating rates (degrees C/min) and tolerance times (min) of the respective groups were: C- 0.02, 235; A- 0.08, 58; A D- 0.06, 94; and A + D + PH- 0.04, 143. Administration of D with A significantly decreased heating rate, and D + PH more than doubled the thermal tolerance of A-treated rats. Thus, the combination of A + D + PH not only restores PH-induced performance and thermoregulatory decrements of rats exercised in a moderate environment, but also reduces A-induced heat intolerance.     

Chronic vs acute carbamate administration in exercising rats

Physostigmine (PH), alone, and pyridostigmine (PY), in combination with atropine and 2-PAM, have been shown to protect animals against organophosphate poisoning. While acute administration of either of these carbamates increased heating rates and decreased endurance of exercising rats, chronically administered PY did not induce these decrements, and we hypothesized that chronic administration of PH could also result in similar attenuation of these effects. Thus, PH was administered acutely (iv) or chronically (osmotic mini-pump) in the following 4 groups (510-530g, male, N = 10/group): C (control, saline iv), AC-200 (acute, 200 ug/kg, 58% whole blood cholinesterase (ChE) inhibition), CH-7 (chronic, 125 ug/hr, 7 days, 60% inhib.), and CH-14 (chronic, 125 ug/hr, 14 days, 56% inhib.). Rats were run (11 m/min, 26 degrees C) to exhaustion. The run times and heating rates (% of control) were: AC-200 - 47, 213%; CH-7 - 60, 157%; CH-14 - 92, 109%. Additionally, ultrastructural changes noted in diaphragms of acutely treated animals were less evident in chronically treated animals. Thus, the decremental effects of acute PH administration on endurance, thermoregulation, and ultrastructure were attenuated with chronic administration at similar levels of ChE inhibition.     

In vivo dose response relationship between physostigmine and cholinesterase activity in RBC and tissues of rats

Dose response of physostigmine (Phy) was studied in rat using various doses (25-500 micrograms/kg i.m.). Rats were sacrificed 15 min after Phy administration. Blood and tissues were analyzed for ChE activity by radiometric method and Phy concentration by HPLC method. A comparison of ChE values in different tissues of rats indicated that ChE activity was highest in brain (7.11 mumol/min/g) and least in diaphragm (0.67 mumol/min/g). The enzyme activity was eleven times more in brain as compared to diaphragm. Phy produced a dose-dependent inhibition of ChE in RBC (18-42%), brain (23-35%) and diaphragm (25-35%) from 50 to 200 micrograms/kg, then ChE inhibition was plateaued from 200 to 500 micrograms/kg in these tissues. A dose related ChE inhibition was seen in heart (16-50%) and thigh muscle (8-53%) from 50 to 500 micrograms/kg. Phy concentration increased linearly from 50 to 400 micrograms/kg in plasma, brain, heart and thigh muscle. These results indicate that ChE inhibition is linear up to 200 micrograms/kg in RBC, 150 micrograms/kg in brain and 300 micrograms/kg in heart. This linearity is not consistent in other tissues.     

Carbamates, atropine, and diazepam: effects on performance in the running rat

We have reported that when rats (500 g, male) are exercised to exhaustion on a treadmill, pretreatment with the centrally acting carbamate physostigmine reduced endurance (run time, RT) and increased the rate of rise of core temperature (Tc+). Both RT and Tc+ were restored to control levels by pretreatment with either or a combination of atropine (A), and diazepam (D). Our objective in the present work was to determine whether A+D could also restore the performance and thermoregulatory decrements induced by the peripherally acting carbamate pyridostigmine (PY). After drug administration, rats were run (11 m/min, 6 degrees elevation, Ta = 26 degrees C) to exhaustion. PY treatment resulted in a reduced RT and an increased heat gain that neither A nor D alone (A+PY and D+PY) could restore to control levels. On the other hand, a combination of both A and D restored these variables to control levels. In conclusion, A+D can restore the performance and thermoregulatory decrements resulting from the administration of either a centrally or a peripherally acting carbamate.     

Reversal of androgen inhibition of estrogen-activated sexual behavior by cholinergic agents

Androgens have been found to inhibit lordosis activated by estrogen treatment of ovariectomized female rats. In the present experiments, dihydrotestosterone propionate (200 micrograms for 3 days) inhibited the incidence of lordosis in ovariectomized females treated with estradiol benzoate (1 microgram for 3 days). This inhibition of lordosis was reversed 15 min after bilateral intraventricular infusion of physostigmine (10 micrograms/cannula), an acetylcholinesterase inhibitor, or carbachol (0.5 microgram/cannula), a cholinergic receptor agonist. This reversal of inhibition appears to be mediated by cholinergic muscarinic receptors since pretreatment with scopolamine (4 mg/kg, ip), a muscarinic receptor blocker, prevented the reversal of androgen inhibition by physostigmine. These results indicate that androgens may inhibit estrogen-activated lordosis through interference with central cholinergic muscarinic mechanisms.     

Plasma volume expansion in rats: effects on thermoregulation and exercise

Administration of polyethylene glycol (PEG, intraperitoneal, 3 ml, 30% solution) to adult male rats (300 g) resulted in an approximately 20% increment in plasma volume (PV) 24 h after PEG injection. When these animals were exercised (9.14 m/min, level treadmill) in a warm (30 degrees C, 30-40% relative humidity) environment, their mean endurance was increased from 67.9 (saline-treated controls, CONT) to 93.6 min (P less than 0.01). Total water loss was increased from 12.2 (CONT) to 17.2 g (PEG, P less than 0.01). Atropine administration (ATR, 200 micrograms/kg, tail vein) significantly (P less than 0.05) reduced both the endurance and the salivary water loss of CONT and PEG-treated rats, whereas it increased the heating rate (P less than 0.01) of both groups. PEG treatment reduced (P less than 0.01) the hematocrit and circulating protein levels both before and subsequent to exercise in the warm environment. Clinical chemical indexes of heat/exercise injury were generally unaffected by pharmacological intervention, whereas clinical chemical responses to exercise were related to the endurance time of each group. We concluded that expansion of PV by PEG provided significant beneficial effects on performance and thermoregulation during exercise in a warm environment.     

Epinephrine, glucose, and lactate infusion in exercising adrenodemedullated rats

The purpose of this study was to determine the metabolic function of the marked increase in plasma epinephrine which occurs in fasted rats during treadmill exercise. Fasted adrenodemedullated (ADM) and sham-operated (SHAM) rats were run on a rodent treadmill (21 m/min, 15% grade) for 30 min or until exhaustion. ADM rats were infused with saline, epinephrine, glucose, or lactate during the exercise bouts. ADM saline-infused rats showed markedly reduced endurance, hypoglycemia, elevated plasma insulin, reduced blood lactate, and reduced muscle glycogenolysis compared with exercising SHAM's. Epinephrine infusion corrected all deficiencies. Glucose infusion restored endurance run times and blood glucose to normal without correcting the deficiencies in blood lactate and muscle glycogenolysis. Infusion of lactate partially corrected the hypoglycemia at 30 min of exercise, but endurance was not restored to normal and rats were hypoglycemic at exhaustion. We conclude that in the fasted exercising rat, actions of epinephrine in addition to provision of gluconeogenic substrate are essential for preventing hypoglycemia and allowing the rat to run for long periods of time.     

Angiotensin II-induced hypothermia in rats

Systemic administration of angiotensin II (ANG II) (200 micrograms/kg sc) to the rat induced a hypothermic response that was characterized within 12 min by a reduction in the rate of O2 consumption, vasodilation of the tail, and a 1.3 degrees C fall in colonic temperature. Administration of ANG II in doses ranging from 10 to 200 micrograms/kg resulted in a decrease in colonic and an increase in tail skin temperature. Angiotensin I (ANG I) (200 micrograms/kg sc) induced a similar hypothermic response which was abolished by pretreatment with the ANG I-converting enzyme inhibitor, captopril (35 mg/kg ip). The interaction of ANG II with cholinergic and adrenergic pathways was evaluated to determine possible mechanisms. Treatment with ANG II (200 micrograms/kg sc) and propranolol, a beta-adrenoceptor antagonist (6 mg/kg ip), resulted in a greater depression of colonic temperature (Tco) than was observed with ANG II alone but did not affect the increase in tail skin temperature (Tsk) accompanying administration of ANG II. When ANG II was administered in combination with the beta-adrenergic agonist, isoproterenol (50 micrograms/kg ip), Tco remained at control levels, whereas an enhancement of the ANG II-induced increase in Tsk occurred. Administration of ANG II in combination with atropine sulfate (6 mg/kg ip), a muscarinic receptor antagonist which crosses the blood-brain barrier, significantly reduced the extent of the fall in Tco without affecting the increase in Tsk. The combined treatment of ANG II and the quaternary analogue, atropine methyl nitrate (3.25 mg/kg ip), which does not cross the blood-brain barrier, failed to affect the hypothermic responses to ANG II. These results suggest that the hypothermic responses to ANG II may be mediated through a central cholinergic pathway and possibly influenced by an adrenergic component. The inability of both adrenergic and cholinergic blockers to affect the vasodilatory response of the tail of the rat to administration of ANG II suggests that the mechanisms subserving heat production can be blocked independently of those subserving heat loss.     

The antiinflammatory activity of Icacina trichantha tuber.

Five fractions (hexane, chloroform, ethylacetate, methanol and water) of Icacina trichantha tuber were obtained by gradient solvent extraction and tested for their ability to inhibit the Croton oil-induced ear edema in mice. The most active fraction was the chloroform one which significantly inhibited ear edema in a dose-dependent manner, showing an ID50 (dose giving 50% edema inhibition) of 107 micrograms/cm2. The ID50 of the reference drug indomethacin was 93 micrograms/cm2. The chloroform fraction significantly reduced also the carrageenin-induced paw edema in rats, after oral adiminstration: 50, 100 or 200 mg/kg of the fraction reduced the global edematous response by 15, 20 or 34%, whereas 10 mg/kg of indomethacin induced 40% inhibition.     

Involvement of platelet-activating factor (PAF) in endotoxin-induced intestinal motor disturbances in rats

Intestinal myoelectrical activity was investigated in conscious fasted rats chronically implanted with Nichrome electrodes in the duodeno-jejunum. Motility of the small intestine was characterized by the presence of migrating myoelectric complex (MMC) occurring regularly at 16.2 +/- 5.8 minute intervals. Intravenous administration of endotoxin (E. coli S.0111:B4) at a dose of 50 micrograms/kg increased the interval between MMC to 112.6 +/- 26.8 min, the duration of these effects being dose-related between 10 to 100 micrograms/kg. Such a typical myoelectrical alteration, corresponding to rapidly propagated groups of spike bursts, was mimicked by the IP administration of PAF at doses of 10 to 50 micrograms/kg. Previous administration of BN 52021, a specific PAF antagonist at a dose of 50 mg/kg abolished the motor alterations induced by IP injection of PAF (25 micrograms/kg) and significantly (p less than 0.01) reduced by 61.2% those induced by IV endotoxin (50 micrograms/kg). Indomethacin (10 mg/kg IP) as well as SC 19220 (5 mg/kg IV), a PGE2 antagonist, injected prior to endotoxin (50 micrograms/kg IV) or PAF (25 micrograms/kg IP) also reduced significantly (p less than 0.01) the duration of MMC inhibition. It is concluded that endogenous release of PAF is partly responsible for the intestinal motor alterations induced by endotoxin; these effects, strongly reduced after treatment with BN 52021, are also mediated through the release of prostaglandins.     

Effects of intranasal administration of atrial natriuretic hormone on spontaneously hypertensive rats

The effects of the intranasal administration of synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) were investigated in 14 anesthetized spontaneously hypertensive rats (SHR; Okamoto-Aoki strain). They were given intranasally synthetic alpha-hANP in distilled water at doses of 10 micrograms/kg, 50 micrograms/kg and 100 micrograms/kg. Intranasal application of 200 microliter of distilled water as a control was also performed in 3 anesthetized SHR. Sixteen anesthetized SHR were examined for the effects of intravenous administration of alpha-hANP at doses of 4 micrograms/kg, 10 micrograms/kg, 20 micrograms/kg and 40 micrograms/kg. Urinary volume and the urinary excretion of sodium increased 2- to 3-fold during the 50 minutes following intranasal administration of a single dose of 50 micrograms/kg or 100 micrograms/kg, although neither the urinary volume nor the urinary excretion of sodium increased after intranasal administration of 10 micrograms/kg of alpha-hANP or 200 microliter of distilled water. There were no significant changes in arterial pressure or heart rate after the intranasal administration of synthetic alpha-hANP or distilled water. In contrast, arterial pressure was decreased and urinary volume and urinary excretion of sodium were increased, in a dose dependent manner, within 5 minutes after intravenous bolus-injection of alpha-hANP and returned to their baseline levels within 20 minutes. These results indicate that intranasal administration of synthetic alpha-hANP exerts its diuretic effect without concomitant changes in arterial pressure or heart rate in SHR.     

Effect of physostigmine on relative acetylcholine output induced by systemic treatment with scopolamine in in vivo microdialysis of rat frontal cortex

By means of an in vivo brain microdialysis, the effect of different concentrations of physostigmine on the acetylcholine level in the dialysate of rat frontal cortex was studied. Perfusion of the various degrees of physostigmine (eserine) concentration (10 nM−10 μM) into the cortex through the dialysis membrane increased the basal acetylcholine level in a dose-dependent manner. In the presence of 10 nM, 0.1 μM and 10 μM physostigmine in the perfusate, systemic treatment with scopolamine (0.5 mg/kg, i.p.) increased 200, 270 and 510%, respectively, the relative acetylcholine level in the dialysates in comparison with the corresponding basal levels, while in the absence of physostigmine the treatment increased it only 40%. From these results, it appears that perfusion of physostigmine at a variety of concentrations, changes not only the basal level of acetylcholine induced by the inhibition of acetylcholinesterase but also the relative acetylcholine output induced by systemic treatment with scopolamine.     

Low density lipoprotein (LDL) inhibits histamine release from human mast cells

We examined the effect of low density lipoprotein (LDL) on histamine release from purified human lung mast cells. LDL inhibited anti-IgE- induced histamine release in a dose-dependent manner, with 100 micrograms/ml LDL-protein inhibiting histamine release by 53 +/- 8% (mean +/- SEM); half-maximal inhibition occurred at 40-80 micrograms/ml. LDL also inhibited calcium ionophore A23187-induced histamine release in a dose-dependent manner, with 1 mg/ml of LDL inhibiting histamine release by 83 +/- 9%; half maximal inhibition occurred at 220-280 micrograms/ml. Inhibition by LDL was time-dependent: half-maximal inhibition of anti-IgE- induced histamine release by LDL occurred at 30-50 minutes of incubation. The inhibitory effect of LDL was independent of buffer calcium concentrations (0-5 mM) or temperature (0-37 degrees C). These data are consistent with a newly defined immunoregulatory role for LDL.     

Thermoregulatory responses to exercise in dehydrated dogs

Measurements of rectal temperature (Tre), water lost by evaporation (Eresp) and drooling, cardiac output (CO), and common carotid blood flow (CCBF) were made in dogs (mean hydrated wt 31.0 +/- 1.5 kg) running for 1 h on a level treadmill at 7.5 km/h at an ambient temperature of 25 degrees C. Each animal was studied when it was hydrated ad libitum and when it had been dehydrated by removal of drinking water until 9-10% of the initial body weight had been lost. Dehydrated exercising animals had significantly higher Tre and lower rates of Eresp, CO, and CCBF. Tre and Eresp were measured in seven animals. Average Tre during running was 39.11 +/- 0.10 degrees C in hydrated and 39.80 +/- 0.25 degrees C in dehydrated animals (P less than 0.01). Average Eresp during running was 3.9 +/- 0.3 g/min in hydrated animals and 2.3 +/- 0.3 g/min in dehydrated animals (P less than 0.01). Average CO during exercise, measured in five animals, was 11.1 +/- 0.7 1/min in the hydrated state and 8.6 +/- 0.5 1/min in the dehydrated state (P less than 0.01). Unilateral CCBF during exercise, measured in four animals, was 602 +/- 40 ml/min in the hydrated state and 418 +/- 22 ml/min in the dehydrated state (P less than 0.01). Water lost by drooling in seven exercising animals was 41.5 +/- 11 g/h when they were hydrated and 0.6 +/- 0.4 g/h when they were dehydrated. It is concluded that dehydrated dogs doing mild exercise can save water by reducing Eresp and regulating body temperature above hydrated levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuromodulatory effects of TRH upon swim and cholinergic analgesia

In addition to short-acting analgesic actions by itself and modulation of analgesic responses induced by endogenous opioids and neurotensin, central administration of thyrotropin-releasing hormone (TRH) potentiates footshock analgesia. The present study evaluated the effects of TRH upon the neurohormonally-mediated though nonopioid analgesia induced by swims in rats. Intracerebroventricular TRH (10 and 50 micrograms) dose-dependently potentiated swim (21, 15, 2 degrees C baths) analgesia on the tail-flick test, an effect which was not due to the hypothermic or basal pain threshold changes. Intravenous (8 mg/kg) TRH potentiated swim (21 degrees C) analgesia; the 600:1 difference in potency between routes strongly suggests central sites of neuromodulatory action. Intracerebroventricular diketopiperazine (50 micrograms), a TRH metabolite, and RX77368 (50 micrograms), a TRH analogue, also potentiated swim (21 degrees C) analgesia, effects also independent of hypothermia and basal reactivity to pain. Finally, given the excitatory interaction between TRH and acetylcholine as well as the cholinergic involvement in swim analgesia, intracerebroventricular TRH potentiated pilocarpine (10 mg/kg, IP) analgesia.     

Factors affecting angiotensin II-induced hypothermia in rats

Systemic administration of angiotensin II (AII) to the rat has previously been shown to induce a dose-dependent, hypothermic response manifested by a fall in colonic temperature (CT), a decrease in heat production and an increase in tail skin temperature (TST). The factors mediating AII-induced hypothermia and their site of action were the subjects of the present investigation. To this end, intracerebroventricular administration of 1 microgram of AII induced a 0.4 degrees C reduction in CT and a 2.4 degrees C increase in TST. In contrast, SC administration of 200 micrograms angiotensin III/kg induced a slight increase in CT but had no affect on TST. Pretreatment with the AII-receptor antagonist, saralasin, at either 1 or 10 micrograms/kg, SC did not affect either the fall in CT or the increase in TST induced by administration of 200 micrograms AII/kg, SC. However, the administration of 100 micrograms saralasin/kg, SC attenuated both the fall in CT and the increase in TST induced by either 100 or 200 micrograms AII/kg. Since both the presynaptic alpha adrenoceptor agonist, clonidine, and the opioid antagonist, naloxone, modulate the pressor and dipsogenic responses to AII, their effects on AII-induced hypothermia were tested. Both clonidine (25 micrograms/kg, SC) and naloxone (1 mg/kg, IP) enhanced the fall in CT. Clonidine lengthened the duration of the increase in TST while naloxone had no effect. Pretreatment with the presynaptic adrenoceptor antagonist, yohimbine (300 micrograms/kg, SC), did not alter the hypothermic response to administration of AII. To determine whether vasodilation of the tail of the rat was mediated by AII-induced prostaglandin release, indomethacin (4 and 6 mg/kg) was administered.(ABSTRACT TRUNCATED AT 250 WORDS)     

GABAergic modulation of ventilation and peak oxygen consumption in obese Zucker rats.

Obesity is often associated with a reduced ventilatory response and a decreased maximal exercise capacity. GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. Altered GABAergic mechanisms have been detected in obese Zucker rats and implicated in their hyperphagic response. Whether altered GABAergic mechanisms also contribute to regulate ventilation and influence exercise capacity in obese Zucker rats is unknown and formed the basis of the present study. Eight lean [317 +/- 18 (SD) g] and eight obese (450 +/- 27 g) Zucker rats were studied at 12 wk of age. Ventilation at rest and ventilation during hypoxic (10% O(2)) and hypercapnic (4% CO(2)) challenges were measured by the barometric method. Peak O(2) consumption (VO(2 peak)) in response to a progressive treadmill test to exhaustion was measured in a metabolic treadmill. Ventilation and VO(2 peak) were assessed after administration of equal volumes of DMSO (vehicle) and the GABA(A) receptor antagonist bicuculline (1 mg/kg). In lean animals, bicuculline administration had no effect on ventilation and VO(2 peak). In obese rats, bicuculline administration significantly (P < 0.05) increased resting ventilation (465 +/- 53 and 542 +/- 72 ml. kg(-1). min(-1) for control and bicuculline, respectively), ventilation during exposure to hypoxia (899 +/- 148 and 1,038 +/- 83 ml. kg(-1). min(-1) for control and bicuculline, respectively), and VO(2 peak) (62 +/- 3.7 and 67 +/- 3.5 ml. kg(-0.75). min(-1) for control and bicuculline, respectively). However, in obese Zucker rats, ventilation in response to hypercapnia did not change after bicuculline administration (608 +/- 96 vs. 580 +/- 69 ml. kg(-1). min(-1)). Our findings indicate that endogenous GABA depresses ventilation and limits exercise performance in obese Zucker rats.     

The human renin infused rat: use as an in vivo model for the biological evaluation of human renin inhibitors

The human renin infused rat model (HRIRM) was used as an in vivo small-animal model for evaluating the efficacy of a collection of inhibitors of human renin. The intravenous infusion of recombinant human renin (2.4 microg x kg(-1) x min(-1)) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47+/-3 mm Hg (1 mm Hg = 133.3 Pa), which was reduced by captopril, enalkiren, and losartan in a dose-dependent manner following oral administration, with ED50 values of 0.3+/-0.1, 2.5+/-0.9, and 5.2+/-1.6 mg/kg, respectively. A series of peptidomimetic P2-P3 butanediamide renin inhibitors inhibited purified recombinant human renin in vitro in a concentration-dependent manner, with IC50 values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values (0.8-80 nM) observed at pH 7.4. Following i.v. administration of renin inhibitors, the pressor response to infused human renin in the HRIRM was inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600 microg/kg. The in vivo inhibition of human renin following i.v. administration in the rat correlated significantly better with the in vitro inhibition of human renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5). Oral administration of renin inhibitors also resulted in a dose-dependent inhibition of the pressor response to infused human renin, with ED50 values ranging from 0.4 to 6.0 mg/kg and the identification of six renin inhibitors with an oral potency of <1 mg/kg. The ED50 of renin inhibitors for inhibition of angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor response. These results demonstrate the high potency, dose dependence, and availability following oral administration of the butanediamide series of renin inhibitors.     

Effect of glibenclamide on thyroid hormone metabolism in rats

This study was undertaken to elucidate the effect of glibenclamide, one of sulfonylurea drugs, on thyroid hormone metabolism in vivo and on the conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) in the isolated perfused rat liver and kidney. Glibenclamide (0.2 mg/kg body weight) was intraperitoneally administered to normal and streptozotocin-induced (50 mg/kg) diabetic rats for 14 days. The liver and kidney of normal rats were perfused for 30 minutes with a synthetic medium containing 20 micrograms/dl T4 and glibenclamide (200 or 400 ng/ml), and production of T3 in the tissues was measured by radioimmunoassay. Serum T4 and T3 levels in control and streptozotocin-induced diabetic rats were not changed by daily intraperitoneal glibenclamide administration. The production of T3 (111 +/- 40 and 95 +/- 16 ng/g/30 min, mean +/- SD) and the conversion rate of T4 to T3 (11.1 +/- 2.9 and 10.2 +/- 2.3%) in the liver perfused with glibenclamide (200 and 400 ng/ml) were not significantly different from those in controls (109 +/- 41 ng/g/30 min and 12.8 +/- 5.4%). And those (120 +/- 33 and 99 +/- 19 ng/g/30 min, and 3.5 +/- 0.6 and 2.5 +/- 0.4%) in the kidney perfused with glibenclamide (200 and 400 ng/ml) were similar to those in controls (98 +/- 33 ng/g/30 min and 3.0 +/- 1.5%).     

Cholecystokinin-8 protects gastric mucosa against ethanol-induced lesions in rats

Subcutaneous administration of cholecystokinin-8 (CCK-8, 10-100 micrograms/kg) reduces in a dose-dependent manner gastric lesions induced by 96% ethanol in rats, and CCK-4, CCK-7, and the CCK-8 nonsulfated form (all up to 100 micrograms/kg sc) were inactive. The presence of the entire molecule and sulfation of the tyrosine in position 2 are necessary for the mucosal protective properties of CCK-8 against 96% ethanol-induced gastric lesions. These effects are probably at least in part, due to a sulfhydryl-sensitive process.