Effect In Intact Animals Research Articles

Interstitial-Matrix’ Fluid-Fluxes In Vivo: Subatmospheric Pressure Reverses Hydration-Potential in Heat-Denatured Dermis

Interstitial flows modulate (a) the interchange of nutrients and metabolites between blood and parenchyma; (b) paracrine and endocrine signals; and (c) fibroblast mechanical responses. Previously, we found that hydration potential (HP), a measure of the local forces that drive interstitial flows, increases in dermis heated ex vivo. Here, we measured HP in dermis heated in vivo to probe its effectinintact animals. Subatmospheric pressure, 125mmHg, was applied in vivo for 3 hours to heated (15 sec, 100°C) and control dermis obtained as by-products from unrelated studies as approved by the IRB. Differential scanning calorimetry was used to determine the extent of collagen unfolding, and 1H magnetic resonance imaging to determine apparent diffusivity and anisotropy. HP was measured by osmotic stress, 3-219 mmHg, and influx/efflux trajectories were followed for ∼20 h to near equilibrium. The extent of unfolded collagen in vivo and ex vivo was 33 ± 3 and 34 ± 2 % of controls, respectively; apparent diffusion coefficients increased (10.1 ± 2 and 11.3 ± 1.5 versus 6.3 ± 3.7 x10−4 mm2/s), while fractional anisotropy decreased (0.289 ± 0.15 and 0.174 ± 0.07 versus 0.689 ± 0.27). These results suggest similar structural changes in both type-specimens. Mean HP of in-vivo denatured dermis decreased relative to the control and ex-vivo denatured explants: −15.2 ± 12.6 versus 30.9 ± 4.8 and 98 ± 7.4 mmHg, respectively (P-value < 0.05). After subatmospheric pressure, mean HP (48.1 ± 4.6 mm Hg) in in-vivo denatured dermis returned to baseline, while diffusivity decreased, and anisotropy increased. Lower HP values indicate excess fluid accumulation, consistent with suction forces developing in vivo upon denaturation; emerging convection-enhanced interstitial flows could explain the local edema (HP decrease) and its reversal (HP increase) by externally applied subatmospheric pressure.

Adverse Effects of Cigarette Smoke and Induction of Oxidative Stress in Cardiomyocytes and Vascular Endothelium

Active and passive exposure to cigarette smoke (CS) increases the risk of, and has deleterious effects in, ischaemic heart disease. Exposure to CS increases infarct size in experimental models of coronary occlusion and reperfusion. Among many possible mechanisms for these deleterious effects in intact animals and humans three have more substantial evidence: 1) functional alterations of endothelial cells, neutrophils and platelets; 2) impaired mitochondrial function and energy metabolism caused by toxins in CS, including oxidative free radicals; 3) increased arterial stiffness and vulnerability of the atherosclerotic plaque. In addition to the various pro-mitogenic, carcinogenic and apoptotic pathways thought to be affected and upregulated by CS, a direct necrotic action on cardiomyocytes is also believed to exist. Many, if not all, of these alterations are caused by oxidative stress, either as a direct consequence of inhalation of free radicals, or by induction from the vast range of chemicals present in both the gas and solid phase of tobacco smoke. Here, some of the proposed mechanisms will be reviewed and their impact on the cardiomyocytes and peripheral vasculature discussed.

Effects of melatonin administration on plasma leptin concentration and adipose tissue leptin secretion in mice

Both melatonin and leptin show a circadian variation in circulating levels and participate in energy metabolism. An interrelationship between these two hormones has thus been proposed. In addition, melatonin has been shown to be capable of influencing circulating leptin concentration. However, whether melatonin will increase or decrease leptin production is still uncertain. This study was undertaken to examine the effect of melatonin on leptin production using male C57BL/6 adult mice treated with or without daily melatonin supplements (10 mug/mL) in drinking water for 1 month. In addition, in vitro experiments using adipose tissue fragments derived from epididymal fat pads of adult mice incubated with or without melatonin (1 nM) administration were also conducted. The results showed that melatonin-supplemented mice had significantly higher plasma leptin levels than control mice. However, melatonin incubation did not cause any marked changes in the amount of leptin secreted from adipose tissue fragments. Our findings from this study indicate that melatonin does not affect leptin secretion via mouse adipose tissue. Nevertheless, melatonin could still influence leptinemia indirectly via regulatory effects in intact animals.

NMDA‐mediated release of glutamate and GABA in the subthalamic nucleus is mediated by dopamine: an in vivo microdialysis study in rats

The present study investigated the effects of N-methyl-D-aspartic acid.H2O (NMDA) on the dopamine, glutamate and GABA release in the subthalamic nucleus (STN) by using in vivo microdialysis in rats. NMDA (100 micromol/L) perfused through the microdialysis probe evoked an increase in extracellular dopamine in the STN of the intact rat of about 170%. This coincided with significant increases in both extracellular glutamate (350%) and GABA (250%). The effect of NMDA perfusion on neurotransmitter release at the level of the STN was completely abolished by co-perfusion of the selective NMDA-receptor antagonist MK-801 (10 micromol/L), whereas subthalamic perfusion of MK-801 alone had no effect on extracellular neurotransmitter concentrations. Furthermore, NMDA induced increases in glutamate were abolished by both SCH23390 (8 micromol/L), a selective D1 antagonist, and remoxipride (4 micromol/L), a selective D2 antagonist. The NMDA induced increase in GABA was abolished by remoxipride but not by SCH23390. Perfusion of the STN with SCH23390 or remoxipride alone had no effect on extracellular neurotransmitter concentrations. The observed effects in intact animals depend on the nigral dopaminergic innervation, as dopamine denervation, by means of 6-hydroxydopamine lesioning of the substantia nigra, clearly abolished the effects of NMDA on neurotransmitter release at the level of the STN. Our work points to a complex interaction between dopamine, glutamate and GABA with a crucial role for dopamine at the level of the STN.

Failure of $gamma;-hydroxybutyric acid both to increase neuroactive steroid concentrations in adrenalectomized?orchiectomized rats and to induce tolerance to its steroidogenic effect in intact animals

Failure of $gamma;-hydroxybutyric acid both to increase neuroactive steroid concentrations in adrenalectomized?orchiectomized rats and to induce tolerance to its steroidogenic effect in intact animals

Failure of γ-hydroxybutyric acid both to increase neuroactive steroid concentrations in adrenalectomized–orchiectomized rats and to induce tolerance to its steroidogenic effect in intact animals

γ-Hydroxybutyric acid (GHB), a drug proposed in the treatment of alcohol withdrawal syndrome, increases the cerebrocortical and plasma concentrations of the neuroactive steroids allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC). In the present study, we examined the role of hypothalamic–pituitary–adrenal (HPA) axis in the effect of GHB by measuring the concentrations of these steroids in the brain and plasma of adrenalectomized–orchiectomized (Adx–Orx) rats. The acute administration of GHB (500 mg/kg, i.p.) induced in 30 min an increase in the concentrations of allopregnanolone, THDOC and their precursors pregnenolone and progesterone in different brain areas (cerebral cortex, hypothalamus and cerebellum) and plasma of sham-operated rats but had no effect on the concentrations of these compounds in Adx–Orx rats, suggesting that activation of the HPA axis mediates the effect of GHB on brain and plasma concentrations of neuroactive steroids. Moreover, we evaluated whether repeated exposure of GHB induces tolerance to its steroidogenic effects. Chronic administration of GHB (500 mg/kg, i.p., twice a day for 10 days) to intact animals failed to affect the levels of progesterone, allopregnanolone, or THDOC measured 3 or 48 h after the last drug administration, whereas a challenge injection of GHB or ethanol was still able to increase the concentrations of these steroids in brain and plasma. These results indicate that repeated exposure to GHB fails to induce tolerance or cross-tolerance to the steroidogenic action of GHB or ethanol, respectively.

Vasodilation and Mechanoenergetic Inefficiency Dominates the Effect of the "Ca 2+ -sensitizer" MCI-154 in Intact Pigs

Objective : Ca 2+ -sensitizing agents hold potential as ideal cardiac inotropes, but effects in intact animals are scarcely described. We evaluated a pyridazinone derivative, MCI-154, for hemodynamic, inotropic, mechanoenergetic and oxidative metabolic effects. Design : Intracavitary left ventricular (LV) pressure and conductance (volume) was assessed in open chest anesthetized pigs ( n = 6). Contractile performance, pressure-volume area (PVA) and myocardial oxygen consumption (MVO 2 ) were assessed. Myocardial substrate uptake and production of 14 CO 2 (from glucose) and 3 H 2 O (from fatty acids) were monitored. MCI-154 administration: "low range": 0.1, 0.2, 0.3, 0.5 µ g/kg/min and "high range": 0.75, 1.0, 2.0, 3.0 µ g/kg/min. Parameters were compared with baseline and a time reference group ( n = 7). Results : MCI-154 induced a progressive dose-dependent decrease in systemic vascular resistance, with a concomitant increase in heart rate and cardiac output. Contractility increased only in the high-dose range, and mechanoenergetic efficiency was significantly reduced by drug infusion in all doses. Conclusion : The pyridazinone derivative MCI-154 has minimal inotropic action, induces a significant "oxygen waste", and decreases vascular resistance in intact pigs. A potent phosphodiesterase inhibitory effect may explain this, which suggests further drug refinement.

The yohimbine-induced anticonflict effect in the rat, Part I. Involvement of noradrenergic, serotonergic and endozepinergic(?) mechanisms.

The alpha 2-adrenoceptor antagonist yohimbine has in several previous studies been found to produce anticonflict effects comparable to those produced by the benzodiazepines (BDZ) in rat punished conflict models. In this and a following paper we have tried to elucidate the neurochemical mechanisms underlying these effects in a modified Vogel's drinking conflict test. Since yohimbine previously has been demonstrated to interfere both with noradrenaline (NA) and serotonin (5-HT) neurochemistry, and, in addition, shows affinity for the BDZ binding site, we have focused on the putative involvement of these neuronal systems in the yohimbine-induced anticonflict effect. The alpha 2-adrenoceptor agonist clonidine (10 micrograms/kg, i.p.) completely antagonized the anticonflict effect of yohimbine (4.0 mg/kg, i.p.), whereas the alpha 1-adrenoceptor agonist ST 587 (1.0 mg/kg, i.p.) had no effect. The anticonflict effect of yohimbine was totally abolished also following lesioning of NA neurons with 6-hydroxy-dopamine. A high dose of the mixed beta 1 and beta 2 adrenoceptor antagonist propranolol (8.0 mg/kg, i.p.) caused a partial blockade of the yohimbine-induced effect in intact animals, whereas the selective beta 1-adrenoceptor antagonist metoprolol (4.0 mg/kg, i.p.) had no significant effect and the alpha 1-adrenoceptor antagonist prazosin instead potentiated the anticonflict action. The anticonflict effect of yohimbine was dose-dependently antagonized also by the 5-HT precursor L-5-hydroxytryptophan (25-100 mg/kg, i.p.). The BDZ receptor antagonist flumazenil (10 mg/kg, p.o.), as well as Ro 15-4513 (1.0 mg/kg, p.o.), a partial inverse agonist at BDZ receptors, partly, but significantly, counteracted the yohimbine-induced anticonflict effect, whereas low doses of both the chloride channel blocker picrotoxin and the GABAA antagonist bicuculline only tended to counteract the yohimbine effect. Taken together, the results in the present behavioral paper indicate that the anticonflict effect of yohimbine involves both increased NA and decreased 5-HT activity, and that direct or indirect activation of BDZ receptors may also be involved. Neurochemical findings related to these behavioral results are presented in a following paper.

Hepatocyte Proliferation and Gene Expression Induced by Triiodothyronine In Vivo And In Vitro

Subcutaneous injections of hormone triiodothyronine in rats resulted in peak blood levels at 24 hr with return to baseline by 96 hr. The injections stimulated a liver regeneration response that resembled in timing and in magnitude of DNA synthesis (peak, 24 hr) that induced by 40% hepatic resection. The principal proliferation was of hepatocytes. Although there were some temporal differences from the gene expression of transforming growth factor-alpha, transforming growth factor-beta, and c-Ha-ras that are known to follow partial hepatectomy, the overall profile of these changes was similar to those after partial resection. The effect was liver specific and could be reproduced three times with no diminution in response in the same animal with injections at 10-day intervals. No response was detected in kidney or intestine. This effect in intact animals contrasted with the minimal ability of triiodothyronine to stimulate hepatocytes in culture. However, when the culture medium was enriched with epidermal growth factor, there was a dose-related response to triiodothyronine. The totality of these experiments provides a preliminary basis for the creation with pharmacological techniques of an in vivo hyperplastic hepatic condition permissive of transfection of new genes, as an alternative to partial hepatectomy. Although triiodothyronine was the test agent used, other hepatic growth factors singly or in combination could be candidates for this purpose.

Potentiation of ethanol via interference with calcium channels

The relevance of ethanol's ability to inhibit voltage-gated and receptor-gated calcium ion conductance in vitro to its acute effects in intact animals was examined. Specifically, nimodipine (a voltage-sensitive calcium antagonist of the dihydropyridine class), indole-2-carboxylic acid (a competitive antagonist of the strychnine-insensitive glycine binding site), MK-801 (a noncompetitive allosteric antagonist of the NMDA receptor complex), and d-cycloserine (a partial agonist of the strychnine-insensitive glycine binding site) were examined for their ability to alter ethanol's antiseizure efficact in an incremental electroconvulsive shock paradigm. The resulrs showed that drugs known to interfere with voltage-gated and receptor-gated calcium ion conductance potentiated ethanol's antiseizure efficacy. These results implicate voltage-gated and receptor-gated calcium ion conductance in ethanol's acute pharmacologic effects in intact animals.

Role of Vasopressin in Cardiovascular and Blood Pressure Regulation

At low concentrations and in physiologic states vasopressin is a potent antidiuretic hormone. Its cardiovascular effects have been more complex and their role in circulatory adjustments to hypovolemia and hypotension difficult to define with precision. Although recognized as a powerful vasoconstrictor, its pressor effect in intact animals, even at high concentrations, is minimal. The reasons for this blunted pressor response have been explored. This report is a review of previously published work from our laboratories which highlights the direct and indirect vasodilator actions of this hormone in animals and humans. The indirect vasodilator effect is caused by inhibition of sympathetic efferents, and facilitation of the baroreflex through a central action of the hormone and its sensitization of arterial baroreceptors as well as cardiac afferents.

Effects of the l isomer of fenfluramine on dopamine mechanisms in rat brain: further studies

Experiments were carried out to gain additional evidence that l-fenfluramine reduces the dopamine-mediated effects in intact animals. l-Fenfluramine 5 and 10 mg/kg i.p. dose dependently raised the levels of homovanillic acid in the striatum and nucleus accumbens of rats 1 h after injection. The effect of 5 mg/kg l-fenfluramine disappeared and was actually reversed 4 and 8 h after injection. The effect of 10 mg/kg l-fenfluramine, administered 48 h after the last haloperidol dose, was completely antagonized in both striatum and nucleus accumbens of animals made tolerant to the effect of haloperidol on homovanillic acid levels (through repeated treatment with 1 mg.kg haloperidol i.p. twice daily for 11 days). Unlike haloperidol (0.25 mg/kg), l-fenfluramine in various doses (2.5–20 mg/kg i.p.) did not modify the levels of striatal 3-methoxytyramine or change the decrease induced by a s.c. injection of 0.5 mg/kg apomorphine. The effect of apomorphine was not antagonized by 10 or 20 mg/kg l-norfenfluramine, an active metabolite of l-fenfluramine but 20 mg/kg l-norfenfluramine significantly raised striatal 3-methoxytyramine levels. l-Fenfluramine 20 mg/kg (but not 10 mg/kg) significantly enhanced the output of striatal acetylcholine assessed by trans-striatal microdialysis, for 60 min after injection. Apomorphine 1 mg/kg i.p. completely antagonized the increase of acetylcholine caused by 1 mg/kg haloperidol or 20 mg/kg l-fenfluramine. The results confirm that the 1 isomer of fenfluramine produces effects on the responses to dopamine and acetylcholine similar to those of neuroleptics by a mechanism not involving direct blockade of receptors.

Supersensitivity of presynaptic receptors involved in the dopaminergic control of striatal high affinity glutamate uptake after 6-hydroxydopamine lesion of nigrostriatal dopaminergic neurons.

The effects on striatal high affinity glutamate uptake (HAGU) of an apomorphine injection administered either alone or along with an electrical stimulation of the frontal cortex were compared between intact control rats and animals with 6-hydroxydopamine (6-OHDA) induced lesions of the nigrostriatal dopaminergic neurons. 6-OHDA injury was previously shown to have no effect either on basal HAGU or on the HAGU increase occurring in response to cortical stimulation. Apomorphine injected 1 h before HAGU determination at a dose of 5 mg/kg did not modify basal HAGU but totally abolished HAGU responsiveness to cortical stimulation applied 30 min after the apomorphine administration in both groups of animals. However, the duration of apomorphine induced inhibition of the cortically evoked striatal HAGU response in animals with 6-OHDA injury greatly exceeded that observed in intact rats. Indeed, in intact animals, cortical stimulation again became able to increase striatal HAGU when applied more than 6 h after apomorphine injection, while in 6-OHDA injected rats, HAGU responsiveness to cortical stimulation was restored only as from 7 days after apomorphine administration. Moreover, in rats given 6-OHDA injections apomorphine efficiently inhibited the activating effect of cortical stimulation on HAGU at doses at least 20 times lower than those required to obtain the same effect in intact animals. These results suggest that in both intact and 6-OHDA injected rats, apomorphine acts by counteracting the HAGU increase occurring in response to cortical stimulation and that the sites involved in this action develop a supersensitivity response to striatal dopaminergic deafferentation.(ABSTRACT TRUNCATED AT 250 WORDS)

Specific effects of thoracic vagotomy on the electrical activity of the gastric antrum and pylorus in rabbits.

The electrical activity of the antrum and the pylorus was recorded in rabbits, with chronically implanted electrodes. Effects of food intake were studied before and after bilateral vagotomy (b.v.), ventral vagotomy (v.v.) or dorsal vagotomy (d.v.) performed just above the diaphragm. In fasted animals, the electrical activity was characterized by bursts of potentials at a frequency of 1.93 +/- 0.09/min, initiated 45 mm or 20 mm from the pylorus in the greater and the lesser curvature respectively. The velocity of propagation of the bursts increased from 5-6 mm/s in the proximal antrum to 12-25 mm/s in the last 10 mm of the antrum along the greater curvature and from 2-4 mm/s to 5-15 mm/s along the lesser curvature. Feeding led to a rapid increase in the frequency of both antral and pyloric bursts up to 4.01 +/- 0.10/min, lasting 30-60 min after a large meal but only 15 min when the amount of food was restricted. The behaviour of the rabbits was not significantly affected by bilateral or ventral vagotomy. In contrast, dorsal vagotomy resulted in a drastic decrease of food intake. The mean frequency (fo) of bursts before meals was significantly reduced after vagotomy in v.v. animals (1.49 +/- 0.11/min, P less than 0.02) and in d.v. animals (1.34 +/- 0.08/min, P less than 0.001) but not in b.v. or sham-operated rabbits. For the first 3 d after surgery, the frequency (f) of bursts during the 30 min after the beginning of meals was significantly different from fo and reduced relative to f before nerve sections (1.9 +/- 0.11/min and 2.32 +/- 0.20/min respectively in b.v. and v.v. animals). In sham-operated animals, the value of f was closely similar to f before surgery. The effects of meals on the frequency of bursts were again similar to the effects in intact animals within 4-6 d for v.v. animals and 6-9 d for b.v. animals. In the pylorus, a different pattern for electrical activity, which consisted of trains of spikes at a frequency of 0.3/s, was superimposed on the bursts and was most marked in d.v. animals. The spiking activity was not affected by atropine, phentolamine or propranolol. The role of the vagus nerve in the motile responses of the antrum to food intake is discussed. These results indicate the existence of a non-cholinergic, non-adrenergic innervation of the pylorus which is involved in the opening of the sphincter and appears to be mediated by the dorsal vagal trunk.

Digitalis and the autonomic nervous system

Digitalis produces many of its effects in intact animals and human beings by modifying the properties of the autonomic nervous system. The parasympathetic limb of the autonomic nervous system is most sensitive to these effects of digitalis, and its properties are significantly altered with therapeutic concentrations of the drug. These actions are particularly important in mediating the electrophysiologic effects of digitalis. With toxic concentrations of digitalis, stimulation of sympathetic nerve activity may also occur. This latter action may be involved in the arrhythmogenic effects of digitalis. These effects of digitalis on the autonomic nervous system play a major role in determining the pharmacodynamic actions of the drug in patients. The effects of digitalis on the autonomic nervous system also provide a setting for important interactions with other drugs that modify the properties of the sympathetic and parasympathetic nervous systems.

Antigonadal Actions of Olfactory and Light Deprivation. II. Effects of Pinealectomy or Melatonin Injections in Olfactory Bulb Deafferented or Bulbectomized Male Rats

Since olfactory bulb deafferentation (peripheral anosmia) potentiates the antigonadal effects of light deprivation, we studied a) the pineal involvement in this action and b) whether peripheral anosmia might increase the response to melatonin injections. Four-week-old male rats were used in two experimental series. The first included rats in which blindness + peripheral anosmia was associated with either pinealectomy or sham pinealectomy. In the second series, intact, olfactory bulb deafferented and bulbectomized rats received daily injections of either melatonin (50 micrograms) or the vehicle alone. In both experiments animals were killed at 10 weeks of age. The reduction in the weight of accessory sexual glands and prostates, as well as in the serum testosterone levels, induced by blindness + peripheral anosmia was fully prevented by pinealectomy, whereas body and pituitary weight reduction induced by the dual sensory deprivation were only partially prevented. Melatonin produced no effects in intact animals whereas in rats with either peripheral anosmia or bulbectomy it reduced the weight of body, accessory sexual glands, and prostates. Serum testosterone levels were not modified in any case with melatonin treatment.

Brain stem tonic inhibition of thermoregulation in the rat

It was shown, by selective levels of decerebration, that a drop in body temperature occurred in a midpontine rat due to impairment in thermoregulatory responses. Lowering the level of decerebration to the lower pons restored a coordinated thermoregulatory response. The response was inadequate to raise the core temperature to normal level, but it was nevertheless an integrated response of vasoconstriction, piloerection, and shivering and was appropriately turned off by warming the skin or core. In intact unanesthetized rats, microinjection of a local anesthetic in the pontine tegmentum resulted in thermoregulatory responses, such as curling of the body, piloerection, tremor in facial muscles, and shivering. Similar injections in the pontine tegmentum of the midpontine decerebrate rat also restored some heat gain responses, including shivering. These experiments suggest that in rats the heat gain responses are powerfully regulated by a tonic inhibitory mechanism located in the midbrain and upper pons that exerts a complete inhibitory effect on the thermoregulatory areas caudal to the midbrain in decerebrate rats and a partial inhibitory effect in intact animals. These experiments also confirm the previous observation in the cat of the presence of a facilitatory area(s) in lower levels of the central nervous system which is responsible for coordinated heat gain responses observed in low-level decerebrate animals. In addition, these experiments suggest that the brain stem thermoregulatory mechanisms are in fact functioning in intact unanesthetized animals.

Mineralocorticoid modulation of prolactin effect on renal solute excretion in the rat.

The effects of ovine PRL (oPRL) on renal solute and water handling were examined in 1) intact, 2) salt-loaded (6 meq NaCl ip X 8 days), 3) adrenalectomized (adx), 4) adx plus corticosterone-treated (133 micrograms/100 g BW im), and 5) adx plus dexamethasone-treated (10 micrograms/100 g BW im) male rats. After 7 days treatment rats received a water load (3% BW ip) before a 4-h urine collection. Rats also received 0.9% NaCl im (controls) or 1.0 mg oPRL on days 4-7. Treatments were continued to day 8 for inulin clearance determination. The effects of arginine vasopressin (AVP) (173 microU im, days 4-7) on renal solute and water excretion were also examined in salt-loaded rats to see if renal effects of oPRL treatment were due to AVP contamination of the oPRL preparation. In intact rats drinking tap water, oPRL decreased sodium clearance (CNa) and potassium clearance (CK) (P less than 0.05) vs. controls, with no change in free water clearance (CH2O). In intact rats receiving 1.0% NaCl and 1.0% glucose as a replacement for drinking water, oPRL decreased CNa (P less than 0.05) and increased CK (P less than 0.05) vs. controls, with no change in osmolar clearance or CH2O. In salt-loaded rats oPRL increased CNa and CK (P less than 0.05) vs. controls, with no change in CH2O. AVP administration to salt-loaded rats, however, had no effect on CNa and decreased CK vs. controls. oPRL increased CK (P less than 0.05) in adx rats, with no effect on CNa. In adx plus corticosterone-treated rats oPRL decreased CNa and CK (P less than 0.005), similar to its effect in intact animals. oPRL had no effect on renal solute or water excretion as compared to control animals in dexamethasone-treated adx rats. oPRL did not alter glomerular filtration rate at any time. These data suggest that 1) oPRL requires the presence of mineralocorticoids for an effect on sodium, but not potassium, excretion, 2) elevated sodium intake reverses the effect of oPRL on potassium excretion, 3) oPRL potentiates the effects of corticosterone on sodium reabsorption, and 4) glucocorticoids may block the effects of oPRL on the kidney.

The involvement of opiate and monoaminergic neuronal systems in the analgesic effects of ketamine

The anesthetic agent, ketamine, has the potential to recruit spinopetal noradrenergic and serotonergic neuronal pathways for its antinociceptive effect. Neurochemically, ketamine has been shown to interact with opiate receptors and thus may increase neuronal activity in the spinopetal monoaminergic (norepinephrine and serotonin) systems in a manner similar to morphine. In addition, ketamine should facilitate the antinociceptive effect of the monoamines at the level of the spinal cord by an action of the drug to prevent the neuronal reuptake of the monoamines. In this study, the analgesic action of both ketamine and morphine, as measured by the tail-flick test in rats, was inhibited by norepinephrine, serotonin and opiate receptor antagonists. Monoaminergic receptor inhibitors were more potent as antagonists of ketamine's analgesia while the opiate receptor antagonist naloxone was more effective against morphine analgesia. The greater sensitivity of the antinociceptive effect of ketamine to monoaminergic antagonist may reflect the importance of the inhibition of norepinephrine and serotonin reuptake in the analgesic action of the drug. Transecting the spinal cord of rats at T4-6 revealed distinct differences between the analgesic mechanisms of ketamine and morphine. For example, the potency of ketamine was increased nearly 9-fold in spinal rats whereas morphine's potency was decreased. This observation suggests that ketamine may activate both analgesic and antanalgesic systems supraspinally, and that its antinociceptive effect in intact animals is a summation of these opposing actions. Partial evidence that supraspinal noradrenergic neurons might be involved in the antanalgesic component of ketamine's action was provided by experiments demonstrating enhanced analgesia in intact animals after depletion of norepinephrine with FLA-63. In spinal animals a significant difference was also observed in the neuronal processes mediating the residual analgesic effects of morphine and ketamine. The analgesic effect of morphine remained primarily sensitive to naloxone but seemed to use a local serotonergic process (sensitive to the serotonergic antagonist methysergide) at higher doses of the opiate. Ketamine's analgesia, on the other hand, was only inhibited by methysergide. In conclusion, although it appears that morphine and ketamine may both activate spinopetal monoaminergic processes through an opiate mechanism, the two drugs differ significantly with regard to some of the components of their antinociceptive actions. The differences may be related to ketamine's ability to alter the metabolism of monoaminergic neurotransmitters involved in pain processing.

A comparative study of the role of vasopressin and ACTH in the regulation of growth and function of rat adrenal glands

The regulation of the function of adrenal zona glomerulosa appears to be under the control of several factors, ACTH being an important one among them. Recent studies using crude posterior pituitary extract and purified vasopressin have shown that these preparations cause significant stimulation of mitotic activity of female rat adrenal zona glomerulosa. The mitogenic activity is very evident with the hypophysectomized animal model in which 2 days of treatment with vasopressin causes almost complete restoration of mitotic activity while ACTH is only weakly effective. Vasopressin also increases the plasma aldosterone in the normal animal in a manner comparable to ACTH in terms of dose response and time course for short-term treatment. In long-term treatment vasopressin also increased the plasma aldosterone while ACTH did not cause a significant change. A similar pattern was observed for plasma corticosterone. The lack of increment of plasma aldosterone to vasopressin in hypophysectomized animals indicates that the observed in vivo steroidogenic effect in intact animals is probably mediated through other factors.