Biomedical subjects

N E Rowland

Publications and source records attributed to N E Rowland.

At least 73 records · Page 4Linked to original sources

PubMed1995

Increased dipsogenic responsiveness to angiotensin II in rats exposed to cold: rate of loss after return to thermoneutral ambient temperature.

Subcutaneous administration of angiotensin II (Ang II) to rats exposed chronically to 5 degrees C induced an increased drinking response compared with that of warm-acclimated controls. The exaggerated drinking response was also observed when graded doses of Ang II were administered into the lateral cerebroventricle (icv) of chronically cold-exposed rats. A maximal drinking response occurred in cold-treated, but not in control, rats when the lowest dose of Ang II (1.6 ng/rat) was administered icv. Thus, it is clear that the dipsogenic responsiveness to either centrally or peripherally administered Ang II is increased by chronic exposure to cold. To assess whether the increased responsiveness was retained after removal from cold, graded doses of Ang II were administered to rats removed from cold to a thermoneutral environment. The results again showed a maximal responsiveness to the lowest dose of Ang II administered (25 micrograms/kg, sc) to cold-treated rats that had either just been removed from cold or removed from cold 2 hr prior to treatment. Cold-exposed rats had an ED50 for Ang II-induced drinking that was about half that of their warm-acclimated controls. To assess how long the cold-induced increase in dipsogenic responsiveness to Ang II lasted after return to a thermoneutral temperature, rats were removed from cold for 24, 48, or 60 hr and then administered graded doses of Ang II (25, 50, or 100 micrograms/kg, sc). The results suggest that between 46 and 52 hr after removal from cold, the cold-induced increase in dipsogenic responsiveness to Ang II returned to the level of the controls. Hence, the physiological changes in the dipsogenic mechanism induced by exposure to cold are not immediately reversible when the rats are returned to a thermoneutral ambient temperature.

Angiotensin II↗

PubMed1994

c-fos expression in the rat brain following central administration of neuropeptide Y and effects of food consumption.

Administration of neuropeptide Y (NPY) intracerebroventricularly (i.c.v.) results in the release of a number of hypothalamic and pituitary hormones and stimulation of feeding and suppression of sexual behavior. In this study, we sought to identify cellular sites of NPY action by evaluating perikaryal Fos-like immunoreactivity (FLI), a marker of cellular activation, in those hypothalamic and extrahypothalamic sites previously implicated in the control of neuroendocrine function and feeding behavior. Additionally, we compared the topography of FLI in these brain sites when food was either available ad libitum or withheld after NPY injection (1 nmol/3 microliters, i.c.v.). The results showed that one hour after NPY injection a larger number of cells in the parvocellular region of the paraventricular nucleus (PVN) were FLI-positive in the absence of food consumption. However, in association with food intake, a significant number of cells were intensely stained in the magnocellular region of the PVN. An analogous increase in FLI in association with feeding was apparent in the supraoptic nucleus (SON), the dorsomedial nucleus and the bed nucleus of the stria terminalis in the hypothalamus. Among the extrahypothalamic sites, feeding facilitated FLI in a large number of cells located in the lateral subdivision of the central amygdaloid nucleus and the lateral subdivision of the solitary tract. FLI was observed in a moderate number of cells in the hypothalamic arcuate nucleus (ARC) and ventromedial nucleus, and this response was not changed by feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Involvement of angiotensin in water intake induced by peripheral administration of a serotonin agonist, 5-carboxyamidotryptamine.

Rats were given peripheral injections of a 5HT1 agonist, 5-carboxy-amidotryptamine (5-CT), and various behavioral, physiological, and neuronal outcomes were documented. 5-CT caused short latency water intake. In rats with a choice between water and hypertonic NaCl, about half of the rats drank only water while the other half showed an initial robust intake of NaCl. Blood pressure was reduced and plasma renin activity increased following 5-CT. The effective half life was 1-3 h, with water intake inhibiting further consumption. Fos-like immunoreactivity (FLI) was induced by 5-CT in regions of the brain identical to those previously shown to be activated by peripheral administration of angiotensin (Ang) II. The role of endogenously-generated Ang II in the dipsogenic action of 5-CT was suggested because captopril inhibited the water intake. Possible mechanisms of 5-CT and Ang II-induced thirst are reviewed, including roles of hypotension and the vagus nerve.

Analysis of Variance↗

PubMed1994

Action of angiotensin converting enzyme inhibitors in rat brain: interaction with isoproterenol assessed by Fos immunocytochemistry.

Low and high doses of angiotensin converting enzyme (ACE) inhibitors have been shown either to enhance or suppress, respectively, the water intake of rats induced by acute administration of isoproterenol. In order to assess the role and sites of action of angiotensin II (Ang II) in this dual action of ACE inhibitors, rats were administered either low or high doses of enalapril or captopril, followed by isoproterenol, and were sacrificed 1 h later for determination of Fos-like immunoreactivity (FLI) in brain. Isoproterenol induced strong FLI in the magnocellular paraventricular (PVN) and supraoptic (SON) nuclei, and moderate staining along the structures of the rostral wall of the lamina terminalis (LT). Low doses of ACE inhibitors either had no effect or slightly increased FLI along the LT following isoproterenol. Enalapril reduced FLI in some other regions, including the parvocellular PVN. In contrast, high doses of ACE inhibitors abolished FLI along the LT, and reduced FLI in the PVN and SON. Captopril, but not enalapril, induced some FLI in the LT, SON and PVN. The data are discussed in terms of access of ACE inhibitors to the brain, and interactions with structures involved in Ang-related water intake.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Reversal of dexfenfluramine-induced anorexia and c-Fos/c-Jun expression by lesion in the lateral parabrachial nucleus.

The external subdivision of the lateral parabrachial nucleus (LPBE) shows strong Fos-like immunoreactivity (FLI) following anorectic doses of the indirect serotonin agonist dexfenfluramine (DFEN). In an effort to determine the contribution of the LPBE to DFEN-induced anorexia, bilateral ibotenate lesions were made in the LPBE, and the effects of the lesion on DFEN-induced anorexia and FLI as well as c-Jun-like immunoreactivity (JLI) were examined. It was found that LPBE lesion significantly attenuated DFEN anorexia: in a 1-h food intake test following 24-h food deprivation, DFEN (2 mg/kg) suppressed food intake by 60% in intact rats but only 34% in rats with LPBE lesions. In addition to this behavioral change, LPBE lesion completely abolished DFEN-induced FLI and JLI in the lateral subdivision of the central nucleus of the amygdala (CeL) and laterodorsal subdivision of the bed nucleus of stria terminalis (BSTLD), both of which showed strong FLI and JLI in intact rats. DFEN-induced FLI and JLI in other brain regions were not affected by LPBE lesion, including the ventromedial and lateral hypothalamus, caudate-putamen, and the nucleus of the solitary tract (NST). The parallel loss of DFEN-induced anorexia and FLI/JLI following LPBE lesion raises the novel possibility that LPBE-CeL/BSTLD pathway may be involved in DFEN anorexia.

Animals↗

PubMed1994

Cholecystokinin- and dexfenfluramine-induced anorexia compared using devazepide and c-fos expression in the rat brain.

It has been proposed that there might be a link between the anorectic actions of cholecystokinin (CCK) and serotonin (5HT). The present study compared the patterns of c-fos protein-like immunoreactivity (FLI) induced in rat brain by CCK and the indirect 5HT agonist dexfenfluramine (DFEN), as well as the ability for devazepide, a CCK-A receptor antagonist, to antagonize both anorexia and FLI induced by these agents. Devazepide reversed the anorectic effect of CCK but not that of DFEN in food deprived rats. The FLI induced by CCK and DFEN occurred in similar brain regions, but in different subdivisions. Such regions included the bed nucleus of the stria terminalis (BST), the lateral central nucleus of the amygdala (CeL), and the lateral parabrachial nucleus (LPB). Devazepide abolished the FLI induced by CCK in most of these brain regions, but had no effect on FLI induced by DFEN. These results suggest that the LPB-CeL/BST pathway might be responsible for the anorectic effects of both CCK and DFEN, but different parts or neuronal populations in these structures might be differentially engaged by CCK and DFEN. The putative interaction between CCK and 5HT might happen along this pathway, rather than in the periphery.

Animals↗

PubMed1994

Tolerance to the anorectic effect of dexfenfluramine in rats: role of serotonin, cholecystokinin, and neuropeptide Y.

Tolerance to the anorectic effect of dexfenfluramine (DFEN) is shown in rats treated either chronically with low doses or once with a high dose of the agent. Rats given DFEN regimens that result in complete loss of DFEN anorexia showed no change in the anorexia caused by peripheral injection of cholecystokinin (CCK). The orexigenic effects of metergoline and neuropeptide Y were also unaltered as a function of DFEN pretreatment. Both the magnitude and duration of tolerance to a test dose of DFEN seemed to depend, in part, upon contingent (situational) factors, and were independent of whether brain serotonin (5-HT) measures were either unaffected or decreased by the DFEN pretreatment (low and high doses, respectively).

Animals↗

PubMed1994

Effect of desalivation on water and sodium chloride intake in rats.

Desalivate rats consumed significantly less water than sham-operated rats in response to acute challenges with a variety of dipsogens, including polyethylene glycol (PEG), isoproterenol, serotonin, and an angiotensin I converting enzyme inhibitor (CEI). Nonsignificant reductions were recorded after treatments with either angiotensin II or hypertonic NaCl. Meal-related hyperdipsia, and resultant possible hyperhydration, of desalivate rats does not account fully for these reductions in experimental thirsts. The mean 24-h intake of three concentrations of NaCl, in choice with water, showed no difference in the preferences for NaCl of desalivate and sham-operated animals. During chronic administration of CEIs, both desalivate and sham-operated rats showed comparable induction of NaCl appetite.

Angiotensin II↗

PubMed1994

Long-term administration of dexfenfluramine to genetically obese (ob/ob) and lean mice: body weight and brain serotonin changes.

The weight-reducing and brain 5-HT-depleting properties of dexfenfluramine (DFEN) or dexnorfenfluramine (DNOR) were measured in genetically obese (ob/ob) and lean mice. These agents were infused for 14 days via osmotic minipumps to mice fed either a low fat or a moderate fat diet. Weight loss was observed in only the obese mice, with DNOR more potent than DFEN. At the end of 14 days, neither agent caused a consistent change in either plasma glucose or corticosterone concentrations, although some effects of diet and differences between batches of mice were apparent. The levels of brain 5-HT, or of paroxetine binding that correlates with 5-HT level, were reduced by 24 mg DFEN/kg/day, a decline that persisted for at least 14 days after the end of treatment. Plasma and brain concentrations of DFEN and DNOR were measured on the last day of pump function. DNOR accounted for about 30% of the total drug + metabolite content, a ratio comparable to that in human plasma. Brain concentrations exceeded plasma by 10-fold at 6 mg DFEN/kg/day and by 17-fold at 24 mg DFEN/kg/day. The levels were higher in mice fed the moderate-fat compared with the low-fat diet. Depletions in brain 5-HT parameters were found only in the high-dose groups, and at brain total levels above about 20 microM.

Animals↗

PubMed1994

Localization of changes in immediate early genes in brain in relation to hydromineral balance: intravenous angiotensin II.

Immediate early genes, detected by Fos- and Jun-like immunoreactivity (FLI, JLI), were induced in discrete regions of the rat brain by intravenous infusion of angiotensin II (Ang II) at dipsogenic doses. The regions included subfornical organ (SFO), organum vasculosum laminae terminalis (OVLT), median preoptic nucleus (MnPO), supraoptic nucleus (SON), and the magnocellular part of the paraventricular hypothalamus (PVH). These responses were sustained for up to 6 h of infusion. In SFO, FLI was induced preferentially in the posterior part, while JLI occurred in more central regions. Cerebroventricular (ICV) injection of the Ang II type 1 receptor (AT-1) antagonist, losartan potassium, completely prevented the FLI induced by Ang II in these brain regions. ICV injection of the Ang II type 2 receptor (AT-2) antagonist, PD 123319, did not reduce Ang II-induced FLI in SFO, OVLT and MnPO, but markedly attenuated the activation in SON and PVH. To determine whether SFO is the primary site for transduction of the circulating Ang II signal, electrolytic lesions were made in or rostral to the SFO. Rats with complete lesions showed a complete absence of Ang-induced FLI in SON and PVH. The data are discussed in terms of functional mapping of the brain regions activated by circulating Ang II and neural circuitry for water intake, including the possible role of AT-2 receptors in PVH and SON.

Angiotensin II↗

PubMed1994

Comparison of fos-like immunoreactivity induced in rat brain by central injection of angiotensin II and carbachol.

Rats were given intracerebroventricular injections of either angiotensin II (ANG II) or the cholinomimetic carbachol. Some rats received cotreatment with ANG II antagonists selective for either angiotensin receptor AT1 (losartan) or AT2 (PD-123319, CGP-42112A). One hour later, the rats were killed and the brains processed for immunocytochemical detection of Fos-like immunoreactivity (FLI). ANG II treatment induced strong FLI in the anterior subfornical organ (SFO), median preoptic nucleus (MnPO), organum vasculosum laminae terminalis (OVLT), and supraoptic and paraventricular hypothalamic nuclei (SON, PVH). The AT1 antagonist abolished FLI in all regions normally stimulated by ANG II. The AT2 antagonist PD-123319 reduced FLI in SON and PVH, but CGP-42112A was less effective. Carbachol induced strong FLI in SON, PVH, and MnPO and only moderate FLI in SFO and OVLT. The AT1 antagonist prevented carbachol-induced FLI in the MnPO only. The distributions of FLI are compared between these central dipsogens and with that previously reported after peripheral infusion of ANG II, and their implications for mapping central thirst pathways are discussed.

Angiotensin II↗

PubMed1993

Loss of serotonin uptake sites and immunoreactivity in rat cortex after dexfenfluramine occur without parallel glial cell reactions.

The frontal cortices of rats which received either D,L- or D-fenfluramine (DFEN) for 4 days were examined 18 h to 2 weeks following treatment for changes in synaptosomal uptake of serotonin (5HT), paroxetine binding, 5HT-immunoreactivity (5HT-IR), and both astrocytic (GFAP) and microglial markers. Additional rats received intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT). Consistent with previous reports, D,L- and DFEN produced dose-dependent losses of both 5HT uptake and paroxetine binding, and loss of 5HT-IR which coincided with an abnormal or 'swollen' appearance of immunoreactive axon processes. Recovery of these serotonergic indices was greatest following the lowest doses of DFEN, but was absent after 5,7-DHT treatment. No evidence for an increase in GFAP synthesis or microglial activation was observed in frontal cortices of rats treated with either DFEN or 5,7-DHT. We conclude that the presence of swollen 5HT-IR axons in the cortices of both the 5,7-DHT and DFEN groups is insufficient to trigger the glial responses often associated with neuronal degeneration. Thus, it remains to be determined if swollen 5HT-IR axons are a prelude to neurodegeneration, or whether they represent reversible changes in axonal immunochemistry associated with decreases in 5HT levels. The implications of the data for the clinical safety of DFEN are briefly discussed.

Administration, Oral↗

PubMed1993

Increased feeding after treatment with fructose, but not glucose, antimetabolites in rats with dopamine-depleting brain lesions.

Rats were given dopamine-depleting lesions either as adults or as neonates. Compared with intact controls, lesioned rats failed to increase their food intake after acute administration of the glucoprivic agent, 2-deoxy-D-glucose. In contrast, both lesioned and control rats increased food intake after acute treatment with a peripherally-acting fructose antimetabolite, 2,5-anhydro-D-mannitol. These data suggest that the failure of lesioned rats to respond behaviorally to glucoprivation is related to inhibition of glycolysis in the brain, rather than the acute nature of the metabolic challenge.

Animals↗

PubMed1993

Adrenalectomy enhances the anorectic effect of dexfenfluramine: relation to mineralocorticoids and salt appetite.

A previous observation that adrenalectomized (ADX) rats were more anorectic and lost more weight than intact controls when treated with the serotonergic agent, d,l-fenfluramine, was confirmed using a high dose of the more selective d-enantiomer, dexfenfluramine (DFEN). However, ADX rats were not more anorectic than intact controls to a lower dose of DFEN. The extreme weight loss at high doses was accompanied by a loss of appetite for NaCl solution. The rapid deterioration of these animals may have been due to excessive loss of sodium ions and extracellular fluid volume, although this was not assessed directly. This interpretation was supported in a second study in which treatment of ADX rats with a selective mineralocorticoid, which eliminates both the need and appetite for NaCl, normalized weight loss during DFEN treatment. These data do not support the idea of an interactive role of glucocorticoids and brain serotonin in anorexia. The density of serotonin uptake sites in frontal cortex was reduced by DFEN in a dose-dependent manner, but did not differ between ADX and intact control groups.

Adrenal Glands↗

PubMed1993

Effect of nonpeptide angiotensin AT-1 and AT-2 antagonists on isoproterenol-induced renin release.

The AT-1 receptor antagonist, losartan potassium, produced a large rise in plasma renin activity (PRA) after peripheral, but not intracerebroventricular (ICV), administration. Peripheral, but not ICV administration of losartan also augmented the release of renin induced by peripheral administration of the beta-adrenergic agonist, isoproterenol. The increase in PRA induced by losartan plus isoproterenol was greater than the sum of the increases in PRA induced by the individual treatments. There was, however, no significant enhancement of the hypotensive action of isoproterenol by peripherally administered losartan. The AT-2 receptor antagonist, PD 123319, produced no increase in PRA after either peripheral or ICV injection. However, peripheral injection of PD 123319 slightly increased PRA after peripheral administration of isoproterenol. The data are discussed in terms of the relationship between renin-angiotensin systems and fluid intake, with special reference to the failure of peripherally administered losartan to block isoproterenol-induced water intake.

Angiotensin I↗

PubMed1993

Induction of hyperhydration in rats by IP loading with graded concentrations of NaCl solution.

IP loads of NaCl solution (1% of body weight) varying in concentration from 0.15-1.0 M were used to assess their ability to induce hyperhydration in rats that were allowed access to water for 6 h after loading. The hypertonic concentrations (0.25, 0.50, and 1.0 M) increased water intake in a concentration-related fashion. Only loads of 0.50 and 1.0 M NaCl solution increased urine output above that of water-loaded controls. All hypertonic concentrations increased fluid exchange (i.e., water intake less urine output) significantly. There was a direct concentration-related increase in accumulative mean fluid exchange (delta FE, fluid exchange of NaCl-loaded group less that of control group). There was also a direct concentration-related increase in the time of hyperhydration. When related to each other, delta FE was a direct linear function of time of hyperhydration. The slope and intercept of this relationship were compared with those found in an earlier study for angiotensin II (AngII) and isoproterenol (ISO), both potent dipsogens. Comparison revealed that slopes, but not intercepts, of the relationship between delta FE and time of hyperhydration for any two of the three treatments differed significantly. These data suggest that a given time of hyperhydration can be achieved at a lower delta FE with NaCl loads than with administration of either AngII or ISO. This suggests, in turn, that loading with NaCl solutions produces a more effective hyperhydration than is achieved with administration of either AngII or ISO.

Angiotensin II↗

PubMed1993

Dexfenfluramine induces Fos-like immunoreactivity in discrete brain regions in rats.

Administration of the anorectic agent, dexfenfluramine (DFEN) to rats induced dose- and time-dependent expression of Fos-like immunoreactivity in several discrete brain regions of rats. At moderate doses, the regions showing the most intense Fos immunostaining included the bed nucleus of the stria terminalis, the lateral part of the central amygdala, midline thalamic nuclei, habenular nuclei, lateral parabrachial nucleus, and nucleus of the solitary tract. It is suggested that these nuclei, many of which are known to receive gustatory or visceral input, may form part of a functional circuit via which DFEN modulates food intake. Rats that were made hungry by either food deprivation or administration of insulin also showed induction of Fos in several brain regions, but only that in the supramamillary/ventral tegmental area was suppressed by pretreatment with an anorectic dose of DFEN. The functional significance of these sites requires further investigation.

Animals↗

PubMed1993

Brain angiotensin AT-2 receptor antagonism and water intake.

Intracerebroventricular administration of the angiotensin AT-2 receptor antagonist, PD 123319, inhibited drinking induced in rats by hypertonic NaCl, carbachol, isoproterenol, hypovolemia, and water deprivation, but had no effect on food intake. In contrast, the AT-1 antagonist, losartan potassium, had no effect on these intakes. A model of thirst is presented that incorporates an AT-2 receptor in a final common pathway for drinking.

Angiotensin Receptor Antagonists↗