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1.
Am J Physiol ; 267(6 Pt 1): E921-6, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7810635

ABSTRACT

We report here that with a direct method for measurement of cardiovascular parameters in conscious rats, intracerebroventricular administration of the mineralocorticoid receptor (MR) antagonist RU-28318 (100 ng) reduces the blood pressure, heart rate, and the corticosterone response to a brief restraint stress, provided the rats were previously subjected to a daily 30-min exposure to 32 degrees C for 2 wk. The daily exposure to warming and restraint stress are applied identically to the training procedure required for indirect blood pressure measurement using the tail-cuff method. The basal arterial pressure is not affected by the MR antagonist. The effect of the MR antagonist on the stress-induced pressor response develops with a delay of several hours in the normotensive rats. The corticosterone response to daily warming and stress is also attenuated by the intracerebroventricular infusion of MR antagonist but with shorter onset and shorter duration. The findings suggest that conditioning to daily warming and stress imposes mineralocorticoid dependency of the pressor response, which involves MR functioning in brain.


Subject(s)
Blood Pressure/drug effects , Mineralocorticoid Receptor Antagonists/pharmacology , Spironolactone/analogs & derivatives , Stress, Physiological/physiopathology , Adrenocorticotropic Hormone/blood , Aldosterone/blood , Animals , Corticosterone/blood , Heart Rate/drug effects , Hot Temperature , Male , Rats , Rats, Wistar , Spironolactone/pharmacology
2.
Am J Physiol ; 267(6 Pt 1): E927-33, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7810636

ABSTRACT

The role of brain mineralocorticoid receptor (MR) sites in the pathogenesis of mineralocorticoid hypertension was studied after an intracerebroventricular injection of the MR antagonist RU-28318. Male Wistar rats received subcutaneously implanted deoxycorticosterone acetate (DOCA) pellets and were maintained on 0.9% saline as drinking solution. Under these conditions hypertension developed in approximately 5 wk as assessed in conscious rats by means of the tail-cuff technique. During the development of this hypertension (after 3 wk of DOCA-salt treatment) a single intracerebroventricular injection of the specific MR antagonist RU-28318 reduced systolic blood pressure (SBP) as measured with the tail-cuff method. A decrease in SBP was observed 2-24 h after this intracerebroventricular injection, with the lowest SBP values occurring at 8 h. In these animals (3 wk after DOCA implantation) continuous direct blood pressure recording via chronic cannulation revealed, on the day of the intracerebroventricular injection of RU-28318, a slight increase in arterial pressure during the light phase, followed by a decrease during the dark phase. In the established hypertensive rats (5 wk after DOCA RU-28318 on the arterial pressure or heart rate was detectable. It is concluded that central MR blockade during the development of the DOCA-salt hypertension reduces blood pressure within 24 h assessed with 1) the indirect method at certain time points after exposure to warming and stress and 2) the direct method during the dark phase of the diurnal cycle.


Subject(s)
Blood Pressure/drug effects , Brain/drug effects , Hypertension/physiopathology , Mineralocorticoid Receptor Antagonists/pharmacology , Spironolactone/analogs & derivatives , Animals , Desoxycorticosterone , Heart Rate/drug effects , Male , Rats , Rats, Wistar , Receptors, Mineralocorticoid/physiology , Sodium Chloride , Spironolactone/pharmacology
4.
J Steroid Biochem Mol Biol ; 47(1-6): 183-90, 1993 Dec.
Article in English | MEDLINE | ID: mdl-8274434

ABSTRACT

Mineralocorticoid receptors (MRs) in neurons of the anterior hypothalamus and the periventricular brain regions mediate aldosterone-selective actions on sodium homeostasis, salt appetite and cardiovascular regulation. Corticosterone is not effective in these neurons, possibly because it is enzymatically inactivated. However, MRs in limbic brain regions, notably in the hippocampal neurons, do already respond to very low concentrations of both corticosterone and aldosterone. The MR-mediated effects stabilize neuronal transmission and appear critical for neuronal integrity of a sub-region of the hippocampus: the dentate gyrus. Higher concentrations of corticosterone induced by stress and the circadian rise progressively activate the lower affinity glucocorticoid receptors (GRs), which in coordination with MR-mediated actions then facilitate adaptive processes required for recovery of homeostasis. It is postulated that this balanced MR- and GR-mediated action of corticosterone is of critical importance for regulation of the stress response and behavioural adaptation.


Subject(s)
Brain/physiology , Receptors, Mineralocorticoid/physiology , Aldosterone/pharmacology , Aldosterone/physiology , Animals , Behavior, Animal/physiology , Hippocampus/physiology , Homeostasis , Neurons/physiology , Raphe Nuclei/physiology , Sodium/metabolism
5.
Endocr Regul ; 26(3): 111-8, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1339189

ABSTRACT

The action of corticosteroids in the central nervous system (CNS) is mediated by two distinct corticosteroid receptors: the mineralocorticoid and glucocorticoid receptors (MR and GR respectively). Using an established in vitro binding assay system, MR and GR binding parameters were determined in the hippocampal, hypothalamic and pituitary cytosol of various rat models. In the (pharmaco-)genetically selected rat lines, the apomorphine susceptible (APO-SUS) rats showed a significant increase in the hippocampal and pituitary MR binding capacities (but not affinity) compared to those in the apomorphine-unsusceptible (APO-UNSUS) rats. In immunologically-altered Lewis (LEW/N) rats and in spontaneously hypertensive rats (SHR), increased hippocampal MR capacity (but not affinity) and hypothalamic MR capacity were observed compared to their respective control, Wistar (WIST) and Wistar Kyoto (WKY) rats. In addition, compared to WKY rats, SHR rats also showed a much greater pituitary but lesser hypothalamic GR binding capacity. In rats subjected to alteration in environmental conditions, the long-term effects of a short inescapable stress resulted in a significant increase in both hippocampal MR and GR while the pituitary and hypothalamic MR and GR do not differ in the stress and control groups. In rats subjected to a defeat test, a decrease in hippocampal MR and GR was observed 3 weeks (but not 1 week) later.


Subject(s)
Hippocampus/metabolism , Hypothalamus/metabolism , Pituitary Gland/metabolism , Receptors, Glucocorticoid/metabolism , Receptors, Steroid/metabolism , Animals , Apomorphine/pharmacology , Male , Rats , Rats, Inbred Lew , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Wistar , Receptors, Mineralocorticoid
6.
Eur J Pharmacol ; 205(2): 183-9, 1991 Nov 26.
Article in English | MEDLINE | ID: mdl-1812008

ABSTRACT

Evidence indicates that endogenous opioid peptides and glucocorticoids participate in the control of cardiovascular regulation during hemorrhagic shock. In the present study, we investigated a possible interaction between brain opioid peptides and adrenal corticosteroids regarding the control of arterial pressure during hemorrhage. The bleeding volumes required to lower arterial pressure to 80, 60 and 40 mmHg were studied in anesthetized sham-operated (SHAM) and adrenalectomized (ADX) rats. I.c.v. administration of 10 micrograms of naloxone resulted in a significant increase in the bleeding volume required to lower arterial pressure from 60 to 40 mmHg in SHAM animals, whereas no effect of naloxone was observed in ADX animals. Replacement therapy with a 100% corticosterone pellet (100 mg, s.c.), but not with a 12.5% corticosterone pellet (12.5 mg corticosterone and 87.5 mg cholesterol, s.c.), resulted in an effect of naloxone on the bleeding volume in ADX animals. The effect of replacement therapy could be inhibited by i.c.v. pretreatment with the synthetic glucocorticoid receptor antagonist, RU38486 (100 ng). These data suggest that (1) opioid mechanisms are involved in the regulation of blood pressure during hemorrhage, and (2) occupancy of glucocorticoid receptors is required for naloxone to exert its hemodynamic effect during hemorrhagic hypotension in ADX rats.


Subject(s)
Mifepristone/therapeutic use , Naloxone/pharmacology , Receptors, Glucocorticoid/drug effects , Shock, Hemorrhagic/drug therapy , Adrenalectomy , Animals , Corticosterone/therapeutic use , Drug Interactions , Hemodynamics/drug effects , Male , Rats , Rats, Inbred Strains
7.
Endocrinology ; 126(1): 118-24, 1990 Jan.
Article in English | MEDLINE | ID: mdl-2293978

ABSTRACT

Systolic blood pressure was measured, using an indirect tail method, in conscious male rats at several time intervals after the intracerebroventricular injection of mineralo-and glucocorticoid agonists and antagonists. Intracerebroventricular administration of the antimineralocorticoid RU 28318 (10 ng) decreased blood pressure, while the antiglucocorticoid RU 38486 (10 ng) caused an increase, which was slower in onset and of longer duration. The effect of the antimineralocorticoid was maximal at 8 h and had disappeared after 24 h. The antiglucocorticoid had a significant effect 24 and 48 h after injection. Neither antagonist was effective when administered sc at the same dose (10 ng). Intracerebroventricular administration of aldosterone (10 ng) and the selective glucocorticoid agonist RU 28362 (10 ng) increased and decreased blood pressure, respectively. Corticosterone given intracerebroventricularly (10-100 ng) did not affect blood pressure unless the dose was increased to 1 microgram. Two weeks after adrenalectomy a decrease in blood pressure was observed when the rats were given 0.9% saline instead of water to drink. Replacement therapy with corticosterone (12.5-mg steroid pellet, sc) restored blood pressure to the level in the sham-operated controls. The chronically elevated level of circulating corticosterone produced by a 100-mg sc corticosterone pellet increased blood pressure. The 12.5-and 100-mg sc corticosterone pellets resulted in plasma corticosterone levels of approximately 3 and 20 micrograms/100 ml, respectively. Intracerebroventricular administration of the glucocorticoid and mineralocorticoid antagonists (10 ng) increased and decreased, respectively, the blood pressure of the adrenalectomized rats receiving corticosterone substitution. From these data we conclude that corticosteroids can affect the central regulation of blood pressure. The mineralo- and glucocorticoids have opposite effects, which differ in onset and duration. The mineralocorticoids increased blood pressure, whereas the glucocorticoid decreased it.


Subject(s)
Blood Pressure/drug effects , Brain/physiology , Glucocorticoids/physiology , Mineralocorticoids/physiology , Adrenalectomy , Aldosterone/pharmacology , Androstanols/pharmacology , Animals , Brain/drug effects , Corticosterone/pharmacology , Glucocorticoids/antagonists & inhibitors , Injections, Intraventricular , Male , Mifepristone/pharmacology , Mineralocorticoid Receptor Antagonists/pharmacology , Mineralocorticoids/antagonists & inhibitors , Rats , Rats, Inbred Strains , Spironolactone/analogs & derivatives , Spironolactone/pharmacology
8.
J Hypertens Suppl ; 7(6): S202-3, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2561139

ABSTRACT

A single intracerebroventricular injection of 10 ng of the mineralocorticoid aldosterone in normotensive male Wistar rats induced a transient increase in blood pressure. Corticosterone produced this response only at a 100-fold higher dose. In contrast, a decrease in systolic blood pressure occurred following the intracerebroventricular administration of a selective glucocorticoid agonist (Ru 28362; 10 ng). The intracerebroventricular administration in normotensive and adrenalectomized, corticosterone-replaced, male rats of an antimineralocorticoid (Ru 28318; 10 ng) decreased systolic blood pressure, while an antiglucocorticoid (Ru 38486; 10 ng) caused an increase. These data suggest that adrenal steroids affect central mechanisms underlying cardiovascular regulation by binding to central mineralo- and glucocorticoid receptors.


Subject(s)
Blood Pressure/physiology , Brain/physiology , Receptors, Glucocorticoid/physiology , Animals , Blood Pressure/drug effects , Brain/drug effects , Dose-Response Relationship, Drug , Homeostasis/drug effects , Homeostasis/physiology , Male , Mineralocorticoids/physiology , Rats , Rats, Inbred Strains , Receptors, Glucocorticoid/drug effects , Receptors, Mineralocorticoid , Receptors, Steroid/drug effects , Receptors, Steroid/physiology
9.
Cancer Immunol Immunother ; 26(2): 145-52, 1988.
Article in English | MEDLINE | ID: mdl-3282654

ABSTRACT

In a delayed-type hypersensitivity reaction serotonin released from mast cells plays an important role in the induction of a cellular infiltrate at the site of antigen challenge. In analogy, we have studied whether it is possible to enhance the number of intratumoral macrophages by injecting serotonin into a s.c. SL2 lymphosarcoma. The vessels in the tissue surrounding the tumor responded well to serotonin, as there was an influx of i.v. injected 51Cr-labeled sensitized spleen cells in this tissue during the first 4 h after intratumoral injection of serotonin. At 24 h after serotonin injection there was an influx of macrophages into this tumor-surrounding tissue. No influx of cells was detected in the tumor itself during the first hours after injection of serotonin. In the tumor, similar phenomena occurred as in the surrounding tissue, but with a delay of about 24 h. This suggests that lymphocytes leave the blood circulation in the tumor-surrounding tissue and migrate to the tumor. The influx of macrophages into the tumor after intratumoral injection of serotonin is probably due to an immunological reaction as the lymphocyte influx preceeds the macrophage influx into tumors. In addition, transfer of sensitized lymphocytes, as well as lymphocytes from a tumor-bearing host caused an enhanced influx of macrophages into the tumor. To test the specificity and serotonin dependency of the phenomenon of infiltrating cells in tumors we have used a footpad swelling assay in which the serotonin dependency and the antigen specificity of the response against syngeneic tumor cells was shown. The following picture emerged: an intratumoral serotonin injection enables lymphocytes to leave blood vessels in the tumor-surrounding tissue. These lymphocytes with specificity for tumor antigens migrate to the tumor. After contact with the antigenic tumor cells, these lymphocytes secrete chemoattractive factors for monocytes/macrophages. Also these monocytes/macrophages leave the circulation in the tumor-surrounding tissue. Subsequently the macrophages invade the tumor. We conclude that the number of intratumoral macrophages can be enhanced by serotonin.


Subject(s)
Hypersensitivity, Delayed/pathology , Lymphocytes/immunology , Macrophages/physiology , Sarcoma, Experimental/pathology , Serotonin/physiology , Animals , Blood Physiological Phenomena , Bone Marrow/physiology , Bone Marrow Transplantation , Capillary Permeability/drug effects , Cell Movement , Disease Models, Animal , Female , Hypersensitivity, Delayed/immunology , Lymphocyte Transfusion , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Neoplasm Transplantation , Sarcoma, Experimental/immunology , Serotonin/toxicity
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