SEARCH · PubMed Health

Results for “MR antagonists”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed1999

The stereoselective kappa-opioid receptor antagonist Mr 2266 does not exhibit stereoselectivity as an antagonist at the orphan opioid (ORL1) receptor.

Mr 2266 [(-)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorpha n] is an antagonist at kappa-opioid receptors and at ORL1 receptors as well. The aim of our study was to examine whether the known stereoselective antagonism of Mr 2266 at kappa-opioid receptors also extends to ORL1 receptors. In mouse brain cortex membranes, the binding of the ORL1 receptor agonist [3H]nociceptin was equipotently inhibited by Mr 2266 and its enantiomer Mr 2267 (pK(i) 4.82 and 5.14, respectively), whereas the binding of the kappa-opioid receptor agonist [3H]U-69,593 was inhibited by Mr 2266 more potently (pK(i) 9.11) than by its enantiomer Mr 2267 (pK(i)7.15). In mouse brain cortex slices preincubated with [3H]noradrenaline, the concentration-response curve of nociceptin for inhibition of the electrically evoked overflow of tritium was equipotently shifted to the right by Mr 2266 and Mr 2267 (pA2 5.77 and 5.64, respectively). On the other hand, the inhibitory effect of U-69,593 on the electrically evoked overflow of tritium in guinea-pig brain cortex slices preincubated with [3H]noradrenaline was more potently antagonized by Mr 2266 (pA2 8.81) than by Mr 2267 (pA2 7.15). These data show that the stereoselective antagonism of Mr 2266 at kappa-opioid receptors does not extend to ORL1 receptors.

Animals↗

PubMed1989

The effect of naloxone and the kappa antagonist MR 1452 MS on myocardial infarction in rats.

The intravenous infusion of naloxone (Nal) (0.17 mg/kg/min) and of the selective kappa antagonist MR 1452 MS (0.07 mg/kg/min) on rats with left coronary artery occlusion was studied. The results demonstrated significant improvement of cardio-circulatory parameters, i.e., mean arterial pressure (MAP), heart rate (HR) and cardiac output (CO). The action of Nal is peripheral and central with prevalence of central effect, since its hypertensive effect is due to a rise in total peripheral resistance (TPR) (by 12%), rather than to an increase of CO (by 3% compared to saline-treated rats 20 min postinfarction). The effect of MR 1452 MS is mainly peripheral, since MAP increased due to increased CO (by 5% and by 8% compared to saline-treated animals 20 min and 2 h postinfarction). As a result of increased MAP and CO a reduction of myocardial oxygen deficiency was evident, and the development of cardiogenic shock in Nal- and MR 1452 MS-treated animals decreased by 7% and by 17% 2 and 24 h postinfarction. Reduction of the incidence of early arrhythmias (20 min-2 h postinfarction) by 25% and 16%, respectively, was found. Mortality was significantly reduced in both groups by 8% 2 h postinfarction and by 17% 24 h postinfarction, which suggested a comparable effect of both drugs in cardiogenic shock.

Acid-Base Equilibrium↗

PubMed1990

Effects of the kappa opioid receptor antagonist MR-2266-BS on the acquisition of ethanol preference.

Using a paradigm by which rats forced to drink a weak ethanol solution (2.5% w/v) (conditioning session) develop ethanol preference in consecutive retention testing days, the effects of the administration of the kappa opioid antagonist MR-2266-BS, prior to or after the forced ethanol session, were studied. Pre-conditioning subcutaneous (s.c.) administration of 1 mg/kg of MR-2266-BS induced a decrease in subsequent ethanol consumption without significantly modifying the acquisition of ethanol preference. Post-conditioning administration of MR-2266-BS (0.1, 1, 5 or 10 mg/kg) induced both a dose-dependent reduction in ethanol consumption and in preference throughout the three following days. The results of the present study provide further support of the involvement of kappa-type opioids on drinking behavior, and suggest that kappa receptors may be involved in the consumption and development of preference to ethanol.

Alcohol Drinking↗

PubMed1989

[Effects of kappa-opiate receptor antagonist MR-2266-BS on ACTH and prolactin release].

The effect of intravenous injection of different doses of MR-2266-BS, a selective antagonist of kappa-opiate receptor, on plasma adrenocorticotropin (ACTH) and prolactin (PRL) in conscious male rats bearing an intrajugular cannulae was assessed. The results revealed that the MR-2266-BS of 3 mg/kg completely blocked the restraint stress-induced increase in plasma ACTH levels, and further elevated plasma PRL levels in these animals, while there were no effects on the resting levels of ACTH and PRL. MR-2266-BS of 6 mg/kg significantly increased the resting levels of plasma ACTH and also further elevated the restraint stress-induced increase of plasma ACTH and PRL. The present data suggest that kappa-opiate receptor and its endogenous ligand may be involved in the regulation of the resting and restraint stress-induced release of ACTH, and their action appears to be both stimulatory and inhibitory. Furthermore, kappa-opiate receptor and its endogenous ligand may only inhibit the stress-induced release of PRL.

Adrenocorticotropic Hormone↗

PubMed2026

GPER and EGFR cross-talk highlight aldosterone- and MR antagonist-induced NO production in cultured endothelial cells.

INTRODUCTION: Aldosterone induces rapid, non-genomic vasodilation of the rat mesenteric vasculature, and mineralocorticoid receptor (MR) antagonists are widely used in cardiovascular disease, yet their pharmacological profiles beyond classical MR blockade remain unclear. We examined whether the G protein-coupled estrogen receptor (GPER/GPR30), functionally coupled to the epidermal growth factor receptor (EGFR), accounts for the rapid endothelial nitric oxide (NO) component of aldosterone action, and whether MR antagonists display intrinsic GPER-linked activity. METHODS: Aldosterone-induced vasodilation was assessed in isolated perfused rat mesenteric arterial beds precontracted with noradrenaline, and NO production was quantified in primary mesenteric endothelial cell cultures by DAF-FM fluorescence with validated vehicle controls. The mechanisms engaged by spironolactone, eplerenone and finerenone were interrogated with selective pharmacological tools and by endothelium removal. Ligand recognition was explored by molecular docking in a comparative model of the rat GPER built on the human GPER cryo-EM template. RESULTS: Aldosterone elicited concentration-dependent endothelial NO production (EC50 = 2.26 ± 0.3 nM) and vasodilation (EC50 = 0.9 ± 0.2 nM) that were closely correlated (R2 = 0.969, p < 0.01). All three MR antagonists blocked the aldosterone responses, yet each also evoked intrinsic, concentration-dependent NO production in the absence of aldosterone, eplerenone and spironolactone showing greater intrinsic efficacy than finerenone. Pretreatment with 100 nM of the GPER antagonist G-36 or 100 nM AG-1478 significantly reduced both aldosterone-induced DAF-NO signaling and vasodilation, whereas endothelium removal or L-NAME converted vasodilation into vasoconstriction. Aldosterone signaling additionally required PI3K, PKA and IP3 receptor-gated Ca2+ mobilization. Docking identified plausible receptor-engaging poses, with steroidal ligands converging on a shared cavity and finerenone adopting a distinct binding mode. DISCUSSION: MR antagonists elicit endothelial NO production through a G-36-sensitive, GPER-linked pathway functionally coupled to EGFR signaling, rather than acting as pure competitive antagonists in this context. Because recent cryo-EM work reveals a non-canonical extracellular GPER architecture, the docking results are interpreted as structurally plausible interaction scenarios rather than definitive orthosteric assignments; whether the behaviour reflects direct partial agonism at GPER or an indirect, GPER-dependent mechanism remains to be established by direct-binding studies. These findings expand current understanding of MR antagonist pharmacology.

GPER/GPR30↗

PubMed1991

Prevention of hyperthermia-induced convulsions in immature rat by MR-2266, a kappa antagonist.

The opioid receptor subtypes involved in hyperthermia-induced convulsions were studied by testing different opioid receptor-selective antagonists in unrestrained 15-day-old rats. Saline-injected animals exposed to an ambient temperature of 40 degrees C showed a gradual increase in body temperature reaching a maximum of 40.4 +/- 0.2 degrees C at 60 min. At this time all rat pups had convulsions and died. Similar results were obtained when the animals were pretreated with beta-funaltrexamine or 1 mg/kg ICI-154129. However, the injection of 10 mg/kg ICI-154129 prevented hyperthermia-induced convulsions (only 20% of the rats showed generalized convulsions at 90 min). Rats treated with the kappa antagonist MR-2266 also showed an increase in rectal temperature. However, none of the animals had convulsions or died. These results suggest that the kappa-opioid receptors are involved in convulsions induced by hyperthermia.

Animals↗

PubMed2004

Differences in the determinants of eplerenone, spironolactone and aldosterone binding to the mineralocorticoid receptor.

The importance of mineralocorticoid receptor (MR) antagonists in the treatment of cardiovascular disease has been emphasised by two recent clinical trials, one using spironolactone and the other using a new selective MR antagonist, namely eplerenone. Eplerenone has a very low affinity for the glucocorticoid receptor (GR). Determinants of binding specificity of eplerenone to the MR were investigated using chimeras created between the ligand-binding domains (LBD) of the MR and the GR. These chimeras had been used previously to investigate aldosterone and spironolactone binding specificity to the MR. Eplerenone competed strongly for [(3)H]-dexamethasone binding to a MR/GR chimera containing amino acids 804-874 of the MR and weakly to a chimera containing amino acids 672-803 of the MR. Within the 804-874 region, eplerenone competed for [(3)H]-dexamethasone binding to a chimera containing amino acids 820-844 of the MR, although the calculated affinity was approximately 10-fold lower than for binding to the full-length MR LBD. Similar results were obtained using another MR antagonist, namely spironolactone. Modelling of eplerenone binding to the MR LBD, based on the GR LBD crystal structure, suggests that amino acids 820-844 affect the overall shape of the ligand-binding pocket and that eplerenone acts as an MR antagonist because it fails to stabilize the active conformation of the receptor. In contrast with results with the MR antagonists eplerenone and spironolactone, amino acids 820-844 are sufficient in themselves to confer high-affinity aldosterone binding to the MR, suggesting that the binding determinants of the two antagonists are similar to each other but differ from those of aldosterone.

Aldosterone↗

PubMed2003

Mineralocorticoid receptor function in major depression.

BACKGROUND: Negative feedback regulation of the hypothalamic-pituitary-adrenal axis occurs through a dual-receptor system of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Their affinity for cortisol and their distribution in the brain differ. Studies using an MR antagonist have demonstrated that MR is active throughout the circadian rhythm. Because major depression is accompanied by increased glucocorticoid secretion and insensitivity to glucocorticoid feedback, and because glucocorticoids are capable of down-regulating MR and GR, we expected that major depression would be accompanied by decreased MR activity. METHODS: To test this hypothesis, we administered spironolactone, an MR antagonist, to individuals with major depression and matched control subjects and assessed levels of corticotropin and cortisol secretion in response to this acute challenge. Studies were conducted in the morning, the time of peak activation of the hypothalamic-pituitary-adrenal axis. All patients were currently depressed and free of all medications. All controls were free of all psychiatric diagnoses and of all medications. RESULTS: Spironolactone treatment resulted in a significant increase in cortisol secretion levels in both groups. Depressed patients demonstrated higher cortisol secretion levels than control subjects. In addition, depressed patients demonstrated a different pattern of increase in cortisol secretion levels after spironolactone administration. Furthermore, a significant effect of spironolactone treatment on corticotropin secretion levels can be observed in depressed patients, whereas controls show no such effect. CONCLUSIONS: Despite high baseline cortisol levels, patients with major depression show high functional activity of the MR system. Paired with the body of evidence regarding decreased sensitivity to GR agonists, these data suggest an imbalance in the MR/GR ratio. The balance of MR and GR is known to affect brain serotonin systems and may play an etiologic role in serotonin receptor changes observed in patients with major depression.

Adult↗

PubMed2000

Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralocorticoid receptor antagonist spironolactone.

The hippocampal mineralocorticoid receptor (MR) is critical for the regulation of the basal activity of the hypothalamus-pituitary-adrenocortical (HPA) system. It has been hypothesized that reduced capacity of the hippocampal MR is involved in the HPA-system dysregulation found in depression and aging. We applied the combined dexamethasone suppression/corticotropin releasing hormone stimulation (DEX/CRH) test to six healthy young females both before and after 12 days of treatment with the MR antagonist spironolactone to assess HPA regulation. Treatment with spironolactone caused a significant increase in post-dexamethasone cortisol concentrations (75.1+/-56.7 vs. 36.6+/-24.6 nmol/l, p<0.05). Furthermore, we observed a significant rise in peak cortisol concentration after additional human CRH (hCRH) application (223. 6+/-139.1 vs. 126.7+/-73.3 nmol/l, p<0.02). There was no change in ACTH plasma concentrations. We thus conclude that (1) the MR antagonist spironolactone affects HPA system regulation as reflected in the DEX/CRH test and (2) these findings are in accordance with the assumption that MR dysfunction may underlie HPA-system dysfunction in depression and/or aging.

Adrenal Glands↗

PubMed1994

Mineralocorticoid antagonist inhibits stress-induced blood pressure response after repeated daily warming.

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.

Adrenocorticotropic Hormone↗

PubMed1995

Anxiolytic-like effects of selective mineralocorticoid and glucocorticoid antagonists on fear-enhanced behavior in the elevated plus-maze.

The effects of intracerebroventricular (ICV) administration of the mineralocorticoid receptor (MR) antagonist, RU28318, and the glucocorticoid receptor (GR) antagonist, RU38486, were studied on behavior of rats exposed to a compartment previously associated with a stressor, and placed subsequently in an elevated plus-maze test. Fear-motivated immobility behavior was attenuated by the MR antagonist in a dose of 50 or 100 ng ICV, whereas the GR antagonist alone or simultaneous administration of both antagonists had no significant effect. In the elevated plus-maze, immediately after the exposure to the conditioned stressor, both the GR antagonist (50 ng) and MR antagonist (50 ng) increased the percentage of time the rats spent on open arms, and increased the amount of entries into these open arms. These data are interpretated in terms of the involvement of the GR and MR in fear and anxiety.

Animals↗

PubMed1997

Facilitation of feedback inhibition through blockade of glucocorticoid receptors in the hippocampus.

In the present study the effects of intracerebroventricular (i.c.v.) and intrahippocampal administration of corticosteroid antagonists on basal hypothalamic-pituitary-adrenal (HPA) activity around the diurnal peak were compared in male Wistar rats. In two separate experiments the glucocorticoid receptor (GR) antagonist RU 38486 and the mineralocorticoid receptor (MR) antagonist RU 28318 were tested. One hour after GR antagonist injection, significant increases in plasma ACTH and corticosterone levels were observed in the i.c.v. treated rats, when compared to vehicle. In contrast, a significant decrease in ACTH levels, and a slight, but non-significant decrease in corticosterone concentrations were attained one hour after intrahippocampal injection of the GR antagonist. Injection of the MR antagonist, on the other hand, resulted in enhanced ACTH and corticosterone levels irrespective of the site of injection. These findings suggest that negative feedback inhibition at the circadian peak involves hippocampal MRs and extrahippocampal (hypothalamic) GRs. The latter feedback inhibition overrides a positive feedback influence exerted by endogenous corticosteroids through hippocampal GRs.

Adrenocorticotropic Hormone↗

PubMed2006

Combination therapy with aldosterone blockade and renin-angiotensin inhibitors confers organ protection.

There is increasing evidence that aldosterone exerts major adverse cardiovascular effects through classical mineralocorticoid receptors (MR) in nonepithelial tissues such as the brain and heart. This nonepithelial role of aldosterone has been underscored by the recent Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS). These studies also showed that when using MR antagonist as an "organ protecting" drug, further organ protection could be derived by the addition of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type 1 receptor blocker (ARB). The long-term effect of aldosterone was not inhibited in some subjects, so the possibility of organ damage due to so-called "breakthrough" aldosterone cannot be ignored. Nonepithelial MR-mediated effects played a major role in this aldosterone effect. These effects can be inhibited by MR antagonist at a small dose, not lower blood pressure. Therefore, the idea is now to combine a small dose of MR antagonist with an ACE inhibitor or ARB. However, warnings have been given recently due to the emergence of hyperkalemia and other adverse effects associated with inappropriate combination therapy. It is important to note that, if the eligibility criteria of RALES and EPHESUS are fulfilled, the potassium level will rarely become problematic. Therefore, the recent increase in the incidence of adverse effects can be attributed to the incorrect application of combination therapy. Elderly patients or those with dehydration, renal dysfunction, and aggravated heart failure require further close monitoring or termination of spironolactone administration. The combination of an MR antagonist and renin-angiotensin inhibitors should be a useful strategy if subjects are carefully selected, and carefully monitored. Adverse effects will occur only if the usage recommendations based on previous researches are not followed.

Angiotensin II Type 1 Receptor Blockers↗

PubMed1985

Analgesic effects of mu antagonists after naloxone non-reversible stress-induced analgesia.

Three antagonists at the mu opiate receptor site: naloxone, naltrexone and diprenorphine, and one agonist-antagonist compound nalorphine, at doses usually not analgesic elicited analgesia in rats when administered after non-naloxone-reversible shock-induced analgesia had disappeared. The chi receptor antagonist, MR 2266, and the delta antagonist, ICI 154129, were all ineffective. This effect was no longer present when non-naloxone-reversible shock-induced analgesia was inhibited by the administration of the chi receptor antagonist, MR 2266. These results suggest that the mu opiate receptor may change its conformation under particular conditions such as continuous inescapable shock.

Analgesics↗

PubMed2006

Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus.

To determine whether mineralocorticoid receptor (MR) activation plays a role in diabetic renal injury and whether this role differs in types 1 and 2 diabetes mellitus, we examined the effect of a MR antagonist on renal injury in rodent models of type 1 (streptozotocin-treated rat) and type 2 (db/db mouse) diabetes. We studied three groups of 8-wk-old, uninephrectomized Wistar rats for 4 wk: diabetic streptozotocin- (55 mg/kg) treated rats (n = 11), diabetic streptozotocin-treated rats receiving the MR antagonist eplerenone (n = 15), and nondiabetic rats (n = 9). In addition, we studied three groups of 8-wk-old mice for 16 wk: diabetic db/db mice (n = 10), diabetic db/db mice treated with eplerenone (n = 8), and nondiabetic, db/+ littermates (n = 11). Diabetic rats and mice developed albuminuria and histopathological evidence of renal injury, including glomerular hypertrophy, mesangial expansion, and tubulointerstitial injury as well as increased renal cortical levels of MR protein, MR mRNA, TGFbeta mRNA, and osteopontin mRNA. All of these changes were significantly reduced by treatment with eplerenone except for the elevated MR levels. The beneficial effects of eplerenone were not attributable to changes in blood pressure or glycemia. In summary, MR expression was increased in kidneys of diabetic rodents, and MR antagonists effectively reduced diabetic renal injury irrespective of the species or specific cause of the diabetes. Thus, these data suggest that MR activation is a critical factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes mellitus.

Albuminuria↗

PubMed1996

Sleep and waking during acute histamine H3 agonist BP 2.94 or H3 antagonist carboperamide (MR 16155) administration in rats.

The present study evaluated the effects of histamine H3 receptor agonist BP 2.94 or H3 receptor antagonist carboperamide (MR 16155) given by oral route on sleep and waking in rats surgically prepared for long-term recordings. BP 2.94 produced a significant increase of slow-wave sleep (SWS) that was related to slight decreases of waking, light sleep, and REM sleep. Carboperamide significantly increased waking and decreased SWS and REM sleep. Pretreatment with carboperamide prevented the effect of BP 2.94 on SWS. It is suggested that the effects of BP 2.94 or carboperamide on sleep and waking could depend on changes in the availability of histamine at the postsynaptic H1 receptor. Alternatively, activation or blockade of the H3 heteroreceptors found in the central catecholamine, indolamine, and acetylcholine nerve endings could inhibit or increase the release of noradrenaline, serotonin, dopamine, and acetylcholine. This would secondarily result in changes of sleep variables.

Animals↗

PubMed2004

Towards selectively modulating mineralocorticoid receptor function: lessons from other systems.

Although there is clinical utility in blocking mineralocorticoid receptor (MR) action, the usefulness of available MR antagonists is limited because of cross-reactivity with the androgen and progesterone receptors (spironolactone) or possibly by low affinity for MR (eplerenone). MR binds aldosterone and physiologic glucocorticoids, such as cortisol, which both can act as MR agonists in epithelial tissues. However, in preliminary studies aldosterone and cortisol appear to induce different conformations in non-epithelial tissues; in the cardiomyocyte, cortisol usually acts as an MR antagonist, whereas in vascular smooth muscle cortisol mimics aldosterone actions if it can access MR, just as it does in the kidney. Thus, there are needs for improved MR antagonists with higher selectivity and potency and, if possible, for compounds that lock MR into specific desirable conformations. Efforts are underway to modulate selectively the action of many nuclear receptors, and insights from one nuclear receptor may be applicable to others given the similarities in structure and function. We have used traditional approaches aided by X-ray crystallography to obtain several classes of selective ligands that modulate thyroid receptor (TR) action. We describe the properties of these selective TR modulators here, and discuss the possibility that similar approaches to ligand design may yield MR interacting compounds with improved specificity and, possibly, tissue specificity.

Aldosterone↗

PubMed1993

Central actions of corticotropin-releasing hormone (CRH) on behavioral, neuroendocrine, and cardiovascular regulation: brain corticoid receptor involvement.

The effect of intracerebroventricular (icv) infused corticotropin-releasing hormone (CRH), 300 ng, infused at a rate of 16.67 ng/min during 18 min and its relation to the functioning of brain corticoid receptors was investigated in freely moving rats in their home cages. Behavior was sampled before, during, and after the CRH infusion. Cardiovascular measurements were made via a chronically implanted catheter in the descending aorta. Blood samples were withdrawn to determine adrenal hormone concentration. Central administration of the brain mineralocorticoid-like receptor (MR) antagonist (RU 28318, 100 ng) and the glucocorticoid receptor (GR) antagonist (RU 38486, 100 ng) 60 min before CRH infusion served to manipulate adrenal steroid states in the brain. CRH infusion caused behavioral activation which was associated with an increase in heart rate (HR) and mean arterial blood pressure (MAP). Increased plasma corticosterone and norepinephrine levels were observed, while a minor elevation of epinephrine (E) levels also occurred. Both corticoid receptor antagonists failed to affect the CRH-induced behavioral activation. Administration of the GR antagonist significantly enhanced the magnitude of the CRH-induced increase in E, whereas the effect of the MR antagonist just failed to reach significance. These findings suggest the involvement of central corticoid receptors in sympathoadrenomedullary feedback mechanisms. The MR antagonist elevated baseline MAP probably thereby suppressing the magnitude of the CRH response. The increase in HR was diminished by both antagonists shortly after CRH infusion. Together, the data suggest involvement of brain corticosteroid receptor-mediated processes in neuroendocrine and cardiovascular effects of CRH.

Animals↗