TRH Analog Research Articles

Pharmacokinetic Drug Interactions of an Orally Available TRH Analog (Rovatirelin) With a CYP3A4/5 and P-Glycoprotein Inhibitor (Itraconazole).

The effects of itraconazole on the pharmacokinetics of rovatirelin were investigated in an open-label, single-sequence drug-drug interaction study in 16 healthy subjects. Subjects were administered a single oral dose of rovatirelin (1.6 mg) on day 1 and day 15. From day 8 through 16, subjects received daily oral doses of itraconazole (200 mg/day). Concentrations of rovatirelin and (thiazolylalanyl)methylpyrrolidine (TAMP), the major metabolite of rovatirelin formed by cytochrome P450 (CYP) 3A4/5, were determined in plasma and urine. Pharmacokinetic parameters were used to evaluate the drug-drug interaction potential of rovatirelin as a victim. With coadministration, maximum concentration (Cmax ) and area under the concentration-time curve extrapolated to infinity (AUCinf ) of rovatirelin increased 3.05-fold and 2.82-fold, respectively, and the 90% confidence intervals of the ratios for Cmax (2.64-3.52) and AUCinf (2.47-3.23) did not fall within the 0.8-1.25 boundaries. Urinary excretion of rovatirelin increased at almost the same ratio as the AUCinf ratio with coadministration; however, renal clearance did not change. Cmax , AUCinf , and urinary excretion of TAMP were decreased by coadministration. Itraconazole has the potential to inhibit drug transport via intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); therefore, substrate assessments of rovatirelin for the 2 transporters were evaluated using Caco-2 cell monolayers. In vitro studies showed that rovatirelin is a substrate for P-gp but not for BCRP. The current study shows that itraconazole's effect on rovatirelin pharmacokinetics is mediated through inhibition of CYP3A4/5 and intestinal P-gp.

Thyroid Hormone Treatment of Mood Disorders

Both excess and insufficient thyroid hormones can lead to depression that is generally reversible with adequate thyroid treatment. On the other hand, major depression is associated with subtle chronobiological hypothalamic-pituitary-thyroid (HPT) axis dysregulation and thyroid hormones can be an effective adjunct to antidepressant treatment. However, the links between HPT axis status and efficacy of thyroid hormone supplementation in depression remain to be further clarified. While generally, depressed patients are chemically euthyroid, most exhibit a chronobiological HPT axis dysregulation (i.e., loss of the nocturnal thyrotropin [TSH] rise, blunted evening TSH response to protirelin [TRH], reduced difference in TSH response between 11 PM and 8 AM TRH tests [ΔΔTSH]), possibly associated with blunted 8 AM-TSH response to TRH and/or altered levels of circulating thyroxine (FT4) and triiodothyronine (T3). Usually, chronobiological HPT axis abnormalities are unrelated to increased cortisol levels. Normalization of thyroid function tests by antidepressants, especially the ΔΔTSH test, may occur before the clinical response. In patients who are resistant to antidepressants, there is good evidence for adjuvant therapy with thyroid hormones. While there is a limited evidence base to guide long-term adjunctive use, thyroid hormone augmentation can be a safe and effective alternative treatment for euthyroid-depressed patients who receive appropriate baseline and follow-up safety monitoring. However, it remains to be established which bio-clinical subtypes of depression respond preferentially to thyroid hormone supplementation. In the next future, metabolically stable TRH analogs could be used in order to maintain or restore homeostasis, which is frequently disrupted in depressive states.

Bioengineered PLGA-chitosan nanoparticles for brain targeted intranasal delivery of antiepileptic TRH analogues

The bio-engineering of nanoparticles for the transportation of various therapeutic agents specifically to brain has sparked a rapidly growing interest in the field of material chemistry. In this study, L-pGlu-(1-benzyl)–L-His–L-ProNH2 (NP-355) and L-pGlu-(2-propyl)–L-His–L-ProNH2 (NP-647) were synthesized and encapsulated in biodegradable poly-lactide-co-glycolide (PLGA) nanoparticles which were further decorated with mucoadhesive surface coating of chitosan. NP-355 and NP-647 which are analogues of thyrotropin releasing hormone, have been reported to demonstrate potential antiepileptic properties against various animal models of seizures. However, their applicability is limited by their short lives due to rapid metabolism and blood brain barrier. The treatment of disorders associated with central nervous system such as epilepsy has been a major challenge for several decades due to difficulty in delivery of drug molecules and imaging agents to brain. To overcome these issues, development of sustained release delivery system for these neuropeptides is proposed which can be administered directly from nose to brain utilizing olfactory nerve channels. The synthesized nanoparticles were evaluated for their physicochemical properties, sustained release properties, toxicity and antiepileptic potential following intranasal administration. The ability of these nanoparticles to reach the brain was evaluated by utilizing quantum dots as fluorescent probes. Our results proved that the polymeric nanoparticles can be used for successful delivery of neurological drugs to the brain.

Emerging treatments options for narcolepsy throughout a case

BackgroundNarcolepsy is a neurological disorder characterized by disturbances in REM sleep. The symptoms that the patient could present are excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disrupted nocturnal sleep. Its etiology is unknown. Currently, there is established pharmacotherapy for symptomatic treatment, which are often unsatisfactory.ObjectiveReview of new treatments for narcolepsy based on recent advances about its ethiopathogenesis.MethodSeventy-five year-old female with a personal history of arterial hypertension and obstructive sleep apnea syndrome. The patient presented several episodes of abrupt muscular weakness, nightmares, sleep paralysis and excessive daytime sleepiness. Diagnosed of narcolepsy and treated with methylphenidate immediate-release (IR) 10 mg, alprazolam 1 mg, and trazodone 100 mg with good response.ResultsDue to persistent symptoms, treatment was modified to osmotic-release oral system (OROS) – methylphenidate resulting on a substantial weight loss (12 kg) and persistence of symptoms. Another methylphenidate preparations were unsuccessfully tested. Currently she continues treatment based on methylphenidate release-release and she improved significantly though she sometimes presented daytime sleepiness.DiscussionRecent studies have shown that a loss of the hypothalamic neuropeptide hypocretin causes Narcolepsy with cataplexy and that an autoimmune mechanism may be responsible for this loss (related to HLA DQB*0602). Pathophysiology of narcolepsy without cataplexy is less understood.Although amphetamines and its derivatives are the mainstay of management, therapies that involve hypocretine seems to be hopeful (intranasal, peripherical or hipocretin cell transplantation). Monotherapy with GHB, H3 antagonist receptors, TRH analogs and immunotherapy are also being studied.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Thyrotropin-releasing hormone and its analogs accelerate wound healing

BackgroundThyrotropin-releasing hormone (TRH) is a classical hormone that controls thyroid hormone production in the anterior pituitary gland. However, recent evidence suggested that TRH is expressed in nonhypothalamic tissues such as epidermal keratinocytes and dermal fibroblasts, but its function is not clear. This study aimed to investigate the effects of TRH and its analogs on wound healing and explore the underlying mechanisms. Materials and methodsA stented excisional wound model was established, and the wound healing among vehicle control, TRH, and TRH analog taltirelin treatment groups was evaluated by macroscopic and histologic analyses. Primary fibroblasts were isolated from rat dermis and treated with vehicle control, TRH or taltirelin, cell migration, and proliferation were examined by scratch migration assay, MTT, and 5-ethynyl-2′- deoxyuridine (EdU) assay. The expression of α-Smooth muscle actin in fibroblasts was detected by Western blot and immunocytochemical analysis. ResultsTRH or taltirelin-treated wounds exhibited accelerated wound healing with enhanced granulation tissue formation and increased re-epithelialization and tissue formation. Furthermore, TRH or taltirelin promoted the migration and proliferation of fibroblasts and induced the expression of α-Smooth muscle actin in fibroblasts. ConclusionsTRH is important in upregulating the phenotypes of dermal fibroblasts and plays a role in accelerating wound healing.

Synthesis and neuromodulatory effects of TRH-related peptides: inhibitory activity on catecholamine release in vitro

BackgroundA detailed comprehension of central mechanisms underlying feeding behavior holds considerable promise for the treatment of alimentary disorders MethodsIn order to elucidate the tight interrelationships occurring at the hypothalamic neuronal endings between aminergic neurotransmitters and co-localized appetite modulators, we initially studied the effects of two anorexigenic peptides structurally related to thyrotropin-releasing hormone (TRH, 1), namely cyclo(His-Pro) (CHP, 2) and pGlu-His-Gly-OH (3), on [3H]-norepinephrine and [3H]-dopamine release from perfused rat hypothalamic synaptosomes. Furthermore, a number of TRH and CHP analogues were synthesized and tested for their ability to influence neurotransmitter release in the selected neuronal model ResultsPeptide 3 showed only a slight inhibitory activity on norepinephrine release, whereas no effect was observed for compound 2. TRH analogue 8, metabolically stabilized by the replacement of pyroglutamate with the pyrohomocysteic acid (pHcs), was found to be inactive. Conversely, a significant inhibitory effect on dopamine and norepinephrine release was observed for the CHP-related diketopiperazines cyclo(Leu-Pro) (11) and cyclo(His-Gly) (14) ConclusionsThese results suggest a potential role for cyclo-dipeptides 11 and 14 in the hypothalamic modulation of appetite suppressant circuitry

Pyroglutamyl Peptidase II Inhibition Enhances the Analeptic Effect of Thyrotropin-Releasing Hormone in the Rat Medial Septum

Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH(2)) has multiple, but transient, homeostatic functions in the brain. It is hydrolyzed in vitro by pyroglutamyl peptidase II (PPII), a narrow specificity ectoenzyme with a preferential localization in the brain, but evidence that PPII controls TRH communication in the brain in vivo is scarce. We therefore studied in male Wistar rats the distribution of PPII mRNA in the septum and the consequence of PPII inhibition on the analeptic effect of TRH injected into the medial septum. Twelve to 14% of cell profiles expressed PPII mRNA in the medial septum-diagonal band of Broca; in this region the specific activity of PPII was relatively high. Twenty to 35% of PPII mRNA-labeled profiles were positive for TRH-receptor 1 (TRH-R1) mRNA. The intramedial septum injection of TRH reduced, in a dose-dependent manner, the duration of ethanol-induced loss of righting reflex (LORR). Injection of the PPII inhibitor pGlu-Asn-Pro-7-amido-4-methylcoumarin into the medial septum enhanced the effect of TRH. The injection of a phosphinic TRH analog, a higher-affinity inhibitor of PPII, diminished the duration of LORR by itself. In contrast, the intraseptal injection of pGlu-Asp-Pro-NH(2), a peptide that did not inhibit PPII activity, or an inhibitor of prolyl oligopeptidase did not change the duration of LORR. We conclude that in the medial septum PPII activity may limit TRH action, presumably by reducing the concentration of TRH in the extracellular fluid around cells coexpressing PPII and TRH-R1.

TRH誘導体が有効であったearly infantile epileptic encephalopathyの1例

TRH誘導体が有効であったearly infantile epileptic encephalopathyの1例

Protective effects of l-pGlu-(2-propyl)- l-His- l-ProNH 2, a newer thyrotropin releasing hormone analog in in vitro and in vivo models of cerebral ischemia

In the present study, the newly synthesized TRH analog ( l-pGlu-(2-propyl)- l-His- l-ProNH 2; NP-647) was evaluated for its effects in in vitro (oxygen glucose deprivation (OGD)-, glutamate- and H 2O 2-induced injury in PC-12 cells) and in vivo (transient global ischemia) models of cerebral ischemic injury. PC-12 cells were subjected to oxygen and glucose deprivation for 6 h. Exposure of NP-647 was given before and during OGD. In glutamate and H 2O 2 induced injury, exposure of NP-647 was given 1, 6 and 24 h prior to exposure of glutamate and H 2O 2 exposure. NP-647, per se found to be non-toxic in 1–100 μM concentrations. NP-647 showed protection against OGD at the 1 and 10 μM. The concentration-dependent protection was observed in H 2O 2- and glutamate-induced cellular injury. In in vivo studies, NP-647 treatment showed protection of hippocampal (CA1) neuronal damage in transient global ischemia in mice and subsequent improvement in memory retention was observed using passive avoidance retention test. Moreover, administration of NP-647 resulted in decrease in inflammatory cytokines TNF-α and IL-6 as well as lipid peroxidation. These results suggest potential of NP-647 in the treatment of cerebral ischemia and its neuroprotective effect may be attributed to reduction of excitotoxicity, oxidative stress and inflammation.

Tyreoliberin (Trh) – The Regulatory Neuropeptide of Cns Homeostasis

SummaryThe physiological role of thyreoliberin (TRH) is the preservation of homeostasis within four systems (i) the hypothalamic-hypophsysiotropic neuroendocrine system, (ii) the brain stem/midbrain/spinal cord system, (iii) the limbic/cortical system, and (iv) the chronobiological system. Thus TRH, via various cellular mechanisms, regulates a wide range of biological processes (arousal, sleep, learning, locomotive activity, mood) and possesses the potential for unique and widespread applications for treatment of human illnesses. Since the therapeutic potential of TRH is limited by its pharmacological profile (enzymatic instability, short half-life, undesirable effects), several synthetic analogues of TRH were constructed and studied in mono- or adjunct therapy of central nervous system (CNS) disturbances. The present article summarizes the current state of understanding of the physiological role of TRH and describes its putative role in clinical indications in CNS maladies with a focus on the action of TRH analogues.

ChemInform Abstract: Recent Advances in Retrometabolic Drug Design and Targeting Approaches

A number of representative, recent advances achieved within the field of retrometabolic drug design are briefly summarized. For the soft drug approach, some of the results of recent in vivo studies of loteprednol etabonate, a soft corticosteroid approved by the FDA in 1998, are reviewed. For the chemical delivery system (CDS) approach, the latest advances achieved in the brain targeting of peptides such as kyotorphin and TRH analogues are described.

Synthesis and biological evaluations of brain-targeted chemical delivery systems of [Nva2]-TRH.

Various chemical delivery systems for [Nva2]-TRH were synthesized and their CNS activity was investigated and compared with that of a similar chemical delivery system of [Leu2]-TRH, previously studied. Sequential metabolism of the chemical delivery system delivered to the brain, starting with the conversion of the dihydrotrigonellyl (DHT) to the trigonellyl (T+) moiety, will provide the lock-in to the brain of the T+-chemical delivery system, which will undergo hydrolysis of the cholesteryl ester, formation of the Pr-amide and cleavage of the spacer-T+ part, allowing ultimately the sustained release of the active [Nva2]-TRH. The CNS activity was assessed by measuring the extent of antagonizing barbiturate-induced sleeping time in mice. The fully packaged DHT-Pro-Pro-Gln-Nva-Pro-Gly-OCh produced robust antagonism, reducing sleeping time from 89 min to 48 min, similar to the Leu2-analogue (49 min). However, the partially substituted [Nva2]-TRH analogues showed little or no CNS activity. The results indicate that the fully packaged delivery system is necessary to produce the successful brain targeting of the precursor construct and effective release of the Gln-Nva-ProNH2.

Corrigendum to “A novel TRH analog, Glp–Asn–Pro–d-Tyr–d-TrpNH2, binds to [3H][3-Me-His2]TRH-labelled sites in rat hippocampus and cortex but not pituitary or heterologous cells expressing TRHR1 or TRHR2” [Neurosci. Lett. 431 (2007) 26–30

Corrigendum to “A novel TRH analog, Glp–Asn–Pro–d-Tyr–d-TrpNH2, binds to [3H][3-Me-His2]TRH-labelled sites in rat hippocampus and cortex but not pituitary or heterologous cells expressing TRHR1 or TRHR2” [Neurosci. Lett. 431 (2007) 26–30

Preconditioning Stress Prevents Cold Restraint Stress-Induced Gastric Lesions in Rats: Roles of COX-1, COX-2, and PLA2

We investigated the protective effect of mild stress on gastric lesions induced by cold-restraint stress, especially concerning prostaglandins (PGs)/cyclo-oxygenase (COX) isozymes. Rats were exposed to severe stress (cold-restraint stress at 10 degrees C for 6 hr) or mild stress (cold-restraint stress at 10 degrees C for 30 min and kept at room temperature for 60 min) followed by severe stress. Severe stress induced gastric lesions, with a concomitant decrease in body temperature (BT). The ulcerogenic response was inhibited by atropine but worsened by indomethacin and SC-560 but not rofecoxib, although none of these agents had any effect on the change in BT. Mild stress suppressed the gastric ulceration and the decrease in BT induced by severe stress, and these effects were reversed by both COX-1 and COX-2 inhibitors. The expression of COX-2 in the stomach was up-regulated from 4 hr after severe stress and this response was slightly expedited by mild stress. COX-2 was also expressed in the hypothalamus under normal and stressed conditions. Quinacrine (phospholipase A(2) inhibitor) attenuated the protective effect of mild stress on the ulceration and decrease in BT caused by severe stress. TA-0910 (TRH analogue) at a low dose also prevented the gastric ulceration and the decrease in BT induced by severe stress. These results suggest that mild stress protects against cold-restraint stress-induced gastric ulceration, and the effect is peripherally and centrally mediated by PGs derived from both COX-1 and COX-2 through the activation of phospholipase A(2). TRH may also be involved in the protective effect of mild stress, probably through regulation of the thermogenic system.

Brainstem Thyrotropin-Releasing Hormone Regulates Food Intake through Vagal-Dependent Cholinergic Stimulation of Ghrelin Secretion

The brainstem is essential for mediating energetic response to starvation. Brain stem TRH is synthesized in caudal raphe nuclei innervating brainstem and spinal vagal and sympathetic motor neurons. Intracisternal injection (ic) of a stable TRH analog RX77368 (7.5-25 ng) dose-dependently stimulated solid food intake by 2.4- to 3-fold in freely fed rats, an effect that lasted for 3 h. By contrast, RX77368 at 25 ng injected into the lateral ventricle induced a delayed and insignificant orexigenic effect only in the first hour. In pentobarbital-anesthetized rats, RX77368 (50 ng) ic induced a significant bipeak increase in serum total ghrelin levels from the basal of 8.7+/-1.7 ng/ml to 13.4+/-2.4 ng/ml at 30 min and 14.5+/-2.0 ng/ml at 90 min, which was prevented by either bilateral vagotomy (-60 min) or atropine pretreatment (2 mg/kg, -30 min) but magnified by bilateral adrenalectomy (-60 min). TRH analog ic-induced food intake in freely fed rats was abolished by either peripheral atropine or ghrelin receptor antagonist (D-Lys-3)-GHRP-6 (10 micromol/kg) or ic Y1 receptor antagonist 122PU91 (10 nmol/5 microl). Brain stem TRH mRNA and TRH receptor 1 mRNA increased by 57-58 and 33-35% in 24- and 48-h fasted rats and returned to the fed levels after a 3-h refeeding. Natural food intake in overnight fasted rats was significantly reduced by ic TRH antibody, ic Y1 antagonist, and peripheral atropine. These data establish a physiological role of brainstem TRH in vagal-ghrelin-mediated stimulation of food intake, which involves interaction with brainstem Y1 receptors.

Thyrotropin-Releasing Hormone Analogs

Thyrotropin releasing hormone (TRH: pyroglutamic acid-histidine-prolineamide) regulates the activity of cells in the anterior pituitary and within the central and peripheral nervous systems. TRH, which has been the subject of much research over the past three decades, exerts its effects by acting through class A G-protein coupled receptors. The recent discovery of a second receptor subtype has generated an interest in the discovery of receptor subtype-selective TRH analogs. In this review, we describe advances in the development of TRH analogs and in the understanding of their mechanism of interaction with TRH receptors. We also describe the recent breakthrough in the identification of analogs that bind selectively at TRH-R2.

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D‐glucose transport

1 Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. 2 The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (P<0.01). Less potent nootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist Ki's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (P<0.001). 3 Piracetam and TRH have no direct effects on net glucose transport, but competitively antagonise hypnotic drug inhibition of glucose transport. Other nootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. 4 There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. 5 Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis.

Glucose acts in the CNS to regulate gastric motility during hypoglycemia.

Our purposes were to 1) develop an animal model where intravenously (iv) administered d-glucose consistently inhibited antral motility, and 2) use this model to assess whether iv glucose acts to inhibit motility from a peripheral or a central nervous system site and to elucidate the factor(s) that determine(s) whether stomach motor function is sensitive to changes in blood glucose. Rats were anesthetized with alpha-chloralose-urethane, and antral motility was measured by a strain-gauge force transducer sutured to the antrum. In some cases, antral motility and gastric tone were measured by monitoring intragastric balloon pressure. Increases in blood glucose were produced by continuous iv infusion of 25% d-glucose at 2 ml/h. Inhibition of antral motility and gastric tone was observed when gastric contractions were induced by hypoglycemia (subcutaneously administered insulin, 2.5 IU/animal). In contrast, no inhibition of gastric motor function was observed when glucose infusion was tested on gastric contractions that were 1) spontaneously occurring, 2) evoked by iv administered bethanechol in vagotomized animals, and 3) evoked by the TRH analog RX77368, microinjected into the dorsal motor nucleus of the vagus. Using the model of insulin-induced hypoglycemia to increase gastric motor activity, we found that neither sectioning the hepatic branch of the vagus (n = 5), nor treating animals with capsaicin to destroy sensory vagal afferent nerves (n = 5) affected the ability of iv d-glucose to inhibit gastric motor function. Our results indicate that an important factor determining whether stomach motor function will be sensitive to changes in blood glucose is the method used to stimulate gastric contractions, and that the primary site of the inhibitory action of iv glucose on gastric motility is the central nervous system rather than the periphery.

Pharmacological studies of thyrotropin-releasing hormone (TRH) receptors from Xenopus laevis: is xTRHR3 a TRH receptor?

Previously, three receptors, xTRHR1, xTRHR2, and xTRHR3, were cloned from brain tissue of Xenopus laevis with primers designed using sequences from the mammalian TRH receptor (TRHR) subtype 1. We expressed the Xenopus receptors in HEK 293EM cells and studied their binding and signaling properties using a series of TRH analogs substituted at the first, second, and third positions. We observed that the three Xenopus receptors exhibited binding and signaling properties that were distinct. Although xTRHR1 was most similar to mouse TRHR1 (mTRHR1), it exhibited binding affinities that were different from mTRHR1. In contrast to mTRHR2, xTRHR2 exhibited lower affinities and potencies for all TRH analogs than mTRHR1. The xTRHR3 displayed very low affinities and potencies for TRH and TRH analogs and showed little discrimination for TRH analogs; it is likely, therefore, that another peptide is the cognate ligand for xTRHR3. Our findings show differences between TRHR1 and TRHR2 from Xenopus and mammals and suggest that xTRHR3 is a receptor for a ligand other than TRH.

Intravenous urocortin II decreases blood pressure through CRF 2 receptor in rats

Urocortin II (Ucn II) is a new member of the corticotropin-releasing factor (CRF) family that binds selectively to the CRF subtype 2 receptor (CRF 2). CRF or urocortin injected intravenously (iv) induced hypotension. We investigated the influence of iv human Ucn II (hUcn II) on basal mean blood pressure (MAP) and on the sympathetic mediated hypertensive response to TRH analog, RX-77368 injected intracisternally (ic) 20 min after hUcn II in urethane-anesthetized rats. Ucn II (3, 10, and 30 μg/kg, iv) significantly decreased basal MAP from baseline by −20.9±6.5, −21.3±5.4 and −46.8±6.5 mm Hg, respectively, after 10 min. RX-77368 (30 ng, ic) elevated MAP for over 90 min with a maximal hypertensive response at 20 min. Ucn II (3, 10, and 30 μg/kg, iv) did not alter the 20 min net rise in MAP induced by RX-77368 (35.7±7.1, 32.6±3.3 and 24.6±6.9 mm Hg, respectively) compared with vehicle (33.6±4.3 mm Hg). The selective CRF 2 antagonist, astressin 2-B (60 μg/kg, iv) abolished hUcn II hypotensive action while having no effect on basal MAP. These data show that iv hUcn II induces hypotension through peripheral CRF 2 receptor while not altering the responsiveness to sympathetic nervous system-mediated rise in MAP.