Suppression of adrenocorticotrophic hormone secretion by simultaneous antagonism of vasopressin 1b and CRH-1 receptors on three different stress models

Background/Aims: Corticotrophin-releasing hormone (CRH), adrenocorticotrophic hormone (ACTH) and corticosterone are secreted during stress. These mediators may be involved in anxiety, depression and post-traumatic stress disorder, therefore antagonists have been developed to treat such conditions. Methods: the non-peptide CRH receptor type 1 antagonist CP154,526 and the vasopressin receptor type 1b antagonist SSR149415 were used to suppress the secretion of ACTH induced by ether exposure, forced swimming and restraint in adult male Wistar rats. Doses ranged from 3 to 60 mg/kg s.c. (controls with vehicle) alone or in combination, in varying time schedules to assess the duration and effectiveness of treatments. Results: Stressors increased plasma ACTH by 2.5- to 5-fold in control rats. SSR149415 at doses of 30 mg/kg was more effective at suppressing ACTH secretion after ether exposure and restraint but was ineffective against forced swimming. CP154,526 mildly affected ACTH rise after restraint at doses of 30 mg/kg. the combination of both antagonists at doses of 30 mg/kg effectively blocked the rise in plasma ACTH in all three stresses. the drug effects lasted less than 6 h. Conclusion: We demonstrated for the first time that simultaneous blockade of both vasopressin 1b and CRH-R1 receptors effectively abolish the ACTH response to physical and psychological stress modalities. Copyright (c) 2006 S. Karger AG, BaselInst Butantan, Pharmacol Lab, BR-05503900 São Paulo, SP, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilWeb of Scienc

Control of stress-induced acth secretion by vasopressin and crh: additional evidence

Vasopressin and CRH have complementary roles in the secretion of ACTH following different stress modalities. The concomitant use of V-1b and CRF1 receptor antagonists completely inhibits ACTH secretion in response to different stress modalities. The combination of the CRF1 antagonist SSR125543 with the V-1b antagonist SSR149415 effectively suppressed plasma ACTH 1.30 h after injection in rats stressed by ether vapor inhalation for 1 min, restraint stress for 1 h or forced swimming for 5 min. The duration of the effect was also studied. The CRF1 antagonist effectively suppressed ACTH secretion in restraint stress, while the V-1b antagonist was effective against ether inhalation. Both antagonists were necessary to block the forced swimming stress response. SSR125543 induced a prolonged effect and can be used in a model of prolonged HPA axis blockade. (C) 2016 S. Karger AG, BaselAFIPFAPESP [98/14303-3, 04/12871-7, 15/08098-5, 2013/18897-7]CAPESFundacao ButantanDepartment of Psychobiology, Universidade Federal de São Paulo (UNIFESP)Laboratory of Pharmacology, Instituto ButantanLaboratory of Molecular Neuropharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, BrazilDepartment of Psychobiology, Universidade Federal de São Paulo (UNIFESP)Sanofi-Aventis: SSR125543Sanofi-Aventis: SSR149415FAPESP: 98/14303-3FAPESP: 04/12871-7FAPESP: 15/08098-5FAPESP: 2013/18897-7Web of Scienc

Phoneutria nigriventer spider toxin Tx2-6 causes priapism and death: A histopathological investigation in mice

Phoneutria nigriventer spider bite causes priapism, an effect attributed to the peptide toxins Tx2-5 and Tx2-6 and involving nitric oxide. Tx2-6 (MW = 5287) is known to delay the inactivation of Sodium channels in the same fashion as many other venom toxins. In the present study we evaluated the i.p. dose that induces priapism and the other symptoms in mice. Animals killed by the toxin or crude venom (0.85 mg/kg) were autopsied and a pathological study of brain, lung, kidney, liver and heart was undertaken using standard techniques. The same protocol was employed with animals injected with crude venom. Results showed that priapism is the first sign of intoxication, followed by piloerection, abundant salivation and tremors. An i.p. injection of about 0.3 mu g/kg induced only priapism with minimal side-effects. The most remarkable histological finding was a general vascular congestion in all organs studied. Penis showed no necrosis or damage. Lungs showed vascular congestion and alveolar hemorrhage. Heart showed also sub-endothelial hemorrhage. Brain showed only a mild edema and vascular congestion. Results obtained with crude venom closely resemble those of purified toxin. We conclude that Tx2-6 have profound effects on the vascular bed especially in lungs and heart, which may be the cause of death. Interestingly brain tissue was less affected and the observed edema may be attributed to respiratory impairment. To the best of our knowledge this is the first histopathological investigation on this toxin and venom suggesting a possible cause of death. (C) 2012 Elsevier Ltd. All rights reserved.FAPESP [98/02039-0 (gs1), 06/57922-3 (gs1)]FAPES

Erection induced by Tx2-6 toxin of Phoneutria nigriventer spider: Expression profile of genes in the nitric oxide pathway of penile tissue of mice

The peptides Tx2-5 and Tx2-6, isolated from the whole venom of armed-spider Phoneutria nigniventer venom, are directly linked with the induction of persistent and painful erection in the penis of mammals. the erection induced by Tx2-6 has been associated with the activation of nitric oxide synthases. There is a scarcity of studies focusing on the outcome of Tx2-6 at the molecular level, by this reason we evaluated the gene profile activity of this toxin at the nitric oxide (NO) pathway. After microarray analyses on cavernous tissue of mice inoculated with Tx2-6 we found that only 10.4% (10/96) of these genes were differentially expressed, showing a limited effect of the toxin on the NO pathway. We found the genes sparc, ednrb, junb, cdkn1a, bcl2, ccl5, abcc1 over-expressed and the genes sod1, s100a10 and fth1 under-expressed after inoculation of Tx2-6. the differential expressions of sparc and ednrb genes were further confirmed using real-time PCR. Interestingly, ednrb activates the L-arginine/NO/cGMP pathway that is involved in the relaxation of the cavernous body. Therefore the priapism induced by Tx2-6 is a consequence of a highly specific interference of this neurotoxin with the NO pathway. (C) 2009 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ São Paulo, Lab Med Invest LIM55, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilUniv Ibirapuera, São Paulo, BrazilButantan Inst, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilFAPESP: 06/57922-3FAPESP: 06157923-0FAPESP: 04/10372-3FAPESP: 07/52841-8Web of Scienc