CRF1 and CRF2 receptors in the bed nucleus of the stria terminalis modulate the cardiovascular responses to acute restraint stress in rats

The corticotropin-releasing factor (CRF) is involved in behavioral and physiological responses to emotional stress throughits actioninseverallimbic structures,including the bednucleus ofthe stria terminalis (BNST). Nevertheless, the role of CRF1 and CRF2 receptors in the BNST in cardiovascular adjustments during aversive threat is unknown. Therefore, in the present study we investigated the involvement of CRF receptors within the BNST in cardiovascular responses evoked by acute restraint stress in rats. For this, we evaluated the effects of bilateral treatment of the BNST with selective agonists and antagonists of either CRF1 or CRF2 receptors in the arterial pressure and heart rate increase and the decrease in tail skin temperature induced by restraint stress. Microinjection of the selective CRF1 receptor antagonist CP376395 into the BNST reduced the pressor and tachycardiac responses caused by restraint. Conversely, BNST treatment with the selective CRF1 receptor agonist CRF increased restraint-evoked arterial pressure and HR responses and reduced the fall in tail skin temperature response. All effects of CRF were inhibited by local BNST pretreatment with CP376395. The selective CRF2 receptor antagonist antisalvagine-30 reduced the arterial pressure increase and the fall in tail skin temperature. The selective CRF2 receptor agonist urocortin-3 increased restraint-evoked pressor and tachycardiac responses and reduced the drop in cutaneous temperature. All effects of urocortin-3 were abolished by local BNST pretreatment with antisalvagine-30. These findings indicate an involvement of both CRF1 and CRF2 receptors in the BNST in cardiovascular adjustments during emotional stress.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Dysautonomias in parkinson's disease: cardiovascular changes and autonomic modulation in conscious rats after infusion of bilateral 6-OHDA in substantia nigra

It is important to elucidate the mechanism of dysautonomias in patients with Parkinson's disease; therefore, this study aimed to investigate the cardiovascular and autonomic changes that occur in an animal model of Parkinsonism. Adult male Wistar rats were anesthetized before bilateral microinfusions of 6-hydroxydopamine (6-OHDA) into the substantia nigra. The sham group underwent the same surgical procedure but received vehicle. After 7 days, the mean arterial pressure (MAP) and heart rate (HR) were measured, and various drugs were injected into conscious rats through cannulas previously implanted in the femoral artery and vein. Spectral analyses of systolic arterial pressure (SAP) and pulse interval (PI) were conducted with the CardioSeries software as the spontaneous baroreflex gain and effectivity. The animals were subjected to alpha-, beta-adrenergic, or muscarinic receptor antagonism. For confirmation of the lesion, the levels of dopamine in the striatum were quantified by high-performance liquid chromatography. Animals that underwent 6-OHDA microinfusion had lower MAP and HR compared with those in the sham group. Spectral analysis of SAP showed that 6-OHDA animals exhibited a decrease in the sympathetic component. The PI values did not differ between groups. After the administration of muscarinic and beta-adrenergic antagonists, the cardiovascular measures did not differ between the groups. However, upon administration of the alpha-adrenergic antagonist, the 6-OHDA animals exhibited a lower decrease in the MAP. We report cardiovascular impairments in 6-OHDA animals, possibly due to decreased sympathetic activity. Determination of the origin of these changes (central or peripheral) requires further investigation.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq

Chemoreflex and baroreflex alterations in Parkinsonism induced by 6-OHDA in unanesthetized rats

Parkinson's disease (PD) is mainly characterized by motor signals. However, non-motor signals also affect and decrease the quality of life of PD patients. Among these non-motor signs are cardiovascular disorders as orthostatic hypotension, postprandial hypotension and cardiac arrhythmias, which may be due to the involvement of both central nervous system and peripheral autonomic nervous system. In the present study we investigated the cardiovascular function, evaluating cardiovascular reflexes (chemoreflex and baroreflex), in an animal model of Parkinsonism induced by bilateral infusion of the toxin 6-hydroxydopamine (6-OHDA), in the substantia nigra pars compacta (SNpc). The results showed that the animals induced to Parkinsonism had lower arterial pressure (AP) and heart rate HR) compared to control animals. We showed that after activation of the baroreceptors by phenylephrine (Phe) and sodium nitroprusside (SNP), the baroreflex sensitivity index was not changed between the groups. However, there was a greater increase in the AP when stimulated with Phe and greater tachycardia when stimulated with SNP in 6-OHDA animals. After activation of the peripheral chemoreceptors through KCN injection (cytotoxic hypoxia), there was a higher increase in pressor and bradycardic response in injured animals with bilateral 6-OHDA. These changes in the cardiovascular reflexes may be important adjustments mechanisms to maintain the cerebral blood flow in those animals, and may be a result of denervation supersensitivity to catecholamines in autonomic targets.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Cardiovascular Complications following Chronic Treatment with Cocaine and Testosterone in Adolescent Rats

Concomitant use of anabolic androgenic steroids and cocaine has increased in the last years. However, the effects of chronic exposure to these substances during adolescence on cardiovascular function are unknown. Here, we investigated the effects of treatment for 10 consecutive days with testosterone and cocaine alone or in combination on basal cardiovascular parameters, baroreflex activity, hemodynamic responses to vasoactive agents, and cardiac morphology in adolescent rats. Administration of testosterone alone increased arterial pressure, reduced heart rate (HR), and exacerbated the tachycardiac baroreflex response. Cocaine-treated animals showed resting bradycardia without changes in arterial pressure and baroreflex activity. Combined treatment with testosterone and cocaine did not affect baseline arterial pressure and HR, but reduced baroreflex-mediated tachycardia. None of the treatments affected arterial pressure response to either vasoconstrictor or vasodilator agents. Also, heart to body ratio and left and right ventricular wall thickness were not modified by drug treatments. However, histological analysis of left ventricular sections of animals subjected to treatment with testosterone and cocaine alone and combined showed a greater spacing between cardiac muscle fibers, dilated blood vessels, and fibrosis. These data show important cardiovascular changes following treatment with testosterone in adolescent rats. However, the results suggest that exposure to cocaine alone or combined with testosterone during adolescence minimally affect cardiovascular function.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Bed nucleus of the stria terminalis alpha(1) and alpha(2) adrenoceptors differentially modulate the cardiovascular responses to exercise in rats

Dynamic exercise evokes sustained blood pressure and heart rate (HR) increases. Although it is well accepted that there is a CNS mediation of cardiovascular adjustments during dynamic exercise, information on the role of specific CNS structures is still limited. The bed nucleus of the stria terminalis (BST) is involved in exercise-evoked cardiovascular responses in rats. However, the specific neurotransmitter involved in BST-related modulation of cardiovascular responses to dynamic exercise is still unclear. In the present study, we investigated the role of local BST adrenoceptors in the cardiovascular responses evoked when rats are submitted to an acute bout of exercise on a rodent treadmill. We observed that bilateral microinjection of the selective alpha 1-adrenoceptor antagonist WB4101 into the BST enhanced the HR increase evoked by dynamic exercise without affecting the mean arterial pressure (MAP) increase. Bilateral microinjection of the selective alpha 2-adrenoceptor antagonist RX821002 reduced exercise-evoked pressor response without changing the tachycardiac response. BST pretreatment with the nonselective beta-adrenoceptor antagonist propranolol did not affect exercise-related cardiovascular responses. BST treatment with either WB4101 or RX821002 did not affect motor performance in the open-field test, which indicates that effects of BST adrenoceptor antagonism in exercise-evoked cardiovascular responses were not due to changes in motor activity. The present findings are the first evidence showing the involvement of CNS adrenoceptors in cardiovascular responses during dynamic exercise. Our results indicate an inhibitory influence of BST alpha 1-adrenoceptor on the exercise-evoked HR response. Data also point to a facilitatory role played by the activation of BST alpha 2-adrenoceptor on the pressor response to dynamic exercise. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved

Stress vulnerability during adolescence

Objective: This study investigated the physiological and somatic changes evoked by daily exposure to the same type of stressor (homotypic) or different aversive stressor stimuli (heterotypic) in adolescent and adult rats, with a focus on cardiovascular function. The long-term effects of stress exposure during adolescence were also investigated longitudinally. Methods: Male Wistar rats were exposed to repeated restraint stress (RRS, homotypic) or chronic variable stress (CVS, heterotypic). Results: Adrenal hypertrophy, thymus involution, and elevated plasma glucocorticoid were observed only in adolescent animals, whereas reduction in body weight was caused by both stress regimens in adults. CVS increased mean arterial pressure (adolescent: p = .001; adult: p = .005) and heart rate (HR; adolescent: p = .020; adult: p = .011) regardless of the age, whereas RRS increased blood pressure selectively in adults (p = .001). Rest tachycardia evoked by CVS was associated with increased cardiac sympathetic activity in adults, whereas a decreased cardiac parasympathetic activity was observed in adolescent animals. Changes in cardiovascular function and cardiac autonomic activity evoked by both CVS and RRS were followed by alterations in baroreflex activity and vascular reactivity to vasoconstrictor and vasodilator agents in adolescent adult animals. Except for the circulating glucocorticoid change, all alterations observed during adolescence were reversed in adulthood. Conclusions: These findings suggest a stress vulnerability of adolescents to somatic and neuroendocrine effects regardless of stress regimen. Our results indicated an age-stress type-specific influence in stress-evoked cardiovascular/autonomic changes. Data suggest minimal consequences in adulthood of stress during adolescence

Noradrenergic neurotransmission within the bed nucleus of the stria terminalis modulates the retention of immobility in the rat forced swimming test

The bed nucleus of the stria terminalis (BNST) is a limbic structure that has a direct influence on the autonomic, neuroendocrine, and behavioral responses to stress. It was recently reported that reversible inactivation of synaptic transmission within this structure causes antidepressant-like effects, indicating that activation of the BNST during stressful situations would facilitate the development of behavioral changes related to the neurobiology of depression. Moreover, noradrenergic neurotransmission is abundant in the BNST and has an important role in the regulation of emotional processes related to the stress response. Thus, this study aimed to test the hypothesis that activation of adrenoceptors within the BNST facilitates the development of behavioral consequences of stress. To investigate this hypothesis, male Wistar rats were stressed (forced swimming, 15 min) and 24 h later received intra-BNST injections of vehicle, WB4101, RX821002, CGP20712, or ICI118,551, which are selective α1, α2, β1, and β2 adrenoceptor antagonists, respectively, 10 min before a 5-min forced swimming test. It was observed that administration of WB4101 (10 and 15 nmol), CGP20712 (5 and 10 nmol), or ICI118,551 (5 nmol) into the BNST reduced the immobility time of rats subjected to forced swimming test, indicating an antidepressant-like effect. These findings suggest that activation of α1, β1, and β2 adrenoceptors in the BNST could be involved in the development of the behavioral consequences of stress. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

Cardiovascular effects of noradrenaline microinjected into the insular cortex of unanesthetized rats

The insular cortex (IC) has been reported to be involved in central cardiovascular control. In the present study, we investigated the cardiovascular responses evoked by microinjection of noradrenaline into the IC as well as the central and peripheral mechanisms involved in their mediation. Microinjection of noradrenaline into the IC (3, 7, 10, 15,30 and 45 nmol/100 nL) caused long-lasting dose-related pressor and bradycardiac responses. The cardiovascular responses evoked by 15 nmol of noradrenaline were blocked by IC pretreatment with WB4101 or 5-methyl-urapidil, selective alpha(1)-adrenoceptor antagonists. IC pretreatment with either the selective alpha(2)-adrenoceptor antagonists RX821002 or the beta-adrenoceptor antagonist propranolol did not affect noradrenaline cardiovascular responses. Noradrenaline cardiovascular responses were mimicked by microinjection of the selective alpha(1)-adrenoceptor agonist phenylephrine into the IC, thus reinforcing the idea that alpha(1)-adrenoceptors mediate cardiovascular responses to noradrenaline microinjected into the IC. The pressor response to noradrenaline microinjection was potentiated by i.v. pretreatment with the ganglion blocker pentolinium and inhibited by i.v. pretreatment with the selective V(1)-vasopressin receptor antagonist dTyr(CH(2))(5)(Me)AVP. The bradycardiac response to noradrenaline microinjection into the IC was abolished by pretreatment with either pentolinium or the V(1)-vasopressin receptor antagonist, indicating its reflex origin. In conclusion, our results suggest that pressor response evoked by microinjection of noradrenaline into the IC involve the activation of IC alpha(1)-adrenoceptors to cause the release of vasopressin into the circulation. (C) 2010 Elsevier B.V. All rights reserved

Influence of the single or combined administration of cocaine and testosterone in autonomic and neuroendocrine responses to acute restraint stress

Abuse of cocaine and androgenic-anabolic steroids (AASs) has become a serious public health problem. Despite reports of an increase in the incidence of simultaneous abuse of these substances, potential toxic interactions between cocaine and AASs are poorly known. In the present study, we investigated the effects of either single or combined administration of testosterone and cocaine for one or 10 consecutive days on autonomic (arterial pressure, heart rate and tail cutaneous temperature) and neuroendocrine (plasma corticosterone) responses induced by acute restraint stress in rats. Combined administration of testosterone and cocaine for 10 days reduced the increase in heart rate and plasma corticosterone level, as well as the fall in tail skin temperature induced by restraint stress. Furthermore, repeated administration of cocaine inhibited the increase in arterial pressure observed during restraint, and this effect was not affected by coadministration of testosterone. Ten-day combined administration of testosterone and cocaine increased basal values of arterial pressure. Moreover, chronic administration of testosterone induced rest bradycardia and elevated basal level of plasma corticosterone. One-day single or combined administration of the drugs did not affect any parameter investigated. In conclusion, the present study demonstrated that combined administration of testosterone and cocaine changed the autonomic and neuroendocrine responses to acute restraint stress. These findings suggest that interaction between AASs and cocaine may affect the ability to cope with stressful events.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq