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Abstract: In the present study, we investigated the effects induced by fluoxetine treatment (10mg/kg) for either 1 or 21 consecutive days on arterial pressure and heart rate basal levels, baroreflex activity, hemodynamic responses to vasoactive agents and cardiovascular responses to acute restraint stress. Mild hypertension was observed after 21days of treatment, but not after administration for 1day. Moreover, chronic treatment affected the baroreflex control of heart rate, which was characterized by a reduced reflex tachycardia and an enhanced bradycardiac baroreflex response. The pressor responses to systemic administration of the selective α1-adrenoceptor agonist phenylephrine, as well as the depressor responses to systemic infusion of the nitric oxide donor sodium nitroprusside, were reduced after chronic fluoxetine treatment. Fluoxetine treatment for 21days reduced both the pressor and tachycardiac responses evoked by acute restraint stress. In conclusion, the results indicate the development of mild hypertension after chronic fluoxetine treatment. This effect was followed by changes in the baroreflex control of heart rate and altered vascular responsiveness to pressor and depressor agents, which may explain, at least in part, the increase in arterial pressure. Chronic fluoxetine treatment also affected cardiovascular responses to restraint stress, thus indicating that fluoxetine may affect cardiovascular adaptation under conditions of stress. [Copyright &y& Elsevier]

Abstract: 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 45nmol/100nL) caused long-lasting dose-related pressor and bradycardiac responses. The cardiovascular responses evoked by 15nmol of noradrenaline were blocked by IC pretreatment with WB4101 or 5-methyl-urapidil, selective α1-adrenoceptor antagonists. IC pretreatment with either the selective α2-adrenoceptor antagonists RX821002 or the β-adrenoceptor antagonist propranolol did not affect noradrenaline cardiovascular responses. Noradrenaline cardiovascular responses were mimicked by microinjection of the selective α1-adrenoceptor agonist phenylephrine into the IC, thus reinforcing the idea that α1-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 V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP. The bradycardiac response to noradrenaline microinjection into the IC was abolished by pretreatment with either pentolinium or the V1-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 α1-adrenoceptors to cause the release of vasopressin into the circulation. [Copyright &y& Elsevier]

Abstract: Cannabidiol (CBD) is a non-psychotomimetic constituent of the Cannabis sativa plant that inhibits behavioral and cardiovascular responses to aversive situations, facilitating 5-HT1A-mediated neurotransmission. Previous results from our group suggest that the bed nucleus of the stria terminalis (BNST) may be involved in CBD''s anti-aversive effects. To investigate whether the cardiovascular effects of the CBD could involve a direct drug effect on the BNST, we evaluated the effects of CBD microinjection into this structure on baroreflex activity. We also verified whether these effects were mediated by the activation of 5-HT1A receptors. Bilateral microinjection of CBD (60nmol/100nL) into the BNST increased the bradycardiac response to arterial pressure increases. However, no changes were observed in tachycardiac responses evoked by arterial pressure decreases. Pretreatment of the BNST with the selective 5-HT1A receptor antagonist WAY100635 (0.37nmol/100nL) prevented CBD effects on the baroreflex activity. Moreover, microinjection of the 5-HT1A receptor agonist 8-OH-DPAT (4nmol/100nL) caused effects that were similar to those observed after the microinjection of CBD, which were also blocked by pretreatment with WAY100635. In conclusion, the present studies show that the microinjection of CBD into the BNST has a facilitatory influence on the baroreflex response to blood pressure increases, acting through the activation of 5-HT1A receptors. [Copyright &y& Elsevier]

Abstract: In the present study, we investigated the role played by the hypothalamic paraventricular nucleus (PVN) in the modulation of cardiac baroreflex activity in unanesthetized rats. Bilateral microinjections of the nonselective neurotransmission blocker CoCl2 into the PVN decreased the reflex bradycardic response evoked by blood pressure increases, but had no effect on reflex tachycardia evoked by blood pressure decreases. Bilateral microinjections of the selective NMDA glutamate receptor antagonist LY235959 into the PVN caused effects that were similar to those observed after microinjections of CoCl2, decreasing reflex bradycardia without affecting tachycardic response. The microinjection of the selective non-NMDA glutamate receptor antagonist NBQX into the PVN did not affect the baroreflex activity. Also, the microinjection of L-glutamate into the PVN increased the reflex bradycardia, an effect opposed to that observed after PVN treatment with CoCl2 or LY235959, and this effect of L-glutamate was blocked by PVN pretreatment with LY235959. LY235959 injected into the PVN after i.v. treatment with the selective β1-adrenoceptor antagonist atenolol still decreased the reflex bradycardia. Taken together, our results suggest a facilitatory influence of the PVN on the bradycardic response of the baroreflex through activation of local NMDA glutamate receptors and a modulation of the cardiac parasympathetic activity. [Copyright &y& Elsevier]

Abstract: Acute restraint is an unavoidable stress situation that evokes marked and sustained cardiovascular changes, which are characterized by blood pressure and heart rate increases. In the present study, we tested the hypothesis that insular cortex mediates cardiovascular responses to acute restraint stress in rats. To that purpose, the insular cortex synaptic transmission was inhibited by bilateral microinjection of the nonselective synaptic blocker cobalt chloride (CoCl2, 1mM/100nL). Insular cortex pretreatment with CoCl2 decreased restraint-evoked pressor and tachycardiac responses, thus indicating an involvement of synapses within the insular cortex on the modulation of cardiovascular responses to restraint stress. The present results indicate that insular cortex synapses exert a facilitatory influence on blood pressure and HR increase evoked by acute restraint stress in rats. [Copyright &y& Elsevier]

Dynamic exercise evokes sustained cardiovascular changes, which are characterized by blood pressure and heart rate (HR) increases. Although it is well accepted that there is a central nervous system (CNS) mediation of cardiovascular adjustments during dynamic exercise, information on the role of specific CNS structures is limited. The bed nucleus of the stria terminalis (BST) is a forebrain structure known to be involved in central cardiovascular control. Based on this, we tested the hypothesis that BST modulates HR and mean arterial pressure (MAP) responses evoked when rats are submitted to dynamic exercise. Male Wistar rats were tested at three levels of exercise (0.4, 0.8 and 1 km h−1) on a rodent treadmill before and after BST treatment with CoCl2, a non-selective neurotransmission blocker. Bilateral microinjection of CoCl2 (1 nmol in 100 nl artificial cerebrospinal fluid) into the BST reduced the pressor response to exercise at 0.4 km h−1 as well as the tachycardic responses evoked by exercise at 0.4, 0.8 and 1 km h−1. The BST treatment with CoCl2 did not affect baseline MAP or HR, suggesting a lack of tonic BST influence on cardiovascular parameters at rest. Moreover, BST treatment with CoCl2 did not affect motor performance in the open-field test, which indicates that effects of BST inhibition on cardiovascular responses to dynamic exercise are not due to changes in motor activity. The present results suggest that local neurotransmission in the BST modulates exercise-related cardiovascular adjustments. Data indicate that BST facilitates pressor and tachycardic responses evoked by dynamic exercise in rats. [ABSTRACT FROM AUTHOR]

Abstract: The insular cortex (IC) has been reported to modulate the cardiac parasympathetic activity of the baroreflex in unanesthetized rats. However, which neurotransmitters are involved in this modulation is still unclear. In the present study, we evaluated the possible involvement of local IC-noradrenergic neurotransmission in modulating reflex bradycardiac responses. Bilateral microinjection of the selective α1-adrenoceptor antagonist WB4101 (15nmol/100nL), into the IC of male Wistar rats, increased the gain of reflex bradycardia in response to mean arterial pressure (MAP) increases evoked by intravenous infusion of phenylephrine. However, bilateral microinjection of equimolar doses of either the selective α2-adrenoceptor antagonist RX821002 or the non-selective β-adrenoceptor antagonist propranolol into the IC did not affect the baroreflex response. No effects were observed in basal MAP or heart rate values after bilateral microinjection of noradrenergic antagonists into the IC, thus suggesting no tonic influence of IC-noradrenergic neurotransmission on resting cardiovascular parameters. In conclusion, these data provide evidence that local IC-noradrenergic neurotransmission has an inhibitory influence on baroreflex responses to blood pressure increase evoked by phenylephrine infusion through activation of α1-adrenoceptors. [Copyright &y& Elsevier]

Abstract: The aim of this study is to investigate whether extracts and semi-purified fractions obtained from Maytenus ilicifolia leaves have vascular effects in vivo. We tested the ethanolic supernatant of the infusion (ESI), and the ethanolic supernatant of the aqueous extract (ESAE) on the mean arterial pressure (MAP) and heart rate (HR) of anesthetized rats. Intravenous injection of ESAE caused a dose-dependent effect at 10, 20 and 30 mg/kg, reducing MAP by as much as 52.6±5.5 mmHg. Only the highest dose of ESAE (30 mg/kg) caused a significant reduction in HR during its hypotensive effect. The effect of ESAE was unchanged by atropine, propranolol, or bilateral vagotomy, but was significantly reduced (80%) in animals continuously infused with L-NAME. In addition, methylene blue and ODQ, as well as the potassium channel blockers tetraethylammonium, 4-aminopyridine, and glibenclamide, impaired ESAE-induced hypotension. The ethyl acetate fraction (EAF) obtained from ESAE had a potency at least two times greater than ESAE in MAP, without causing any significant change in HR. The hypotension induced by EAF was circumvented by L-NAME, methylene blue and ODQ, strongly reduced by tetraethylammonium and 4-aminopyridine (but not by glibenclamide), and abolished by association of these three potassium channel blockers. Chemical investigation revealed that flavonols, mainly catechin and epicatechin, as well as flavonol glycosides (mono- to triglycosides), and tannins, are the main components of this fraction. Our results demonstrate that preparations obtained from M. ilicifolia present a potent hypotensive effect in vivo, an event predominantly dependent on the nitric oxide/guanylate cyclase pathway. [Copyright &y& Elsevier]

The aim of this work was to test the hypothesis that the bed nucleus of the stria terminalis (BST) and noradrenergic neurotransmission therein mediate cardiovascular responses to acute restraint stress in rats. Bilateral microinjection of the non-specific synaptic blocker CoCl2 (0.1 nmol/100 nl) into the BST enhanced the heart rate (HR) increase associated with acute restraint without affecting the blood pressure increase, indicating that synapses within the BST influence restraint-evoked HR changes. BST pretreatment with the selective α1-adrenoceptor antagonist WB4101 (15 nmol/100 nl) caused similar effects to cobalt, indicating that local noradrenergic neurotransmission mediates the BST inhibitory influence on restraint-related HR responses. BST treatment with equimolar doses of the α2-adrenoceptor antagonist RX821002 or the β-adrenoceptor antagonist propranolol did not affect restraint-related cardiovascular responses, reinforcing the inference that α1-adrenoceptors mediate the BST-related inhibitory influence on HR responses. Microinjection of WB4101 into the BST of rats pretreated intravenously with the anticholinergic drug homatropine methyl bromide (0.2 mg/kg) did not affect restraint-related cardiovascular responses, indicating that the inhibitory influence of the BST on the restraint-evoked HR increase could be related to an increase in parasympathetic activity. Thus, our results suggest an inhibitory influence of the BST on the HR increase evoked by restraint stress, and that this is mediated by local α1-adrenoceptors. The results also indicate that such an inhibitory influence is a result of parasympathetic activation. [ABSTRACT FROM AUTHOR]

Abstract: The diagonal band of Broca (DBB) is involved in cardiovascular control in rats. In the present study, we report the effect of acute and reversible neurotransmission inhibition in the DBB by bilateral microinjection of the nonselective neurotransmission blocker CoCl2 (1mM, 100nL) on the cardiac baroreflex response in unanesthetized rats. Local DBB neurotransmission inhibition did not affect baseline values of either blood pressure or heart rate, suggesting no tonic DBB influence on cardiovascular system activity. However, CoCl2 microinjections enhanced both the reflex bradycardia associated with blood pressure increases caused by i.v. infusion of phenylephrine and tachycardiac response evoked by blood pressure decreases caused by i.v. infusion of sodium nitroprusside. An increase in baroreflex gain was also observed. Baroreflex returned to control values 60min after CoCl2 microinjections, confirming its reversible effect. In conclusion, our data suggest that synapses within DBB have a tonic inhibitory influence on both the cardiac parasympathetic and sympathetic components of the baroreflex. [Copyright &y& Elsevier]

Background and Purpose: We have previously shown that noradrenaline microinjected into the bed nucleus of stria terminalis (BST) elicited pressor and bradycardiac responses in unanaesthetized rats. In the present study, we investigated the subtype of adrenoceptors that mediates the cardiovascular response to noradrenaline microinjection into the BST.Experimental Approach: Cardiovascular responses following noradrenaline microinjection into the BST of male Wistar rats were studied before and after BST pretreatment with different doses of the selective alpha(1)-adrenoceptor antagonist WB4101, the alpha(2)-adrenoceptor antagonist RX821002, the combination of WB4101 and RX821002, the non-selective beta-adrenoceptor antagonist propranolol, the selective beta(1)-adrenoceptor antagonist CGP20712 or the selective beta(2)-adrenoceptor antagonist ICI118,551.Key Results: Noradrenaline microinjected into the BST of unanaesthetized rats caused pressor and bradycardiac responses. Pretreatment of the BST with different doses of either WB4101 or RX821002 only partially reduced the response to noradrenaline. However, the response to noradrenaline was blocked when WB4101 and RX821002 were combined. Pretreatment with this combination also shifted the resulting dose-effect curve to the left, clearly showing a potentiating effect of this antagonist combination. Pretreatment with different doses of either propranolol or CGP20712 increased the cardiovascular responses to noradrenaline microinjected into the BST. Pretreatment with ICI118,551 did not affect cardiovascular responses to noradrenaline.Conclusion and Implications: The present results indicate that alpha(1) and alpha(2)-adrenoceptors mediate the cardiovascular responses to noradrenaline microinjected into the BST. In addition, they point to an inhibitory role played by the activation of local beta(1)-adrenoceptors in the cardiovascular response to noradrenaline microinjected into the BST. [ABSTRACT FROM AUTHOR]

This study investigated the role of AT1, AT2 and Mas angiotensinergic receptors within the MeA in autonomic, cardiovascular and baroreflex changes evoked by a 10‐day (1 hr daily) repeated restraint stress (RRS) protocol. Analysis of cardiovascular function after the end of the RRS protocol indicated increased values of arterial pressure, without heart rate changes. Arterial pressure increase was not affected by acute MeA treatment after the RRS with either the selective AT1 receptor antagonist losartan, the selective AT2 receptor antagonist PD123319 or the selective Mas receptor antagonist A‐779. Analysis of heart rate variability indicated that RRS increased the sympathetic tone to the heart, which was inhibited by MeA treatment with either losartan, PD123319 or A‐779. Baroreflex function assessed using the pharmacological approach via intravenous infusion of vasoactive agents revealed a facilitation of tachycardia evoked by blood pressure decrease in chronically stressed animals, which was inhibited by MeA treatment with losartan. Conversely, baroreflex responses during spontaneous fluctuations of blood pressure were impaired by RRS, and this effect was not affected by injection of the angiotensinergic receptor antagonists into the MeA. Altogether, the data reported in the present study suggest an involvement of both angiotensinergic receptors present in the MeA in autonomic imbalance evoked by RRS, as well as an involvement of MeA AT1 receptor in the enhanced baroreflex responses during full range of blood pressure changes. Results also indicate that RRS‐evoked increase in arterial pressure and impairment of baroreflex responses during spontaneous variations of arterial pressure are independent of MeA angiotensinergic receptors. [ABSTRACT FROM AUTHOR]

We investigated the spontaneous recovery, time course, and the influence of the time of day on the habituation of the cardiovascular responses with repeated exposure to restraint stress in male rats. Habituation of the corticosterone response to repeated restraint stress was also evaluated. The circulating corticosterone response decreased during both the stress and recovery periods of the tenth session of restraint. Habituation of the cardiovascular responses was identified as a faster return to baseline values of the heart rate (HR) and blood pressure (BP) during the recovery period of the tenth session of restraint. Habituation of the HR and BP was still observed after 10 days of discontinuation of the repeated exposure to restraint stress. However, spontaneous recovery of habituated responses was observed 20 days after the final restraint stress session. Time course analysis revealed decreased HR response during the recovery period of the third restraint session, without further reduction on the fifth, seventh, and tenth sessions. Decreased BP response was identified on the third and fifth sessions, whereas reduced tail skin temperature response was observed only on the fifth and seventh sessions. Regarding the time of day, habituation of the tachycardiac response was identified at the tenth session when repeated restraint stress was performed in the morning and night periods, but not in the afternoon. These findings provided evidence of spontaneous recovery of the habituation of cardiovascular responses to repeated restraint stress. Moreover, cardiovascular habituation was dependent on the number of trials and time of day. [ABSTRACT FROM AUTHOR]

The popularity of location-based social networks (LBSNs) has led to a tremendous amount of user check-in data. Recommending points of interest (POIs) plays a key role in satisfying users needs in LBSNs. While recent work has explored the idea of adopting collaborative ranking (CR) for recommendation, there have been few attempts to incorporate temporal information for POI recommendation using CR. In this article, we propose a two-phase CR algorithm that incorporates the geographical influence of POIs and is regularized based on the variance of POIs popularity and users activities over time. The time-sensitive regularizer penalizes user and POIs that have been more time-sensitive in the past, helping the model to account for their long-term behavioral patterns while learning from user-POI interactions. Moreover, in the first phase, it attempts to rank visited POIs higher than the unvisited ones, and at the same time, apply the geographical influence. In the second phase, our algorithm tries to rank users favorite POIs higher on the recommendation list. Both phases employ a collaborative learning strategy that enables the model to capture complex latent associations from two different perspectives. Experiments on real-world datasets show that our proposed time-sensitive collaborative ranking model beats state-of-the-art POI recommendation methods. [ABSTRACT FROM AUTHOR]

This study investigated the influence of exposure to stress during adolescence in autonomic, cardiovascular, neuroendocrine and somatic changes evoked by chronic stress in adult rats. Animals were subjected to a 10-days protocol of repeated restraint stress (RRS, habituating) or chronic variable stress (CVS, non-habituating) during adolescence, adulthood, or repeated exposure to either RRS or CVS in adolescence and adulthood (adolescence+adulthood group). The trials to measure autonomic, cardiovascular, neuroendocrine and somatic changes in all experimental groups were performed in adulthood. CVS increased basal circulating corticosterone levels and caused adrenal hypertrophy in the adolescence+adulthood group, an effect not identified in animals subjected to this stressor only in adulthood or adolescence. CVS also caused a sympathetically-mediated resting tachycardia in the adulthood group. This effect of CVS was not identified in the adolescence+adulthood group once the increased cardiac sympathetic activity was buffered by a decrease in intrinsic heart rate in these animals. Moreover, the impairment in baroreflex function observed in the adulthood group subjected to CVS was shifted to an improvement in animals subjected to repeated exposure to this stressor during adolescence and adulthood. The RRS in the adolescence+adulthood group caused a sympathetically-mediated resting tachycardia, which was not observed in the adulthood group. Our findings suggest that enduring effects of adverse events during adolescence included a vulnerability to neuroendocrine changes and a resilience to autonomic and cardiovascular dysfunctions caused by the CVS. Furthermore, results of RRS indicated a vulnerability to cardiovascular and autonomic changes evoked by homotypic stressors. • Stress in adolescence affects the consequences of chronic stress in adulthood. • Adolescence stress favours neuroendocrine changes of heterotypic stress in adulthood. • Adolescence stress causes resilience to cardiovascular effects of heterotypic stress. • Adolescence stress causes vulnerability to cardiovascular effects of homotypic stress. [ABSTRACT FROM AUTHOR]

A functional lateralization has been reported in control of emotional responses by the medial prefrontal cortex (mPFC). However, a hemisphere asymmetry in involvement of the mPFC in expression of fear conditioning responses has never been reported. Therefore, we investigated whether control by mPFC of freezing and cardiovascular responses during re-exposure to an aversively conditioned context is lateralized. For this, rats had guide cannulas directed to the mPFC implanted bilaterally or unilaterally in the right or left hemispheres. Vehicle or the non-selective synaptic inhibitor CoCl 2 was microinjected into the mPFC 10 min before re-exposure to a chamber where the animals had previously received footshocks. A catheter was implanted into the femoral artery before the fear retrieval test for cardiovascular recordings. We observed that bilateral microinjection of CoCl 2 into the mPFC reduced both the freezing behavior (enhancing locomotion and rearing) and arterial pressure and heart rate increases during re-exposure to the aversively conditioned context. Unilateral microinjection of CoCl 2 into the right hemisphere of the mPFC also decreased the freezing behavior (enhancing locomotion and rearing), but without affecting the cardiovascular changes. Conversely, unilateral synaptic inhibition in the left mPFC did not affect either behavioral or cardiovascular responses during fear retrieval test. Taken together, these results suggest that the right hemisphere of the mPFC is necessary and sufficient for expression of freezing behavior to contextual fear conditioning. However, the control of cardiovascular responses and freezing behavior during fear retrieval test is somehow dissociated in the mPFC, being the former bilaterally processed. • Right mPFC is necessary and sufficient for expression of fear-evoked freezing behavior. • Fear cardiovascular responses are bilaterally processed within the mPFC. • Left mPFC is not related to unilateral processing of fear conditioning responses. [ABSTRACT FROM AUTHOR]

Previous studies showed a prominent role of the medial prefrontal cortex (mPFC), especially the prelimbic (PL) and infralimbic (IL) subregions, in behavioral and physiological responses to stressful stimuli. Nevertheless, the local neurochemical mechanisms involved are not completely understood. In this sense, previous studies identified cholinergic terminals within the mPFC, and stressful stimuli increased local acetylcholine release. Despite these pieces of evidence, the specific role of cholinergic neurotransmission in different subregions of the mPFC controlling the cardiovascular responses to stress has never been systematically evaluated. Therefore, the purpose of this study was to investigate the involvement of cholinergic neurotransmission present within PL and IL in cardiovascular responses to an acute session of restraint stress in rats. For this, rats received bilateral microinjection of the choline uptake inhibitor hemicholinium-3 before exposure to restraint stress. The arterial pressure and heart rate (HR) increases and the decrease in tail skin temperature as an indirect measurement of sympathetically-mediated cutaneous vasoconstriction were recorded throughout the restraint stress session. The results showed that the depletion of acetylcholine within the PL caused by local microinjection of hemicholinium-3 decreased the tachycardia to restraint stress, but without affecting the pressor response and the drop in tail skin temperature. Conversely, IL treatment with hemicholinium-3 decreased the restraint-evoked pressor response and the sympathetically-mediated cutaneous vasoconstriction without interfering with the HR response. Taken together, these results indicate functional differences of cholinergic neurotransmission within the PL and IL in control of cardiovascular and autonomic responses to stressful stimuli. • PL and IL cholinergic neurotransmission mediates stress cardiovascular responses. • Pressor response to restraint is mediated by IL cholinergic neurotransmission. • Drop in skin temperature is also mediated by IL cholinergic neurotransmission. • PL cholinergic neurotransmission is involved in expression of tachycardia to restraint. [ABSTRACT FROM AUTHOR]

Clonidine (CL) and Rilmenidine (RI) are among the most frequently prescribed centrally acting antihypertensives. Here, we compared CL and RI effects on psychogenic cardiovascular reactivity to sonant, luminous, motosensory, and vibrotactile stimuli during neurogenic hypertension. The femoral artery and vein of Wistar (WT – normotensive) and spontaneously hypertensive rats (SHR) were catheterized before (24 h interval) i.p. injection of vehicle (NaCl 0.9%, control ‐ CT group), CL (10 µg/kg), or RI (10 µg/kg) and acute exposure to luminous (5000 lm), sonant (75 dB sudden tap), motor (180° cage twist), and air‐jet (10 L/min – restraint and vibrotactile). Findings showed that: (i) CL or RI reduced the arterial pressure of SHR, without affecting basal heart rate in WT and SHR; (ii) different stimuli evoked pressor and tachycardic responses; (iii) CL and RI reduced pressor response to sound; (iv) CL or RI reduced pressor responses to luminous stimulus without a change in peak tachycardia in SHR; (v) cage twist increased blood pressure in SHR, which was attenuated by CL or RI; (vi) air‐jet increased pressure and heart rate; (vii) CL or RI attenuated the pressor responses to air‐jet in SHR while RI reduced the chronotropic reactivity in both strains. Altogether, both antihypertensives relieved the psychogenic cardiovascular responses to different stimuli. The RI elicited higher cardioprotective effects through a reduction in air‐jet‐induced tachycardia. [ABSTRACT FROM AUTHOR]

Background: Ethanol use is related to a wide variety of negative health outcomes, including cardiovascular diseases. Stress is also involved in numerous pathologies, such as cardiovascular diseases and psychiatric disorders. Sexual dimorphism is an important factor affecting cardiovascular response and has been proposed as a potential risk factor for sex-specific health problems in humans. Here, we evaluated the effect of prolonged ethanol vapor inhalation on arterial pressure, heart rate, and tail skin temperature responses to acute restraint stress, investigating differences between male and female rats. Methods: We exposed male and female Long-Evans rats to ethanol vapor for 14 h, followed by ethanol withdrawal for 10 h, for 30 consecutive days, or to room air (control groups). The animals underwent surgical implantation of a cannula into the femoral artery for assessment of arterial pressure and heart rate values. The tail skin temperature was measured as an indirect measurement of sympathetic vasomotor response. Results: Chronic ethanol vapor inhalation reduced basal heart rate in both female and male rats. Sex-related difference was observed in the decrease of tail cutaneous temperature evoked by stress, but not in the pressor and tachycardiac responses. Furthermore, prolonged ethanol inhalation enhanced the blood pressure and heart rate increase caused by acute restraint stress in male, but not in female rats. However, no effect of chronic ethanol vapor was observed in the tail cutaneous temperature response to restraint in either sex. Conclusion: Chronic ethanol vapor exposure increased the cardiovascular reactivity to stress in male, but not in female rats. [ABSTRACT FROM AUTHOR]

Background: Alcohol abuse is a health concern worldwide. Studies have associated alcohol abuse with cardiovascular impairments. In this study, we investigated differences in the effects of chronic alcohol vapor exposure on cardiovascular function between male and female rats by using the alcohol vapor chamber method to induce alcohol addiction‐like behaviors in rats. Methods: We exposed male and female Long‐Evans rats to alcohol vapor for 14 hours, followed by ethanol withdrawal for 10 hours, for 30 consecutive days or room air (control groups). The animals underwent preparation for the surgical implantation of cannulas into femoral vessels, for allowing the assessment of the basal arterial pressure and heart rate values, baroreflex function, and autonomic activity. Results: Female control rats showed higher basal heart rate compared to male control rats. Chronic alcohol vapor inhalation reduced basal heart rate in females, but not in males; this effect was followed by an increase in the parasympathetic tone of the heart. Further, female rats subjected to alcohol vapor showed an increase in the baroreflex activity. Conclusions: These findings suggest that females are more sensitive to chronic alcohol vapor exposure than males because they had a reduction in basal heart rate and changes in the baroreflex activity. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Nitrergic neurotransmission in the dorsal hippocampus controls baroreflex function. • Hippocampal nNOS and iNOS play an inhibitory role in reflex bradycardia. • Hippocampal iNOS plays a facilitatory role in reflex tachycardia. Abstract The baroreflex is a prominent moment-to-moment mechanism regulating the blood pressure. The hippocampus is a limbic structure in which has been pointed out as part of central network regulating baroreflex. However, the local neurochemical mechanisms involved in control of baroreflex function are not completely understood. Thus, this study aimed to investigate the involvement of nitrergic neurotransmission present in the dorsal hippocampus in baroreflex control of heart rate in conscious rats. For this, we evaluated the effect of bilateral microinjection into the dorsal hippocampus of either the nitric oxide (NO) scavenger carboxy-PTIO, the selective neuronal nitric oxide synthase (nNOS) inhibitor Nω-Propyl- l -arginine (NPLA) or the selective inducible nitric oxide synthase (iNOS) inhibitor 1400 W in bradycardia evoked by blood pressure increases in response to intravenous infusion of phenylephrine, and tachycardia caused by blood pressure decreases evoked by intravenous infusion of sodium nitroprusside. Bilateral microinjection of carboxy-PTIO into the dorsal hippocampus decreased the baroreflex tachycardic response without affecting the reflex bradycardia. Hippocampus treatment with NPLA increased the baroreflex bradycardia gain without affecting the reflex tachycardia. Bilateral hippocampal treatment with 1400 W decreased the reflex tachycardia and increased the baroreflex bradycardic response. Overall, these findings provide evidence that hippocampal nitrergic mechanisms acting in a NOS isoform-specific manner plays a prominent role in control of baroreflex function. Indeed, the results indicate that nNOS and iNOS exerts an inhibitory influence on reflex bradycardia, whereas iNOS mediates the reflex tachycardia. [ABSTRACT FROM AUTHOR]

Habituation of cardiovascular responses upon repeated exposure to stress is controversial. Hence, we hypothesized that habituation of cardiovascular stress responses is influenced by length, frequency, and number of stress sessions in male Wistar rats. Blood pressure and heart rate were recorded via femoral artery catheterization and the tail cutaneous temperature was evaluated using a thermal imager. We observed a faster return of heart rate to baseline values during the post-stress period of the 10th daily session in rats subjected to either 60 (n = 8) or 120 min (n = 7), but not 30 min (n = 7), of restraint. Daily sessions of 120 min also decreased blood pressure during the recovery of the 10th session. The faster return of heart rate to baseline values during the post-stress period at the 10th session in rats exposed to daily 60 min sessions (n = 9) was not identified at the 5th (n = 9) and 20th (n = 9) sessions. Regarding frequency, the tachycardia during the 10th session was enhanced in rats subjected to 60 min of restraint presented every other day (n = 9) and decreased in rats subjected to a protocol of five daily sessions followed by two resting days (n = 9). Thirty-minute sessions of restraint presented twice a day (n = 9) and a protocol of three daily sessions followed by a resting day (n = 9) did not affect the restraint-evoked cardiovascular responses at the 10th session. These results provide evidence of habituation of the cardiovascular responses upon repeated exposure to restraint stress, which is dependent on length, frequency, and number of trials. Lay summary Cardiovascular responses decrease upon repeated exposure to restraint stress. The decrease in cardiovascular stress responses is observed as a faster return to basal values during the post-stress period. The cardiovascular stress response decrease (habituation to stress) is dependent on the length, frequency, and number of stress sessions. [ABSTRACT FROM AUTHOR]

Background and Purpose: The aim of the present study was to assess the interaction of nitrergic neurotransmission within the bed nucleus of the stria terminalis (BNST) with local glutamatergic and noradrenergic neurotransmission in the control of cardiovascular responses to acute restraint stress in rats.Experimental Approach: Interaction with local noradrenergic neurotransmission was evaluated using local pretreatment with the selective α1 -adrenoceptor antagonist WB4101 before microinjection of the NO donor NOC-9 into the BNST. Interaction with glutamatergic neurotransmission was assessed by pretreating the BNST with a selective inhibitor of neuronal NOS (nNOS), Nω-propyl-L-arginine (NPLA) before local microinjection of NMDA. The effect of intra-BNST NPLA microinjection in animals locally pretreated with WB4101 was also evaluated.Key Results: NOC-9 reduced the heart rate (HR) and blood pressure increases evoked by restraint stress. These effects of NOC-9 on HR, but not in blood pressure, was inhibited by pretreatment of BNST with WB4101. NMDA enhanced the restraint-evoked HR increase, and this effect was abolished following BNST pretreatment with NPLA. Administration of NPLA to the BNST of animals pretreated locally with WB4101 decreased the HR and blood pressure increases induced by restraint.Conclusion and Implications: These results indicate that inhibitory control of stress-evoked cardiovascular responses by nitrergic signalling in the BNST is mediated by a facilitation of local noradrenergic neurotransmission. The present data also provide evidence of an involvement of local nNOS in facilitatory control of tachycardia during stress by NMDA receptors within the BNST. [ABSTRACT FROM AUTHOR]

The bed nucleus of the stria terminalis (BNST) is a forebrain structure that has been implicated on cardiovascular responses evoked by emotional stress. However, the local neurochemical mechanisms mediating the BNST control of stress responses are not fully described. In our study we investigated the involvement of glutamatergic neurotransmission within the BNST in cardiovascular changes evoked by acute restraint stress in rats. For this study, we investigated the effects of bilateral microinjections of selective antagonists of either N-methyl-D-aspartate (NMDA) or non-NMDA glutamate receptors into the BNST on the arterial pressure and heart rate increase and the decrease in tail skin temperature induced by acute restraint stress. Microinjection of the selective NMDA glutamate receptor antagonist LY235959 (1 nmol/100 nL) into the BNST decreased the tachycardiac response to restraint stress, without affecting the arterial pressure increase and the drop in skin temperature. Bilateral BNST treatment with the selective non-NMDA glutamate receptor NBQX (1 nmol/100 nL) decreased the heart rate increase and the fall in tail skin temperature, without affecting the blood pressure increase. These findings indicate a facilitatory influence of BNST glutamatergic neurotransmission via coactivation of local NMDA and non-NMDA receptors on the tachycardiac response to stress, whereas control of sympathetic-mediated cutaneous vasoconstriction is selectively mediated by local non-NMDA glutamate receptors. [ABSTRACT FROM AUTHOR]

The insular cortex (IC) is a brain structure involved in physiological and behavioural responses during stressful events. However, the local neurochemical mechanisms involved in control of stress responses by the IC are poorly understood. Thus, this study aimed to investigate the involvement of glutamatergic neurotransmission within the IC in cardiovascular, autonomic and neuroendocrine responses to an acute session of restraint stress. For this, the selective NMDA glutamate receptor antagonist LY235959 (1 nmol/100 nL) or the selective non-NMDA glutamate receptor antagonist NBQX (1 nmol/100 nL) were microinjected into the IC 10 min before the onset of the 60 min session of restraint stress. We observed that the antagonism of NMDA receptors within the IC enhanced the restraint-evoked increase in arterial pressure and heart rate, while blockade of non-NMDA receptors did not affect these cardiovascular responses. Spontaneous baroreflex analysis demonstrated that microinjection of LY235959 into the IC decreased baroreflex activity during restraint stress. The decrease in tail skin temperature during restraint stress was shifted to an increase in animals treated with the NMDA receptor antagonist. Nevertheless, the blockade of either NMDA or non-NMDA glutamate receptors within the IC did not affect the increase in circulating corticosterone levels during restraint stress. Overall, our findings provide evidence that IC glutamatergic neurotransmission, acting via local NMDA receptors, plays a prominent role in the control of autonomic and cardiovascular responses to restraint stress, but without affecting neuroendocrine adjustments. • IC glutamatergic neurotransmission modulates stress responses via NMDA receptors. • NMDA receptors in the IC inhibits restraint-evoked cardiovascular responses. • IC NMDA receptors is involved in baroreflex activity during stress. • NMDA receptors in the IC mediates the drop in skin temperature during stress. • IC glutamatergic neurotransmission is not involved in HPA axis activation. [ABSTRACT FROM AUTHOR]

We investigated the role of corticotropin-releasing factor (CRF) neurotransmission within the lateral hypothalamus (LH) in cardiovascular and anxiogenic-like responses evoked by acute and repeated restraint stress in rats. For this, animals were subjected to intra-LH microinjection of a selective CRF 1 (CP376395) or CRF 2 (antisauvagine-30) receptor antagonist before either an acute or the 10th session of restraint stress. Restraint-evoked arterial pressure and heart rate increases, tail skin temperature decrease and anxiogenic-like effect in the elevated plus maze (EPM) were evaluated. We also assessed the effect of 10 daily sessions of restraint on expression of CRF 1 and CRF 2 receptors within the LH. We identified that antagonism of either CRF 1 or CRF 2 receptor within the LH decreased the tachycardia during both the acute and 10th session of restraint, but the effect of the CRF 1 receptor antagonist was more pronounced during the 10th session. Acute restraint stress also caused anxiogenic-like effect, and this response was inhibited in animals treated with either CP376395 or antisauvagine-30. Anxiety-like behaviors were not changed following the 10th session of restraint, and pharmacological treatments did not affect the behavior in the EPM in chronically stressed animals. Repeated restraint also did not change the level of the CRF receptors within the LH. Taken together, the findings indicate that CRF 1 and CRF 2 receptors within the LH are involved in tachycardic and anxiogenic-like responses to aversive stimuli. Control of tachycardia by the CRF 1 receptor is sensitized by previous stressful experience, and this effect seems to be independent of changes in expression of the receptor. • LH CRF neurotransmission controls cardiovascular and anxiogenic responses to stress. • Control of cardiovascular response is sensitized by previous stress experience. • LH CRF receptors are not involved in habituation of the anxiogenic response to RRS. [ABSTRACT FROM AUTHOR]

Abstract: Systemic administration of cannabidiol (CBD) is able to attenuate cardiovascular responses to acute restraint stress through activation of 5-HT1A receptors. Previous results from our group suggest that the bed nucleus of the stria terminalis (BNST) is involved in the antiaversive effects of the CBD. Moreover, it has been proposed that synapses within the BNST influence restraint-evoked cardiovascular changes, in particular by an inhibitory influence on the tachycardiac response associated to restraint stress. Thus, the present work investigated the effects of CBD injected into the BNST on cardiovascular changes induced by acute restraint stress and if these effects would involve the local activation of 5-HT1A receptors. The exposition to restraint stress increased both blood pressure and heart rate (HR). The microinjection of CBD (30 and 60nmol) into the BNST enhanced the restraint-evoked HR increase, in a dose-dependent manner, without affecting the pressor response. The selective 5-HT1A receptor antagonist WAY100635 by itself did not change the cardiovascular responses to restraint stress, but blocked the effects of CBD. These results showed that CBD microinjected into the BNST enhanced the HR increase associated with acute restraint stress without affecting the blood pressure response. Although these results are not in agreement with those observed after systemic administration of CBD, they are similar to effects observed after reversible inactivation of the BNST. Moreover, similar to the effects observed after systemic administration, CBD effects in the BNST seem to depend on activation of 5-HT1A receptors. [Copyright &y& Elsevier]

Abstract: Dynamic exercise evokes sustained cardiovascular responses, which are characterized by arterial pressure and heart rate increases. Although it is well accepted that there is central nervous system mediation of cardiovascular adjustments during exercise, information on the role of neural pathways and signaling mechanisms is limited. It has been reported that glutamate, by acting on NMDA receptors, evokes the release of nitric oxide through activation of neuronal nitric oxide synthase (nNOS) in the brain. In the present study, we tested the hypothesis that NMDA receptors and nNOS are involved in cardiovascular responses evoked by an acute bout of exercise on a rodent treadmill. Moreover, we investigated possible central sites mediating control of responses to exercise through the NMDA receptor–nitric oxide pathway. Intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK-801) reduced both the arterial pressure and heart rate increase evoked by dynamic exercise. Intraperitoneal treatment with the preferential nNOS inhibitor 7-nitroindazole reduced exercise-evoked tachycardiac response without affecting the pressor response. Moreover, treadmill running increased NO formation in the medial prefrontal cortex (MPFC), bed nucleus of the stria teminalis (BNST) and periaqueductal gray (PAG), and this effect was inhibited by systemic pretreatment with MK-801. Our findings demonstrate that NMDA receptors and nNOS mediate the tachycardiac response to dynamic exercise, possibly through an NMDA receptor–NO signaling mechanism. However, NMDA receptors, but not nNOS, mediate the exercise-evoked pressor response. The present results also provide evidence that MPFC, BNST and PAG may modulate physiological adjustments during dynamic exercise through NMDA receptor–NO signaling. [Copyright &y& Elsevier]

The insular cortex ( IC) has been reported to be involved in the modulation of memory and autonomic and defensive responses. However, there is conflicting evidence about the role of the IC in fear conditioning. To explore the IC involvement in both behavioral and autonomic responses induced by contextual fear conditioning, we evaluated the effects of the reversible inhibition of the IC neurotransmission through bilateral microinjections of the non-selective synapse blocker Co Cl2 (1 m m) 10 min before or immediately after the conditioning session or 10 min before re-exposure to the aversive context. In the conditioning session, rats were exposed to a footshock chamber (context) and footshocks were used as the unconditioned stimulus. Forty-eight hours later, the animals were re-exposed to the aversive context for 10 min, but no shock was given. Behavioral (freezing) as well as cardiovascular (arterial pressure and heart rate increases) responses induced by re-exposure to the aversive context were analysed. It was observed that the local IC neurotransmission inhibition attenuated freezing and the mean arterial pressure and heart rate increase of the groups that received the Co Cl2 either immediately after conditioning or 10 min before re-exposure to the aversive context, but not when the Co Cl2 was injected before the conditioning session. These findings suggest the involvement of the IC in the consolidation and expression of contextual aversive memory. However, the IC does not seem to be essential for the acquisition of memory associated with aversive context. [ABSTRACT FROM AUTHOR]

Abstract: Several studies from our group have indicated that the BNST play an important role in baroreflex modulation. However, the involvement of the BNST in the chemoreflex activity is unknown. Thus, in the present study, we investigated the effect of the local bed nucleus of stria terminalis (BNST) neurotransmission inhibition by bilateral microinjections of the non-selective synaptic blocker cobalt chloride (CoCl2) on the cardiovascular responses to chemoreflex activation in rats. For this purpose, chemoreflex was activated with KCN (i.v.) before and after microinjections of CoCl2 into the BNST. Reversible BNST inactivation produced no significant changes in the magnitude and durations of both pressor and bradycardic responses to intravenous KCN infusion. These findings suggesting that BNST neurotransmission have not influence on both sympathoexcitatory and parasympathoexcitatory components of the peripheral chemoreflex activation. [Copyright &y& Elsevier]

Abstract: 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 α1-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 α2-adrenoceptor antagonist RX821002 reduced exercise-evoked pressor response without changing the tachycardiac response. BST pretreatment with the nonselective β-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 α1-adrenoceptor on the exercise-evoked HR response. Data also point to a facilitatory role played by the activation of BST α2-adrenoceptor on the pressor response to dynamic exercise. [Copyright &y& Elsevier]

Chronic exposure to adverse events has been proposed as a prominent factor involved in etiology and progression of cardiovascular dysfunctions in humans and animals. However, the neurobiological mechanisms involved are still poorly understood. In this sense, chronic stress has been reported to evoke neuroplasticity in corticotropin-releasing factor (CRF) neurotransmission in several limbic structures, including the bed nucleus of the stria terminalis. However, a possible involvement of BNST CRF neurotransmission in cardiovascular dysfunctions evoked by chronic stress has never been reported. Thus, this study investigated the involvement of CRF 1 and CRF 2 receptors within the BNST in cardiovascular changes evoked by chronic stress in rats. We identified that exposure to a 10-day chronic variable stress (CVS) protocol decreased expression of both CRF 1 and CRF 2 receptors within the BNST. These effects were followed by increased arterial pressure and impairment of baroreflex function, but without changes on heart rate. Bilateral microinjection of either the selective CRF 1 receptor antagonist CP376395 or the selective CRF 2 receptor antagonist antisauvagine-30 into the BNST did not affect CVS-evoked arterial pressure increase. Nevertheless, BNST treatment with CP376395 decreased both tachycardic and bradycardic responses of the baroreflex in non-stressed rats; but these effects were not identified in chronically stressed animals. BNST pharmacological treatment with antisauvagine-30 decreased the reflex tachycardia in control animals, whereas reflex bradycardic response was increased in CVS animals. Altogether, the results reported in the present study indicate that down regulation of both CRF 1 and CRF 2 receptors within the BNST is involved in baroreflex impairment evoked by chronic stress. • CVS decreases expression of BNST CRF 1 and CRF 2 receptors. • Downregulation of CRF receptors mediates impaired baroreflex function evoked by CVS. • CRF 1 and CRF 2 receptors in the BNST mediates baroreflex function in nonstressed rats. [ABSTRACT FROM AUTHOR]