Tachycardiac Response Research Articles

Effect of optogenetic excitation of non-orexinergic neurons in the hypothalamic perifornical area on motor behaviors and cardiovascular parameters in rats

Central command, a motor volition originating in the rostral part of the brain, plays a pivotal role in the precise regulation of autonomic nervous and cardiovascular systems. Central neuronal substrates responsible for transmitting central command signals remain incompletely understood. This study aimed to investigate the effect of optogenetic excitation of non-orexinergic (NOrx) neurons in the hypothalamic perifornical area (PeFA), where orexinergic neurons are densely distributed, on motor behaviors and cardiovascular parameters in rats. An adeno-associated viral serotype 2 vector carrying the human synapsin promoter encoding channelrhodopsin 2 (ChR2) fused to EYFP was injected into the PeFA of Sprague-Dawley rats, resulting in selective expression of ChR2-EYFP in NOrx PeFA neurons. In conscious rats, optogenetic excitation of NOrx PeFA neurons rapidly elicited walking or biting behavior, simultaneously causing pressor and tachycardiac responses regardless of the observed behavioral patterns. Under anesthesia, this excitation rapidly increased renal sympathetic nerve activity, immediately followed by sympathoinhibition. These findings suggest that NOrx PeFA neurons transmit central command signals, concurrently regulating somatomotor and autonomic nervous systems for locomotor exercise or biting behavior.

Orexinergic neurons contribute to autonomic cardiovascular regulation for locomotor exercise.

While the hypothalamic orexinergic nervous system is established as having a pivotal role in the long-term regulation of various organismic functions, including wakefulness, metabolism and hypertensive states, whether this system contributes to the rapid autonomic cardiovascular regulation during physical activity remains elusive. This study aimed to elucidate the role of the orexinergic nervous system in transmitting volitional motor signals, i.e. central command, to drive somatomotor and sympathetic cardiovascular responses. We first found that this system is activated by voluntary locomotor exercise as evidenced by an increased expression of Fos, a marker of neural activation, in the orexinergic neurons of Sprague-Dawley rats engaged in spontaneous wheel running. Next, using transgenic Orexin-Cre rats for optogenetic manipulation of orexinergic neurons, we found that optogenetic excitation of orexinergic neurons caused sympathoexcitation on a subsecond timescale under anaesthesia. In freely moving conscious rats, this excitatory stimulation rapidly elicited exploration-like behaviours, predominantly locomotor activity, along with pressor and tachycardiac responses. Meanwhile, optogenetic inhibition of orexinergic neurons during spontaneous wheel running immediately suppressed locomotor activities and blood pressure elevation without affecting basal cardiovascular homeostasis. Taken together, these findings demonstrate the essential role of the orexinergic nervous system in the central circuitry that transmits central command signals for locomotor exercise. This study not only offers insights into the brain circuit mechanisms precisely regulating autonomic cardiovascular systems during voluntary exercise but also likely contributes to our understanding of brain mechanisms underlying abnormal cardiovascular adjustments to exercise in pathological conditions, such as hypertension. KEY POINTS: The hypothalamic orexinergic nervous system plays various roles in the long-term regulation of autonomic and endocrine functions, as well as motivated behaviours. We present a novel, rapid role of the orexinergic nervous system, revealing its significance as a crucial substrate in the brain circuit mechanisms that coordinate somatomotor and autonomic cardiovascular controls for locomotor exercise. Our data demonstrate that orexinergic neurons relay volitional motor signals, playing a necessary and sufficient role in the autonomic cardiovascular regulation required for locomotor exercise in rats. The findings contribute to our understanding of how the brain precisely regulates autonomic cardiovascular systems during voluntary exercise, providing insights into the central neural mechanisms that enhance physical performance moment-by-moment during exercise.

Maternal Hyperglycemia Induces Autonomic Dysfunction and Heart Failure in Older Adult Offspring.

Offspring exposed to an adverse fetal environment, such as gestational diabetes, may manifest increased susceptibility to several chronic diseases later in life. In the present study, the cardiovascular function of three different ages of offspring from diabetic rats was evaluated. Diabetes mellitus was induced in pregnant rats by a single dose of streptozotocin (50 mg/kg). The offspring from diabetic (OD) and control rats (OC) were evaluated at three different ages: 6, 12 or 18 months. In the corresponding OC groups, fasting glycemia, baseline mean arterial pressure, and sympathetic tonus increased in the OD rats at 12 (OD12) and 18 (OD18) months of age, while cardiac hypertrophy was observed in all OD groups. Cardiac function evaluation in vivo showed low left ventricular systolic pressure and+dP/dt in the OD18 rats, suggesting a systolic dysfunction. OD12 and OD18 groups showed high left ventricle end-diastolic pressure, suggesting a diastolic dysfunction. OD groups showed an age-related impairment of both baroreflex-mediated tachycardia and baroreflex-mediated bradycardia in OD12 and OD18 rats. In isolated hearts from OD18 rats, both inotropic and tachycardiac responses to increasing isoproterenol were significantly reduced compared to the corresponding OC group. These results suggest that gestational diabetes triggers the onset of hyperglycemia hypertension with impaired baroreflex sensitivity and heart failure in older age of offspring, representing important risk factors for death. Therefore, ensuring optimal glycemic control in diabetic pregnancy is important and serves as a key to preventing cardiovascular disease in the offspring in their older age.

Central command suppresses pressor-evoked bradycardia at the onset of voluntary standing up in conscious cats.

What is the central question of this study? Standing up can cause hypotension and tachycardia. Accumulated evidence poses the simple question, does the cardiac baroreflex operate at the onset of standing up? If the cardiac baroreflex is suppressed, what mechanism is responsible for baroreflex inhibition? What is the main finding and its importance? In cats, we found blunting of cardiac baroreflex sensitivity in the pressor range at the onset of voluntary hindlimb standing, but not of passive hindlimb standing. This finding suggests that central command suppresses pressor-evoked bradycardia at the onset of standing up, probably in advance, to prevent or buffer orthostatic hypotension. It remains unclear whether cardiac baroreflex function is preserved or suppressed at the onset of standing up. To answer the question and, if cardiac baroreflex is suppressed, to investigate the mechanism responsible for the suppression, we compared the sensitivity of the arterial cardiac baroreflex at the onset of voluntary and passive hindlimb standing in conscious cats. Cardiac baroreflex sensitivity was estimated from the maximal slope of the baroreflex curve between the responses of systolic arterial blood pressure and heart rate to a brief occlusion of the abdominal aorta. The systolic arterial blood pressure response to standing up without aortic occlusion was greater in the voluntary case than in the passive case. Cardiac baroreflex sensitivity was clearly decreased at the onset of voluntary standing up compared with rest (P=0.005) and the onset of passive standing up (P=0.007). The cardiac baroreflex sensitivity at the onset of passive standing up was similar to that at rest (P=0.909). The findings suggest that central command would transmit a modulatory signal to the cardiac baroreflex system during the voluntary initiation of standing up. Furthermore, the present data tempt speculation on a close relationship between central inhibition of the cardiac baroreflex and the centrally induced tachycardiac response to standing up.

Central modulation of cardiac baroreflex moment-to-moment sensitivity during treadmill exercise in conscious cats.

It remains undetermined whether the cardiac component of the entire arterial baroreflex is blunted even at the onset of low‐intensity exercise. We sought to examine the moment‐to‐moment sensitivity of the cardiac baroreflex during walking at different speeds and the presumed mechanisms responsible for baroreflex modulation in conscious cats. Arterial baroreflex sensitivity for heart rate was estimated from the baroreflex ratio between changes in systolic arterial blood pressure and heart rate and from the slope of the baroreflex curve between the cardiovascular responses to brief occlusion of the abdominal aorta. Treadmill walking was performed for 1 min at three levels of speed (low: 20–30 m/min, moderate: 40 m/min, and high: 50–60 m/min) or for 3 min at the stepwise change of speed (low to high to low transition). Cardiac baroreflex sensitivity was blunted at the onset of walking, irrespective of speed. Thereafter, the blunted cardiac baroreflex sensitivity was restored around 15 s of walking at any speed, while the blunting occurred again at 45 s of high‐speed walking. The inhibition of cardiac baroreflex sensitivity also occurred (1) during the speed transition from low to high and (2) at 45 s of high‐speed exercise of the stepwise exercise. The blunted cardiac baroreflex sensitivity was restored immediately to the resting level during the speed transition from high to low, despite sustained pressor and tachycardiac responses. Therefore, moment‐to‐moment modulation of the cardiac baroreflex during exercise would occur in association with motor intention (i.e., exercise onset) and effort (i.e., treadmill speed).

Chronic ethanol vapor exposure potentiates cardiovascular responses to acute stress in male but not in female rats

BackgroundEthanol 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.MethodsWe 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.ResultsChronic 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.ConclusionChronic ethanol vapor exposure increased the cardiovascular reactivity to stress in male, but not in female rats.

Corticotropin-releasing factor neurotransmission in the lateral hypothalamus modulates the tachycardiac response during acute emotional stress in rats

The lateral hypothalamus (LH) is implicated in the physiological and behavioral responses during stressful events. However, the local neurochemical mechanisms related to control of stress responses by this hypothalamic area are not completely understood. Therefore, in this study we evaluated the involvement of CRFergic neurotransmission acting through the CRF1 receptor within the LH in cardiovascular responses evoked by an acute session of restraint stress in rats. For this, we investigated the effect of bilateral microinjection of different doses (0.01, 0.1 and 1 nmol/100 nL) of the selective CRF1 receptor antagonist CP376395 into the LH on arterial pressure and heart rate increases and decrease in tail skin temperature evoked by acute restraint stress. We found that all doses of the CRF1 receptor antagonist microinjected into the LH decreased the restraint-evoked tachycardia, but without affecting the arterial pressure and tail skin temperature responses. Additionally, treatment of the LH with CP376395 at the doses of 0.1 and 1 nmol/100 nL increased the basal values of both heart rate and arterial pressure, whereas the dose of 0.1 nmol/100 nL decreased the skin temperature. Taken together, these findings indicate that CRFergic neurotransmission in the LH, acting through activation of local CRF1 receptors, plays a facilitatory role in the tachycardia observed during aversive threats, but without affecting the pressor and tail skin temperature responses. Our results also provide evidence that LH CRFergic neurotransmission in involved in tonic maintenance of cardiovascular function.

Spontaneous recovery, time course, and circadian influence on habituation of the cardiovascular responses to repeated restraint stress in rats.

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.

Comparison of laryngeal mask airway, cuffed and uncuffed tracheal tubes in pediatric patients during general anesthesia

American Heart Association and the International Liaison Committee on Resuscitation have now accepted cuffed tubes as an alternative to uncuffed ones for pediatric airway. Recently laryngeal mask airway (LMA) has become increasingly popular as an alternative device for airway management in children. The present study was undertaken to evaluate and compare LMA, cuffed and uncuffed Endo tracheal tube (ETT) as airway devices in small children during general anesthesia. The study included 150 patients of age 2-6 years undergoing elective surgery under general anesthesia and randomized to one of the three groups depending on airway device insertion i.e. Group C: Cuffed ETT; Group P: Uncuffed ETT; Group L: cLMA. Variables depicting ease of insertion, hemodynamic parameters and airway morbidity were recorded and assessed. The time taken for insertion of airway device as well as total duration of device in situ was statistically similar in the three groups. First attempt success rate was significantly higher in the cuffed ETT group. Change in size of device was required in 4%, 36.0% and 16.0% patients in groups C, P and L respectively. Number of failures in groups C, P and L respectively was 2%, 0% and 4% (p>0.05). Hypertensive tachycardiac response was minimum in cLMA group. All the three groups were comparable with respect to overall airway morbidity. We conclude that all the three devices including cuffed ETT can be used safely in the pediatric age group.

Corticotropin-releasing hormone projections from the paraventricular nucleus of the hypothalamus to the nucleus of the solitary tract increase blood pressure.

Activation of corticotropin-releasing hormone (CRH) type 2 receptors (CRHR2) in the nucleus of the solitary tract (NTS) contributes to the development of hypertension, but the source of CRH inputs to the NTS that increases blood pressure remains unknown. This study tested the hypothesis that activation of CRH-containing projections from the paraventricular nucleus of the hypothalamus (PVN) to the NTS increase blood pressure. We expressed channelrhodopsin 2 (ChR2), a light-sensitive ion channel, into CRH-containing neurons in the PVN. This was achieved by injecting Cre-inducible virus expressing ChR2 into the PVN of CRH-Cre mice. CRH-Cre mice are genetically modified mice expressing Cre recombinase only in neurons producing CRH. We found that optogenetic stimulation of CRH-containing somas in the PVN or CRH-containing fibers in the NTS originating from the PVN significantly increased blood pressure and heart rate. Microinjection of K-41498 (CRHR2 antagonist) into the NTS attenuated the pressor and tachycardiac responses induced by optogenetic stimulation of CRH-containing somas in the PVN. In vitro loose-patch recordings revealed that optogenetic stimulation of CRH-containing fibers in the NTS originating from the PVN significantly increased the discharge frequency of NTS neurons. This effect was attenuated by pretreatment of K-41498 and was abolished by pretreatment of kynurenic acid (nonselective glutamate receptor antagonist). These results suggest that activation of PVN-NTS CRH-containing projections increases blood pressure and heart rate. The cardiovascular responses may be mediated at least in part by the corelease of CRH and glutamate from NTS CRH-containing axons originating from the PVN. NEW & NOTEWORTHY Optogenetic stimulation of paraventricular nucleus of the hypothalamus (PVN) corticotropin-releasing hormone (CRH)-containing somas or nucleus of the solitary tract (NTS) CRH-containing fibers originating from the PVN increased blood pressure and heart rate. Corelease of CRH and glutamate from NTS CRH-containing axons originating from the PVN may contribute to the pressor and tachycardiac responses elicited by optogenetic stimulation of PVN CRH-containing somas.

Role of Bolus Dose of Fentanyl (4μgm/kg) in Attenuating Presser Response of Laryngoscope and Tracheal Intubation

Fentanyl is an opoid drug. It is effective in controlling pain during intra operative period. It was also observed thermodynamically state intra operatively. Hence it was planned to attenuating the hypertensive and tachycardiac response to laryngoscopey and trachel intubation by using bolus dose of Fentanyl (4μgm /kg).TAJ 2011; 24(2): 124-127

Involvement of CRF1 receptors in bed nucleus of stria terminalis (BNST) on baroreflex responses in chronically stressed rats

INTRODUCTIONStudies suggest the involvement of CRF receptors in bed nucleus of the stria terminalis (BNST) on cardiovascular responses in acute stress. Data from our group had demonstrated that the expression of CRF1 receptors within the BNST is decreased in animals exposed to chronic variable stress (CVS). Nevertheless, an involvement of BNST CRF neurotransmission on cardiovascular changes evoked by CVS has never been investigated.AIMTo evaluate the involvement of CRF1 receptor in the BNST on baroreflex changes evoked by CVS in rats.METHODOLOGYMale Wistar rats (250g) were submitted to stereotaxic surgery for implantation of cannulas into the BNST. After 4 days of recovery, the animals were exposed to a CVS protocol for 10 days. After the last session, the rats had the femoral artery and vein cannulated for cardiovascular record and drug infusion, respectively. Twenty‐four hours later, the experiments were performed. Baroreflex function was assessed by evoking changes on arterial pressure throughout intravenous infusions of phenylephrine and sodium nitroprusside, which evoke pressor and depressor effects, respectively. Baroreflex activity was evaluated in both control rats and animals subjected to ECV protocol before and after bilateral microinjection of the selective CRF1 antagonist CP376395 (5nmol/100nL) into the BNST.RESULTSComparison of values before BNST treatment revealed that ECV decreased the bradycardiac response evoked by blood pressure increase (−48±10 vs −114±23 bpm, P<0.03). Moreover, bilateral microinjection of CP376395 into the BNST decreased reflex bradycardia in control group (−51±13 vs −114±23 bpm, P<0.02), but not in animals subjected to ECV (−51±10 vs −48±10 bpm, P>0.05). The tachycardia evoked by blood pressure decrease was also decreased following ECV (57±5 vs 97±11 bpm, P<0.05). The BNST treatment with CP376395 decreased the tachycardiac response in control animals (50±9 vs 97±11 bpm, P<0.001), but without affecting this response in CVS rats (52±5 vs 57±5 bpm, P>0.05).CONCLUSIONThe impairment of baroreflex function evoked by CVS is related to decreased control of this reflex cardiovascular by CRF1 receptor in the BNST.Support or Funding InformationFINANCIAL SUPPORT: FAPESPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Direct and Indirect Effects of Ephedrine on the Cardiovascular System

After many years of use of ephedrine, there is still confusion as to its exact mode of action: direct agonism (Liles et al., 2007) or actions as an indirect sympathomimetic, or both. We have previously shown that cardiovascular actions of the stimulant cathinone are largely indirect by release of noradrenaline (Alsufyani & Docherty, 2015). We have now investigated, using the same techniques, the cardiac and pressor responses to (±)‐ and (−)‐ephedrine in pentobarbitone anaesthetised male wistar rats. The tachycardiac responses to (±)‐ and (−)‐ephedrine were similar, but pressor responses to (−)‐ephedrine (10 mg/kg) were significantly greater than those to (±)‐ephedrine, and for both, the pressor response was followed by a small depressor response. Sympathectomy did not affect the pressor response, but significantly increased the later depressor response to both compounds. Sympathectomy did not significantly affect cardiac or depressor responses to the direct beta‐adrenoceptor agonist isoprenaline. Sympathectomy significantly reduced the tachycardia to (±)‐ephedrine. It is concluded, firstly, that (−)‐ephedrine is more potent than the racemate mixture at producing pressor responses. Secondly, since the depressor response to the direct agonist isprenaline was unaffected, sympathectomy presumably reduced a later pressor component to the response to (±)‐ and (−)‐ephedrine. Hence, the early pressor response to both (±)‐ and (−)‐ephedrine is direct, but the later pressor response is largely indirect. Ephedrine has both direct and indirect actions on blood pressure.Support or Funding InformationSupported by King Abdelaziz UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Direct and indirect effects of ephedrine on heart rate and blood pressure in vehicle-treated and sympathectomised male rats

We have investigated the cardiac and pressor responses to (±)-ephedrine and (-)-ephedrine in pentobarbitone anaesthetized male wistar rats. The tachycardiac responses to (±)- and (-)-ephedrine were similar, but pressor responses to (-)-ephedrine (10 mg/kg) were significantly greater than those to (±)-ephedrine, and for both, the pressor response was followed by a small depressor response. Sympathectomy did not affect pressor responses, but significantly increased the later depressor response to both compounds. Sympathectomy did not affect tachycardiac or depressor responses to the β-adrenoceptor agonist isoprenaline, but significantly reduced the tachycardia to (±)-ephedrine. (±)-Ephedrine contracted vas deferens from vehicle treatment animals, but in vas deferens from sympathectomised rats, (±)-ephedrine produced almost no tonic contraction (α1A-adrenoceptor mediated), but the phasic contraction was unaffected (α1D-adrenoceptor mediated). It is concluded, firstly, that (-)-ephedrine is more potent than the racemate mixture at producing pressor responses. Secondly, since the depressor response to isoprenaline was unaffected, sympathectomy presumably reduced a pressor component to the response to (±)- and (-)-ephedrine. Hence, a component of the pressor response to both (±)- and (-)-ephedrine is indirect and may involve actions at α1A-adrenoceptors, at which ephedrine does not have marked direct actions.

Control of cardiovascular responses to stress by CRF in the bed nucleus of stria terminalis is mediated by local NMDA/nNOS/sGC/PKG signaling

The aims of the present study were to assess an interaction of corticotropin-releasing factor (CRF) neurotransmission within the bed nucleus of the stria terminalis (BNST) with local nitrergic signaling, as well as to investigate an involvement of activation of local NMDA glutamate receptor and nitric oxide (NO) signaling in control of cardiovascular responses to acute restraint stress by BNST CRF neurotransmission in rats. We observed that CRF microinjection into the BNST increased local NO release during restraint stress. Furthermore, bilateral microinjection of CRF into the BNST enhanced both the arterial pressure and heart rate increases evoked by restraint stress, but without affecting the sympathetically-mediated cutaneous vasoconstriction. The facilitation of both pressor and tachycardiac responses to restraint stress evoked by BNST treatment with CRF were completely inhibited by local pretreatment with either the selective NMDA glutamate receptor antagonist LY235959, the selective neuronal nitric oxide synthase (nNOS) inhibitor Nω-Propyl-l-arginine (NPLA), the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or the protein kinase G (PKG) inhibitor KT5823. Taken together, these results provide evidence that BNST CRF neurotransmission facilitates local NMDA-mediated glutamatergic neurotransmission and activates nitrergic signaling, and this pathway is involved in control of cardiovascular responses to stress.

CRF1 and CRF2 receptors in the bed nucleus of stria terminalis differently modulate the baroreflex function in unanesthetized rats.

The baroreflex is an important blood pressure regulating mechanism. The bed nucleus of stria terminalis (BNST) modulates the baroreflex function. However, the local BNST neurochemical mechanisms involved in control of baroreflex responses are not completely understood. Therefore, in this study, we investigated the involvement of corticotropin-releasing factor (CRF) receptors within the BNST in baroreflex control of heart rate in unanesthetized rats. For this, we evaluated effects of bilateral microinjection into the BNST of either the selective CRF1 receptor antagonist CP376395 (5nmol/100nL) or the selective CRF2 receptor antagonist antisauvagine-30 (5nmol/100nL) in bradycardiac response evoked by blood pressure increases caused by intravenous infusion of phenylephrine as well as tachycardiac response to blood pressure decrease caused by intravenous infusion of sodium nitroprusside. Bilateral microinjection of CP376395 into the BNST decreased the baroreflex bradycardiac response without affecting the reflex tachycardia. Conversely, BNST treatment with antisauvagine-30 decreased heart rate response during blood pressure drop without affecting the reflex bradycardia. Overall, these findings provide evidence of an involvement of CRF neurotransmission within the BNST in baroreflex activity. Nevertheless, data indicate that local CRF1 and CRF2 receptors differently modulate the baroreflex control of heart rate.

Role of the lateral preoptic area in cardiovascular and neuroendocrine responses to acute restraint stress in rats

The lateral preoptic area (LPO) is connected with limbic structures involved in physiological and behavioral responses to stress. Accordingly, exposure to stressors stimuli activates neurons within the LPO. In spite of these evidence, an involvement of the LPO on cardiovascular and neuroendocrine adjustments during aversive threats has not yet been investigated. Therefore, in the present study we tested the hypothesis that the LPO is involved in the control of cardiovascular and neuroendocrine responses to acute restraint stress in rats. Bilateral microinjection of the nonselective synaptic blocker CoCl2 (0.1nmol/100nl) into the LPO did not affect basal values of either arterial pressure, heart rate, tail skin temperature, or plasma corticosterone concentration. However, LPO treatment with CoCl2 enhanced the tachycardiac response and the increase in plasma corticosterone concentration caused by restraint stress. Conversely, LPO synaptic blockade decreased restraint-evoked pressor response. Sympathetic-mediated cutaneous vasoconstriction during restraint stress was not affected by LPO pharmacological treatment. These findings indicate an inhibitory influence of LPO on tachycardiac and plasma corticosterone responses evoked during aversive threats. Additionally, data suggest that LPO plays a facilitatory influence on stress-evoked pressor response.

Both N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptors in the bed nucleus of the stria terminalis modulate the cardiovascular responses to acute restraint stress in rats.

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.

NOP receptors in the prelimbic cortex have an inhibitory influence on cardiovascular responses induced by restraint stress

Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) have structural homology with classic opioids, but constitute a distinct neurotransmitter system because they lack affinity for the opioid peptides and receptors. This neurotransmission is implicated in several physiologic processes, but the role played by NOP receptors during stress situations remains unclear. The acute restraint stress (RS) is a model of unavoidable stress, characterized by sustained increases in mean arterial pressure (MAP), heart rate (HR) and a drop in tail temperature. On another side, the prelimbic (PL) and infralimbic (IL) cortices, subdivisions of the medial prefrontal cortex (MPFC), are implicated in the modulation of functional responses caused by RS. Considering that, the objective of the present study was to investigate the involvement of PL and IL NOP receptors in the control of autonomic responses induced by RS. Bilateral microinjection of nociceptin (NOP agonist) into the PL reduced the cardiovascular responses evoked by RS. Bilateral microinjection of UPF-101 (NOP antagonist) into the PL potentiated the pressor and tachycardiac responses evoked by RS, in a dose-dependent manner. Local pretreatment with UPF-101 blocked the RS-evoked changes following nociceptin administration into the PL. None of these treatments affected the drop in tail temperature induced by RS. Otherwise, the administration of nociceptin or UPF-101 into the IL had no effect on RS-evoked autonomic changes. To investigate the peripheral mechanism involved in the increase in the RS-evoked cardiovascular responses induced by the blockade of PL NOP receptors, rats were intravenous pretreated with either homatropine or atenolol. The intravenous treatment with homatropine blunted the increase in the RS-evoked pressor and tachycardiac response induced by the PL treatment with UPF-101, while the intravenous treatment with atenolol did not affect the RS-evoked pressor and tachycardiac response induced by the PL treatment with UPF-101. In conclusion, our study shows an influence of the PL N/OFQ neurotransmission, but not the IL NOP receptors, in the control of cardiovascular responses observed during acute stress, by increasing cardiac parasympathetic activity.

NMDA and non-NMDA glutamate receptors in the paraventricular nucleus of the hypothalamus modulate different stages of hemorrhage-evoked cardiovascular responses in rats

Here we report the involvement of N-Methyl-d-Aspartate (NMDA) and non-NMDA glutamate receptors from the paraventricular nucleus of the hypothalamus (PVN) in the mediation of cardiovascular changes observed during hemorrhage and post-bleeding periods. In addition, the present study provides further evidence of the involvement of circulating vasopressin and cardiac sympathetic activity in cardiovascular responses to hemorrhage. Systemic treatment with the V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP (50μg/kg, i.v.) increased the latency to the onset of hypotension during hemorrhage and slowed post-bleeding recovery of blood pressure. Systemic treatment with the β1-adrenergic receptor antagonist atenolol (1mg/kg, i.v.) also increased the latency to the onset of hypotension during hemorrhage. Moreover, atenolol reversed the hemorrhage-induced tachycardia into bradycardia. Bilateral microinjection of the selective NMDA glutamate receptor antagonist LY235959 (2nmol/100nL) into the PVN blocked the hypotensive response to hemorrhage and reduced the tachycardia during the post-hemorrhage period. Systemic treatment with dTyr(CH2)5(Me)AVP inhibited the effect of LY235959 on hemorrhage-induced hypotension, without affecting the post-bleeding tachycardia. PVN treatment with the selective non-NMDA receptor antagonist NBQX (2nmol/100nL) reduced the recovery of blood pressure to normal levels in the post-bleeding phase and reduced hemorrhage-induced tachycardia. Combined blockade of both NMDA and non-NMDA glutamate receptors in the PVN completely abolished the hypotensive response in the hemorrhage period and reduced the tachycardiac response in the post-hemorrhage period. These results indicate that local PVN glutamate neurotransmission is involved in the neural pathway mediating cardiovascular responses to hemorrhage, via an integrated control involving autonomic nervous system activity and vasopressin release into the circulation.