Heart failure (HF) is the endstage of multiple cardiovascular diseases.Impaired autonomic regulation and sympathetic-parasympathetic imbalance are considered key factors in HF progression.Baroreflex activation therapy (BAT),a novel device-based therapy which stimulates the carotid sinuses and regulates autonomic function,has demonstrated good efficacy in treating HF and improving prognosis.This review summarized the results of the latest relevant studies to provide support for further study of BAT.
Baroreflex/physiology* ; Heart Failure/therapy* ; Humans

The changes in carotid sinus baroreceptor reflex (CSR) performance induced by intracerebroventricular injection (i.c.v.) of histamine (HA) were investigated. The effects of pretreatment with HA receptors antagonists into the cerebroventricle or nucleus of solitary tract (NTS) on the responses of CSR to HA were also examined. Intracarotid sinus pressure (ISP)-mean arterial pressure (MAP) relationship curve was constructed by fitting to the logistic function with five parameters in 50 Wistar rats anesthetized with pentobarbital sodium. The left and right carotid sinus regions were isolated from the systemic circulation and the ISP was altered in a stepwise manner. The main results obtained are as follows. (1) i.c.v. injection of HA (100 ng) significantly shifted the ISP-MAP relationship curve upwards and moved the middle part of ISP-Gain relationship curve downwards, and reduced the MAP range and maximum gain (G(max)), but increased the threshold pressure (TP), saturation pressure (SP) and ISP at G(max) (ISP (Gmax)). (2) The pretreatment with H(1) or H(2) receptors antagonist, chlorpheniramine (CHL, 5 microg) or cimetidine (CIM, 15 microg), could obviously diminish the above-mentioned changes in CSR performance induced by HA, but the effect of CIM was less remarkable than that of CHL. (3) The pretreatment with both CHL and CIM (5 microg and 15 microg) at the same time abolished the responses of CSR performance to HA completely. (4) After microinjection of CHL (0.5 microg) or CIM (1.5 microg) into the NTS, the responses of CSR to HA were similar to those after i.c.v. CHL or CIM, but the change in TP was significantly decreased. These findings suggest that the intracerebroventricular administration of HA results in a rapid resetting of CSR and a decrease in reflex sensitivity. The response of CSR to HA might be mediated by both central H(1) and H(2) receptors, especially by H(1) receptors. The effects of the central HA on CSR might be related to a histaminergic descending pathway from the hypothalamus to NTS. It is suggested that the HA receptors in the NTS play an important role in the responses of CSR to HA.
Animals ; Baroreflex ; drug effects ; physiology ; Carotid Sinus ; physiology ; Histamine ; administration & dosage ; pharmacology ; Lateral Ventricles ; Male ; Pressoreceptors ; physiology ; Rats ; Rats, Wistar

OBJECTIVETo investigate the effects of central oxidative stress on the baroreflex function and central mechanism responsible for the attenuated baroreflex sensitivity (BRS) in spontaneously hypertensive rats (SHR).

METHODSMale 24-week-old SHR and normal rats were anesthetized with urethane and alpha-chloralose. Intravenous injection of phenylephrine (PE) and sodium nitroprusside (NP) evoked arterial baroreflex. The ratio of change in heart rate (HR) to change in mean aortic pressure (MAP) represented the baroreflex sensitivity (BRS). Alteration in BRS was evaluated before and after intracerebroventricular administration of superoxide dismutase (SOD) mimetic tempol or SOD inhibitor diethyldithiocarbamic acid (DETC).

RESULTSBRS in hypertensive rats was significantly lower than that in normal rats (PE: P < 0.01, NP: P < 0.01). Intracerebroventricular administration of Tempol significantly improved BRS in hypertensive rats (P < 0.05), but not in normal rats. In contrast, DETC decreased BRS to a greater extent in normal group than in hypertension group (P < 0.05). MDA content in hypothalamus of hypertensive rats was higher than that of normal rats (P < 0.01), whereas total antioxidant capacity, total SOD, CuZn-SOD, catalase activity were lower in hypertensive rats than in normal rats (P < 0.05).

CONCLUSIONAttenuated baroreflex function in hypertensive rats is associated with central oxidative stress, which is linked to decreases in antioxidant enzyme activity and antioxidative capacity in the brain.

Animals ; Baroreflex ; physiology ; Central Nervous System ; metabolism ; Male ; Oxidative Stress ; Rats ; Rats, Inbred SHR

The hypothalamic paraventricular nucleus (PVN) is a central site for integration of the endocrine system and the autonomic nervous system. Despite a number of studies have pointed out the importance of the PVN in the central regulation of cardiovascular functions, the chemical mediators in the PVN responsible for mediating baroreflex are not well understood. In the present study, we used the conscious rats to investigate the possible involvement of glycine (Gly) in PVN in the central regulation of baroreflex induced by intravenous injection of phenylephrine (0.8 mug/0.04 mL, in 3 min). Then, the microdialysis sampling was performed in the PVN and the concentration of Gly in the microdialysate was measured by high performance liquid chromatography (HPLC) combined with electrochemical techniques, and mean arterial pressure (MAP) and heart rate (HR) were recorded simultaneously. Injection of phenylephrine elicited a significant increase (P<0.01) in MAP from the baseline of (99.5+/-14.2) mmHg to the maximum of (149.8+/-19.5) mmHg and a decrease (P<0.01) in HR from the baseline of (400.8+/-33.1) beats/min to the minimum of (273.4+/-40.8) beats/min, respectively. Synchronously, the injection of phenylephrine increased the level of Gly in the microdialysate from the PVN to (162.9+/-27.3)% of the basal level (P<0.05). Perfusion of strychnine (100 mumol/L), an antagonist of Gly receptor, into the PVN enhanced the pressor response and attenuated the bradycardic response during the baroreflex, resulting in a decrease in baroreflex sensitivity (P<0.001). Whereas, the perfusion of Gly (1 mmol/L) into the PVN did not affect the pressor response but enhanced the bradycardic response during the baroreflex, resulting in an increase in baroreflex sensitivity (P<0.001). These results suggest that endogenous Gly in the PVN may act via strychnine-sensitive Gly receptor to produce a facilitative effect on baroreflex.
Animals ; Baroreflex ; drug effects ; Glycine ; pharmacology ; Heart Rate ; Microinjections ; Paraventricular Hypothalamic Nucleus ; physiology ; Phenylephrine ; pharmacology ; Rats

Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the arterial baroreflex arc, the pressure sensitivity of arterial baroreceptors is blunted and involved in arterial baroreflex dysfunction in cardiovascular diseases and diabetes. Changes in the arterial vascular walls, mechanosensitive ion channels, and voltage-gated ion channels contribute to the attenuation of arterial baroreceptor sensitivity. Some endogenous substances (such as angiotensin II and superoxide anion) can modulate these morphological and functional alterations through intracellular signaling pathways in impaired arterial baroreceptors. Arterial baroreceptors can be considered as a potential therapeutic target to improve the prognosis of patients with cardiovascular diseases and diabetes.
Animals ; Baroreflex ; physiology ; Blood Pressure ; physiology ; Cardiovascular Diseases ; metabolism ; physiopathology ; Diabetes Mellitus ; metabolism ; physiopathology ; Humans ; Ion Channels ; metabolism ; Pressoreceptors ; metabolism

AIMTo explore the roles of H1 and H2 receptors in the locus ceruleus (LC) in the carotid baroreflex (CBR) resetting resulted from foot-shock stress.

METHODSMale SD rats were divided into two groups (n=18) at random: unstressed and stressed group. The latter were subjected to unavoidable electric foot-shock twice daily for a week and each session of foot-shock lasted 2 hours. The left and right carotid sinus regions were isolated from the systemic circulation in all animals anesthetized with pentobarbital sodium. The intracarotid sinus pressure (ISP) was altered in a stepwise manner in vivo. ISP-mean arterial pressure (MAP), ISP-Gain relationship curves and reflex characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CBR performance induced by stress and the effects of microinjection with histaminergic receptors antagonists into the LC on the responses of CBR to stress were examined.

RESULTSStress significantly shifted the ISP-MAP relationship curve upwards (P < 0.05) and obviously moved the middle part of ISP-Gain relationship curve downwards (P < 0.05), and decreased the value of the MAP range and maximum gain (P < 0.05), but increased the threshold pressure, saturation pressure, set point and ISP at maximum gain (P < 0.05). Microinjection of selective H1 or H2 receptor antagonist, chlorpheniramine (CHL, 0.5 microg/microl) or cimetidine (CIM, 1.5 microg/microl) into the LC, significantly attenuated the above-mentioned changes in CBR performance induced by stress and the alleviate effect of CIM was less remarkable than that of CHL (P < 0.05). The responses of CBR under stress to H1 or H2 receptor antagonist generally occurred 20 min after the administration and lasted approximately for 16 min. Microinjection with the same dose of CHL or CIM into the LC in the unstressed group did not change CBR performance significantly (P > 0.05). However, microinjection of CHL or CIM into the LC could not completely abolish the stress-induced changes in CBR.

CONCLUSIONThe stress results in a resetting of CBR and a decrease in reflex sensitivity. The stress-induced changes in CBR may be mediated, at least in part, by activating the brain histaminergic system. The H1 and H2 receptors in the LC, especially, Hi receptors may play an important role in the resetting of CBR under stress. The descending histaminergic pathway from the hypothalamus to LC may be involved in these effects. Moreover, the effects of stress on CBR also have other mechanisms.

Animals ; Baroreflex ; Carotid Sinus ; physiology ; Locus Coeruleus ; physiology ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, Histamine H1 ; physiology ; Receptors, Histamine H2 ; physiology ; Stress, Physiological

AIMTo investigate the effects of alpha1 and alpha2 receptors in the locus ceruleus (LC) on carotid baroreflex (CBR) resetting induced by intracerebroventricular injection (ICV) of histamine (HA).

METHODSThe left and right carotid sinus regions were isolated from the systemic circulation in 23 Sprague-Dawley rats anesthetized with pentobarbital sodium. The intracarotid sinus pressure (ISP) was altered in a stepwise manner. ISP-mean arterial pressure (MAP) relationship curve and its characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CBR performance induced by ICV HA and the effects of pretreatment with alpha1 or alpha2 receptor antagonist into the LC on the responses of CBR to HA were examined.

RESULTSICV HA (60 micromol x L(-1) in 5 microl) significantly shifted the ISP-MAP relationship curve upwards (P < 0.05) and reduced the MAP range and maximum gain (P < 0.05). The pretreatment with phenoxybenzamine (PBZ, a selective antagonist of alpha1 receptor, 3 micromol x L(-1) in 500 nl) or yohimbine (YOH, a selective antagonist of alpha2 receptor, 2.5 micromol x L(-1) in 500 nl) into the LC could obviously intensify the above-mentioned changes in CBR performance induced by HA, but the intensive effect of PBZ was less remarkable than that of YOH (P < 0.05).

CONCLUSIONThe intracerebroventricular administration of HA results in a rapid resetting of CBR and a decrease in reflex sensitivity, and the functions of alpha1 and alpha2 receptors in the LC may attenuate CBR resetting induced by ICV HA. Furthermore, alpha2 receptor in the LC might play a more important role in regulating the responses of CBR to HA.

Animals ; Baroreflex ; drug effects ; physiology ; Carotid Sinus ; Histamine ; pharmacology ; Locus Coeruleus ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, Neurotransmitter

The role of atrial natriuretic peptide (ANP) in the central regulation of the circulation is known to be a neurotransmitter or a neuromodulator, but its actions on baroreceptor reflex function are not fully resolved. The present study examined the role of ANP (6, 60 ng/0.2 microl) by direct microinjection into the hypothalamic paraventricular nucleus (PVN) in conscious rats. OPC-21268 (0.45 microg/3 microl), an antagonist of the V(1) receptor, was microinjected into the lateral ventricle to examine whether the effect of ANP on baroreflex sensitivity is mediated by vasopressin (VP). ANP significantly increased the baroreflex sensitivity, and OPC-21268 attenuated the increase of baroreflex sensitivity induced by ANP. Intravenous injections of ANP (60 ng/0.04 ml) did not affect baroreflex sensitivity. These results suggest that ANP in the PVN may produce a facilitative effect on baroreflex, and the effect may be via, at least in part, the central vasopressin.
Animals ; Atrial Natriuretic Factor ; pharmacology ; physiology ; Baroreflex ; drug effects ; physiology ; Male ; Microinjections ; Paraventricular Hypothalamic Nucleus ; physiology ; Random Allocation ; Rats ; Rats, Wistar

The carotid sinus baroreceptor reflex (CSR) is an important approach for regulating arterial blood pressure homeostasis instantaneously and physiologically. Activation of the central histaminergic or cholinergic systems results in CSR functional inhibitory resetting. However, it is unclear whether two systems at the nucleus tractus solitarius (NTS) level display cross interaction to regulate the CSR or not. In the present study, the left or right carotid sinus region was isolated from the systemic circulation in Sprague-Dawley rats (sinus nerve was reserved) anesthetized with pentobarbital sodium. Respective intubation was conducted into one side isolated carotid sinus and into the femoral artery for recording the intracarotid sinus pressure (ISP) and mean arterial pressure (MAP) simultaneously with pressure transducers connection in vivo. ISP was set at the level of 0 mmHg to eliminate the effect of initial internal pressure of the carotid sinus on the CSR function. To trigger CSR, the ISP was quickly elevated from 0 mmHg to 280 mmHg in a stepwise manner (40 mmHg) which was added at every step for over 4 s, and then ISP returned to 0 mmHg in similar steps. The original data of ISP and corresponding MAP were fitted to a modified logistic equation with five parameters to obtain the ISP-MAP, ISP-Gain relationship curves and the CSR characteristic parameters, which were statistically compared and analyzed separately. Under the precondition of no influence on the basic levels of the artery blood pressure, the effects and potential regulatory mechanism of preceding microinjection with different cholinoceptor antagonists, the selective cholinergic M1 receptor antagonist, i.e., pirenzepine (PRZ), the M2 receptor antagonist, i.e., methoctramine (MTR) or the N1 receptor antagonist, i.e., hexamethonium (HEX) into the NTS on the changes in function of CSR induced by intracerebroventricular injection (i.c.v.) of histamine (HA) in rats were observed. Meanwhile, the actions and possible modulatory mechanism of preceding microinjection with different histaminergic receptor antagonists, the selective histaminergic H1 receptor antagonist, i.e., chlorpheniramine (CHL) or the H2 receptor antagonist, i.e., cimetidine (CIM) into the NTS on the changes in function of CSR resulted from the i.c.v. cholinesterase inhibitor, physostigmine (PHY) were also examined in order to confirm and to analyze effects of cross interaction between central histaminergic and cholinergic systems on CSR. The main results obtained are as follows. (1) Standalone microinjection of different selective cholinergic receptor antagonists (PRZ, MTR or HEX) or different selective histaminergic receptor antagonists (CHL or CIM) into the NTS with each given dose had no effects on the CSR function and on the basic levels of the artery blood pressure, respectively (P > 0.05). (2) The pretreatment of PRZ or MTR into the NTS with each corresponding dose could attenuate CSR resetting resulted from i.c.v. HA in some degrees, which remarkably moved the posterior half range of ISP-MAP relationship curve downwards (P < 0.05), shifted the middle part of ISP-Gain relationship curve upwards (P < 0.05), and increased reflex parameters such as the MAP range and maximum gain (P < 0.05), but decreased parameters such as saturation pressure and intracarotid sinus pressure at maximum gain (P < 0.05). The catabatic effects of pretreatment with MTR into the NTS on CSR resetting induced by i.c.v. HA were more obvious than those with PRZ (P < 0.05), but pretreatment of HEX with given dose into the NTS had no effects on CSR resetting induced by i.c.v. HA (P > 0.05). (3) The effects of pretreatment of CHL or CIM into the NTS with each corresponding dose on CSR resetting made by i.c.v. PHY were similar to those of pretreatment of PRZ or MTR into the NTS on CSR resetting resulted from i.c.v. HA, and the decreasing effects of pretreatment with CHL into the NTS on CSR resetting induced by i.c.v. PHY were more remarkable than those with CIM (P < 0.05). These findings suggest that CSR resetting resulted from either HA or PHY into the lateral ventricle may partly involve the descending histaminergic or cholinergic pathway from the hypothalamus to NTS, which might evoke a cross activation of the cholinergic system in the NTS, via cholinergic M1 and M2 receptors mediation, especially the M2 receptors showing actions, or trigger another cross activation of the histaminergic system in the NTS, by histaminergic H1 and H2 receptors mediation, especially the H1 receptors displaying effects.
Animals ; Baroreflex ; Carotid Sinus ; physiology ; Chlorpheniramine ; pharmacology ; Cholinergic Antagonists ; pharmacology ; Cimetidine ; pharmacology ; Histamine ; pharmacology ; Pressoreceptors ; physiology ; Rats ; Rats, Sprague-Dawley ; Solitary Nucleus ; physiology

Excessive reactive oxygen species (ROS) (such as the superoxide radical) are commonly associated with cardiac autonomic dysfunctions. Though superoxide dismutase 1 (SOD1) overexpression may protect against ROS damage to the autonomic nervous system, superoxide radical reduction may change normal physiological functions. Previously, we demonstrated that human SOD1 (hSOD1) overexpression does not change baroreflex bradycardia and tachycardia but rather increases aortic depressor nerve activity in response to arterial pressure changes in C57B6SJL-Tg (SOD1)2 Gur/J mice. Since the baroreflex arc includes afferent, central, and efferent components, the objective of this study was to determine whether hSOD1 overexpression alters the central and vagal efferent mediation of heart rate (HR) responses. Our data indicate that SOD1 overexpression decreased the HR responses to vagal efferent nerve stimulation but did not change the HR responses to aortic depressor nerve (ADN) stimulation. Along with the previous study, we suggest that SOD1 overexpression preserves normal baroreflex function but may differentially alter the functions of the ADN, vagal efferents, and central components. While SOD1 overexpression likely enhanced ADN function and the central mediation of bradycardia, it decreased vagal efferent control of HR.
Animals ; Baroreflex ; physiology ; Blood Pressure ; physiology ; Bradycardia ; metabolism ; Heart Rate ; physiology ; Humans ; Mice, Transgenic ; Superoxide Dismutase-1 ; metabolism ; Vagus Nerve ; metabolism