Baroreflex Control Of Blood Pressure Research Articles

Sex differences in carotid baroreflex control of arterial blood pressure in humans: relative contribution of cardiac output and total vascular conductance

It is presently unknown whether there are sex differences in the magnitude of blood pressure (BP) responses to baroreceptor perturbation or if the relative contribution of cardiac output (CO) and total vascular conductance (TVC) to baroreflex-mediated changes in BP differs in young women and men. Since sympathetic vasoconstrictor tone is attenuated in women, we hypothesized that carotid baroreflex-mediated BP responses would be attenuated in women by virtue of a blunted vascular response (i.e., an attenuated TVC response). BP, heart rate (HR), and stroke volume were continuously recorded during the application of 5-s pulses of neck pressure (NP; carotid hypotension) and neck suction (NS; carotid hypertension) ranging from +40 to -80 Torr in women (n = 20, 21 ± 0.5 yr) and men (n = 20, 21 ± 0.4 yr). CO and TVC were calculated on a beat-to-beat basis. Women demonstrated greater depressor responses to NS (e.g., -60 Torr, -17 ± 1%baseline in women vs. -11 ± 1%baseline in men, P < 0.05), which were driven by augmented decreases in HR that, in turn, contributed to larger reductions in CO (-60 Torr, -15 ± 2%baseline in women vs. -6 ± 2%baseline in men, P < 0.05). In contrast, pressor responses to NP were similar in women and men (e.g., +40 Torr, +14 ± 2%baseline in women vs. +10 ± 1%baseline in men, P > 0.05), with TVC being the primary mediating factor in both groups. Our findings indicate that sex differences in the baroreflex control of BP are evident during carotid hypertension but not carotid hypotension. Furthermore, in contrast to our hypothesis, young women exhibited greater BP responses to carotid hypertension by virtue of a greater cardiac responsiveness.

Orthostatic intolerance in the heat: are the α-adrenergic receptors the culprit?

Orthostatic intolerance in the heat: are the α-adrenergic receptors the culprit?

Alterations in carotid baroreflex control of arterial blood pressure during the menstrual cycle in young women

Limited studies have suggested that menstrual cycle variations in sex hormones may influence arterial baroreflex control of heart rate (HR) and sympathetic nerve activity; however, results are equivocal. In addition, the baroreflex control of blood pressure (BP) has not been directly examined as pharmacological perturbations were mainly used to assess baroreflex function. Therefore, 5s pulses of neck suction (NS, −60 Torr) and neck pressure (NP, +40 Torr) were applied to load and unload the carotid baroreflex (CBR), respectively in young women during the early follicular (EF, day 1–5, low estrogen, low progesterone), late follicular (LF, day 10–12, high estrogen, low progesterone), and mid luteal (ML, day 20–24, high estrogen, high progesterone) menstrual cycle phases. Resting HR and BP were not different between the 3 phases. Similarly, HR responses to NP and NS were not significantly different between phases. In contrast, mean BP responses to NP were significantly greater in the ML phase (Δ17±1 vs. Δ13±1 EF; Δ13±2 LF mmHg; P&lt;0.05); however, responses to NS were not significantly different between phases (EF Δ−10±2, LF Δ−10±1, and ML Δ−10±1 mmHg). These preliminary findings suggest a maintained CBR control of HR throughout the menstrual cycle whereas concomitant elevations in estrogen and progesterone selectively augment CBR‐mediated BP responses to hypotension without effect on CBR responses to hypertension.Supported by R01HL093167.

Effects of chronic melatonin treatment in renovascular hypertension

Experimental evidence suggests that reactive oxygen species which occur as a consequence of renal artery stenosis play a significant role in the hypertensive responses to increased Ang II. The aim of this study was to test the hypothesis that melatonin could alleviate renovascular hypertension through its antioxidant effects, as well as by its modulatory role on cardiovascular functions. Male Wistar rats were submitted to Goldblatt surgery (2K‐1C) to induce renovascular hypertension. Melatonin treatment started 5 weeks after surgery (30 mg/Kg, orally, daily) and continuous for 2 weeks. Blood pressure (BP), heart rate (HR) and baroreflex control were evaluated in conscious rats. Melatonin treatment produced a significant reduction in BP when compared to control hypertensive animals (128.1±2,6 x 180.4±16,9 mmHg) with no changes in HR. Hypertension induced profound alterations in the baroreflex control of blood pressure and treatment with melatonin were able to reverse these alterations. In conclusion, melatonin treatment was able to reduce blood pressure and improved baroreflex control in renovascular hypertension, suggesting that melatonin may be of therapeutic use in preventing oxidative stress due to hypertension.

A novel postsynaptic group II metabotropic glutamate receptor role in modulating baroreceptor signal transmission.

The nucleus tractus solitarius (NTS) is essential for orchestrating baroreflex control of blood pressure. When a change in blood pressure occurs, the information is transmitted by baroreceptor afferent fibers to the central network by glutamate binding to ionotropic glutamate receptors on second-order baroreceptor neurons. Glutamate also activates presynaptic group II and III metabotropic glutamate receptors (mGluRs), depressing both glutamate and GABA release to modulate baroreceptor signal transmission. Here we present a novel role for postsynaptic group II mGluRs to further fine-tune baroreceptor signal transmission at the first central synapses. In a brainstem slice with ionotropic glutamate and GABA receptors blocked, whole-cell patch-clamp recordings of second-order baroreceptor neurons revealed that two group II mGluR agonists evoked concentration-dependent membrane hyperpolarizations. The hyperpolarization remained when a presynaptic contribution was prevented with Cd(2+), was blocked by a postsynaptic intervention of intracellular dialysis of the G-protein signaling inhibitor, was mimicked by endogenous release of glutamate by tractus solitarius stimulation, and was prevented by a group II mGluR antagonist. Postsynaptic localization of group II mGluRs was confirmed by fluorescent confocal immunohistochemistry and light microscopy. Group II mGluR induced-currents consisted of voltage-dependent outward and inward components, prevented by tetraethylammonium chloride and tetrodotoxin, respectively. In contrast to group II mGluR-induced hyperpolarization, there was no effect on intrinsic excitability as determined by action potential shape or firing in response to depolarizing current injections. The data suggest a novel mechanism for postsynaptic group II mGluRs to fine-tune baroreceptor signal transmission in the NTS.

Central mechanisms of baroreflex control of blood pressure

Central mechanisms of baroreflex control of blood pressure

Heat Stress and Baroreflex Regulation ofBlood Pressure

In healthy, noninjured, individuals, passive (i.e., nonexercising) whole-body heating has the potential to cause significant cardiovascular stress that may be second only to the cardiovascular stress associated with exercise. For example, such a heat stress can increase heart rate to well over 100 beats min(-1) with cardiac output increasing upward to 13 L min(-1). This increase in cardiac output is necessary to maintain blood pressure due to profound reductions in total vascular conductance associated with cutaneous vasodilation. These responses are accompanied with elevations in sympathetic activity and reductions in vascular conductance (i.e., increased vascular resistance) from noncutaneous beds. While heat-stressed, blood pressure control is compromised resulting in orthostatic intolerance. A plausible explanation for such an event is that heat stress impairs baroreflex responsiveness perhaps due to the reduced range by which baroreflexes can increase heart rate, cardiac output, sympathetic activity, and vascular resistance during a hypotensive challenge. Given that dynamic exercise has the potential to cause large increases in internal temperature, possibly a component of the response to exercise, with respect to baroreflex control of blood pressure, may be affected by the thermal load during the exercise bout. Within this context, the purpose of this review was to summarize findings investigating the effects of heat stress on baroreflex regulation of blood pressure.

Recent Advances in Baroreflex Control of Blood Pressure during Exercise in Humans

This article provides an overview of the history behind the physiological concepts defining the role of the arterial baroreflexes and their regulation of arterial blood pressure during dynamic exercise. Initially, the case is made as to "why the arterial baroreflexes must be involved with blood pressure regulation during exercise." Subsequently, the historical animal and human experiments performed from the late 19th century to the present day describing how the two major neural mechanisms "central command" and "exercise pressor reflex" and their involvement in "resetting" are reviewed. These historical experiments have resulted in the development of a hypothetical model identifying the major factors involved in baroreflex resetting, and these factors are described. The four manuscripts presented in these proceedings address a new set of questions. These new questions address the importance of the baroreflex control of muscle sympathetic nerve activity and vasomotor tone in the regulation of blood flow, not only in the systemic vasculature but also in the cerebral and cutaneous vasculatures.

All the King's horses and all the King's men: maybe Physiology can put Humpty Dumpty back together again

In this issue of The Journal of Physiology we launch an initiative to highlight the potential clinical implications of one or more research papers via a Clinical Perspectives article. Why are we doing this? The simple answer is that integrative physiology, and the clinical outlook that can flow from it, provides a key set of intellectual tools that can frame observations across a spectrum of biological complexity. This permits physiologists, in our role as biological integrators and story tellers, to both reach back to molecular and reductionist observations and at the same time reach forward to implications for disease risk, epidemiology and ideas about novel therapeutic strategies. From the perspective of an integrative physiologist what is missing from both the fashionable (especially with funding agencies) reductionistic and population/outcomes approaches is any sense of a larger biological narrative that links findings from differing levels of intellectual exploration into a coherent story. This is also painfully obvious for those of us who have the pleasure of teaching the very bright graduate and medical students we encounter: they have all the tools needed to tackle interesting projects, but are unable to generate the plans needed to build an ‘intellectual house’. One current and favoured approach to reconciling the reductionist and population based ends of the biomedical research spectrum involves the so-called genome wide association studies (GWAS). The goal with this approach is to link or identify specific genetic variants (or patterns of variation) with the risk or presence of a certain phenotypic trait. For many diseases highly significant gene variants confer levels of ‘risk’ that are barely above what an integrative or clinical physiologist might call the regulatory signal to noise ratio. In other words, when individuals with specific variants are subjected to a ‘physiological’ test that stresses the system of interest, those with variant A don't respond much differently from those with variant B. So it appears that the GWAS approach is sometimes little more than biological bookmaking on a grand scale and falls short of telling a compelling story. Similarly, when critical genes are knocked out, varied or manipulated in animal models, the most obvious conclusions seem to be either that redundant systems compensate to keep physiological parameters ‘normal’ in spite of the intervention, or that the gene of interest really was important because manipulating it had a lethal outcome. Systems biology claims to offer another solution to the problems highlighted above, but so far it seems obscure at best. That having been said, why then is physiology the discipline that can put this biological Humpty Dumpty back together again? The language of physiology captures concepts like homeostasis, redundancy, acute and chronic adaptations to stress, regulation, feedback and feed forward control, compensation and so forth. Using this language narratives and schemes that link the subcellular, cellular, organ and organism's integrated responses are developed. These schemes can then be framed as testable hypotheses and stimulate experiments by investigators at multiple levels. For example ideas about baroreflex control of blood pressure have led to studies ranging from the basic mechanisms of mechanotransduction in cells all the way to population based studies on hypertension. The ‘size principle’ describing how the brain and spinal cord organize motor-unit recruitment and movement is another triumph of physiological conceptualization that operates to inform experiments at every level of biological integration. So, the goal of a Journal of Physiology Clinical Perspectives article is to use physiology's unique set of intellectual tools along with an outstanding paper to explore the larger biological issues and make connections that could lead to solutions. Maybe Humpty Dumpty can live again.

Inhibition of spontaneous neurotransmission in the nucleus of solitary tract of the rat by the cannabinoid agonist WIN 55212-2 is not via CB1 or CB2 receptors

Cannabinoids have been shown to modulate central autonomic regulation and baroreflex control of blood pressure. Both CB1 and CB2 cannabinoid receptors have been described in the nucleus tractus solitarius (NTS), which receives direct afferent projections of cardiovascular reflexes. In the present study we evaluated the effects of WIN 55212-2 (WIN), a cannabinoid agonist, on fast neurotransmission in the NTS. We recorded spontaneous post-synaptic currents using the whole-cell configuration in NTS cells in brainstem slices from young rats (25–30 days old). Application of 5 μM WIN inhibited the frequency of both glutamatergic and GABAergic sPSCs, without affecting their amplitudes. Effects of WIN were not blocked by application of the CB1 antagonist AM251, the CB2 antagonist AM630 or the vanniloid receptor TRPV1 antagonist AMG9810, suggesting that the effect of WIN is via a non-CB1 non-CB2 receptor. Neither the CB1/CB2 agonist HU210 nor the CB1 agonist ACPA affected the frequency of sPSCs. We conclude WIN inhibits the neurotransmission in the NTS of young rats via a receptor distinct from CB1 or CB2.

Impact of age on the vasovagal response provoked by sublingual nitroglycerine in routine tilt testing

NTG (nitroglycerine) is used in routine tilt testing to elicit a vasovagal response. In the present study we hypothesized that with increasing age NTG triggers a more gradual BP (blood pressure) decline due to a diminished baroreflex-buffering capacity. The purpose of the present study was to examine the effect of NTG on baroreflex control of BP in patients with distinct age-related vasovagal collapse patterns. The study groups consisted of 29 patients (16-71 years old, 17 females) with clinically suspected VVS (vasovagal syncope) and a positive tilt test. Mean FAP (finger arterial pressure) was monitored continuously (Finapres). Left ventricular SV (stroke volume), CO (cardiac output) and SVR (systemic vascular resistance) were computed from the pressure pulsations (Modelflow). BRS (baroreflex sensitivity) was estimated in the time domain. In the first 3 min after NTG administration, BP was well-maintained in all patients. This implied an adequate arterial resistance response to compensate for steeper reductions in SV and CO with increasing age. HR (heart rate) increased and the BRS decreased after NTG administration. The rate of mean FAP fall leading to presyncope was inversely related to age (r=0.51, P=0.005). Accordingly, patients with a mean FAP fall >1.44 mmHg/s (median) were generally younger compared with patients with a slower mean FAP-fall (30+/-10 years compared with 51+/-17 years; P=0.001). The main determinant of the rate of BP fall on approach of presyncope was the rate of fall in HR (r=0.75, P<0.001). It was concluded that, in older patients, sublingual NTG provokes a more gradual BP decline compared with younger patients. This gradual decline cannot be ascribed to failure of the baroreflex-buffering capacity with increasing age. Age-related differences in the laboratory presentation of a vasovagal episode depend on the magnitude of the underlying bradycardic response.

Effects of physical training on cardiovascular control after heart transplantation

Background Exercise performance in heart-transplanted patients increases with respect to pre-transplantation but remains subnormal, and it does not improve with time after surgery. Possible causes include persisting denervation, and sympathetic vasoconstriction inducing functional vascular abnormalities that prevent adequate increase in blood flow to the exercising limbs. We tested the effects of physical training on baroreceptors-mediated control of heart rate and blood pressure in recently heart-transplanted subjects. Methods Patients were randomly allocated to physical training ( n = 13, 30 min cycling at 60–70% of peak oxygen consumption for 5 days/week for 6 months) or to control ( n = 11). Upright exercise test to exhaustion was performed at the beginning of the study after 3 and 6 months. Reflex changes in RR interval and blood pressure in response to sinusoidal neck suction (6 and 12 cycles/min 0 to − 30 mm Hg swing) were considered as evidence of reinnervation and baroreflex control of blood pressure, respectively. Results After 6 months peak oxygen consumption ( p < 0.001), exercise time ( p < 0.01) and workload ( p < 0.01) increased in trained patients. Before training RR interval and blood pressure were not modified by neck suction. After physical training systolic ( p < 0.01) and diastolic blood pressure decreased, RR interval and blood pressure could be modulated ( p < 0.05) by slow (6 cycles/min) neck suction, indicating initial cardiac sympathetic reinnervation and restored sensitivity to autonomic modulation on the arteries. No changes were observed in controls. Conclusions Physical training improved exercise performance and the control exerted by the autonomic nervous system through the sympathetic nerves at both cardiac and vascular level.

Role of epicardial and pericardial sensory nerves on spontaneous variations of blood pressure and heart rate in conscious rats

Epicardial and pericardial sensory nerves mediate cardiac inhibitory (Bezold-Jarisch reflex) as well as cardiac sympathoexcitatory reflexes. Although direct stimulation of cardiac sympathetic afferent nerves influences baroreflex control of blood pressure (BP), the contribution of these cardiac sensory nerves to blood pressure control under normal physiological conditions is not fully clear. In the present study we tested whether elimination of cardiac sympathetic reflexes by intrapericardial (IPC) administration of the neurotoxin resiniferatoxin (RTX) would affect spontaneous blood pressure (BPV) and heart rate variability (HRV) in conscious rats. To this end RTX (15 μg/kg) was administered IPC via a catheter implanted in the pericardial sac of Wistar rats. BP and HR were measured via an indwelling catheter placed in the femoral artery. Cardiac sympathetic deafferentation was verified by comparing the magnitude of pressor responses evoked by IPC applied bradykinin before and after RTX. Using immunohistochemistry the density of CGRP containing nerves in the pericard was compared in vehicle and RTX treated rats (n=3). Cardiac sensory deafferentation by RTX (n=7) did not alter steady state BP and HR as measured in the conscious resting state 3 days before and 3 days after RTX treatment. BPV and HRV were quantified by spectral analysis. The magnitude of the low-frequency and high-frequency components of BPV and HRV were not significantly altered after RTX. These data suggest that cardiac sympathetic afferents do not play a major role in determining BPV and HRV under normal physiological conditions.

Group I Metabotropic Glutamate Receptors on Second-Order Baroreceptor Neurons Are Tonically Activated and Induce a Na+–Ca2+Exchange Current

The nucleus tractus solitarius (NTS) is essential for coordinating baroreflex control of blood pressure. The baroreceptor sensory fibers make glutamatergic synapses onto second-order NTS neurons. Glutamate spillover activates Group II and III presynaptic metabotropic glutamate receptors (mGluRs) on the baroreceptor central terminals to inhibit synaptic transmission, but the role of postsynaptic mGluRs is less understood. We used whole cell patch-clamping in anatomically identified second-order baroreceptor neurons in a brain stem slice to test whether Group I, II, and III mGluRs had postsynaptic effects at this first central synapse in the baroreceptor afferent pathway. The Group I agonist DHPG induced a depolarization and spiking that was mimicked by endogenous glutamate. Group I mGluR blockade prevented the depolarization and slightly hyperpolarized the neurons, suggesting a small tonic Group I mGluR activation. The DHPG-induced inward current consisted of voltage-dependent and -independent components; the former was blocked by TEA and the latter was blocked by replacing extracellular NaCl with LiCl or Tris-HCl. The DHPG current was potentiated in a Ca2+-free external solution and was diminished by intracellular dialysis with BAPTA and by perfusion with Na+-Ca2+ exchanger blockers, KB-R7943 or 3',4'-dichlorobenzamil. Intracellular dialysis with GDPbetaS or heparin and perfusion with the PLC inhibitor U-73122 or the Ca2+-calmodulin inhibitor W-7 significantly decreased the DHPG current. The data suggest that Group I mGluRs on baroreceptor neurons are functional; are activated by endogenous glutamate; and activate a Na+-Ca2+ exchanger through G-protein, PLC, IP3, and Ca2+-calmodulin mechanisms to excite the cell, thus providing postsynaptic mechanisms to enhance or prolong baroreceptor signal transmission.

Frequency-dependent baroreflex control of blood pressure and heart rate during physical exercise

Background It is widely recognised that during exercise vagal heart rate control is markedly impaired but blood pressure control may or may not be retained. We hypothesised that this uncertainty arose from the differing responses of the vagus (fast) and sympathetic (slow) arms of the autonomic effectors, and to differing sympatho–vagal balance at different exercise intensities. Methods and Results We studied 12 normals at rest, during moderate (50% maximal heart rate) and submaximal (80% maximal heart rate) exercise. The carotid baroreceptors were stimulated by sinusoidal neck suction at the frequency of the spontaneous high- (during moderate exercise) and low-frequency (during submaximal) fluctuations in heart period and blood pressure. The increases in these oscillations induced by neck suction were measured by autoregressive spectral analysis. At rest neck stimulation increased variability at low frequency (RR: from 6.99 ± 0.24 to 8.87 ± 0.18 ln-ms 2; systolic pressure: from 3.05 ± 1.7 to 4.09 ± 0.17 ln-mm Hg 2) and high frequency (RR: from 4.67 ± 0.25 to 6.79 ± 0.31 ln-ms 2; systolic pressure: from 1.93 ± 0.2 to 2.67 ± 0.125 ln-mm Hg 2) (all p < 0.001). During submaximal exercise RR variability decreased but systolic pressure variability rose ( p < 0.01 vs rest); during submaximal exercise low-frequency neck stimulation increased the low-frequency fluctuations in blood pressure (2.35 ± 0.51 to 4.25 ± 0.38 ln-mm Hg 2, p < 0.05) and RR. Conversely, neck suction at high frequency was ineffective on systolic pressure, and had only minor effects on RR interval during moderate exercise. Conclusion During exercise baroreflex control is active on blood pressure, but the efferent response on blood pressure and heart rate is only detected during low frequency stimulation, indicating a frequency-dependent effect.

Effects of endocannabinoids on discharge of baroreceptive NTS neurons

Previously, we have shown that microinjection of endocannabinoids (ECBs) into the nucleus tractus solitarius (NTS) can modulate baroreflex control of blood pressure (BP), prolonging pressor-induced inhibition of renal sympathetic nerve activity. This suggests that ECBs can modulate excitability of baroreceptive neurons in the NTS. Studies by others have shown that neural cannabinoid (CB 1) receptors are present on fibers in the NTS, suggesting that some presynaptic modulation of transmitter release could occur in this region which receives direct afferent projections from arterial baroreceptors and cardiac mechanoreceptors. This study, therefore, was performed to determine the effects of ECBs on NTS baroreceptive neuronal discharge. Picoinjection of the ECB anandamide (AEA) was found to significantly increase discharge of baroreceptive neurons (20 of 23). Picoinjection of the ECB uptake inhibitor, AM404, which enhances endogenous ECB activity, also significantly increased discharge of baroreceptive neurons (8 of 10 neurons). To determine if effects of ECBs involved a GABAA mechanism, the neuronal responses to AEA and AM404 were tested after prior blockade of postsynaptic GABAA receptors by bicuculline (BIC) or SR 95531 hydrobromide (gabazine—SR 95531), which would eliminate any effects due to modulation of GABA input. The increase in neuronal discharge to both AEA and AM404 was significantly attenuated following BIC or SR 95531, which alone significantly increased discharge of baroreceptive neurons tested. These results support the hypothesis that ECBs enhance baroreflex function through increases in NTS baroreceptive neuronal activity, due in part to modulation of GABAergic inhibitory effects at the neuronal level.

Selective Sensitization by Nitric Oxide of Sympathetic Baroreflex in Rostral Ventrolateral Medulla of Conscious Rabbits

Nitric oxide (NO) deficiency in the rostral ventrolateral medulla (RVLM) has been implicated in impaired baroreflex control in hypertensive and heart failure animals. However, the role of local NO in normal baroreflex regulation remains unclear. This study aimed to examine the role of NO in tonic and baroreflex control of blood pressure (BP) in the RVLM of conscious rabbits. Microinjections of NO donors, S-nitroso-N-acetylpenicillamine and sodium nitroprusside (5 to 20 nmol), or NO itself (20 to 200 pmol) into the RVLM dose-dependently increased BP. Bilateral microinjections of an NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 nmol), its inactive enantiomer D-NAME, or soluble guanylate cyclase (sGC) inhibitors, 1-H-[1,2,4]oxadiaolo[4,3-a]quinoxalin-1-one (ODQ, 250 pmol) and methylene blue (10 nmol), into the RVLM did not affect resting BP, heart rate, or renal sympathetic nerve activity (RSNA). However, L-NAME, methylene blue, and ODQ decreased RSNA baroreflex gain by 42% to 55%, whereas D-NAME did not affect this reflex. Co-microinjections of L-NAME and superoxide scavenger tempol (20 nmol) decreased RSNA baroreflex gain by 37+/-8%. Microinjections of a neuronal NOS (nNOS) inhibitor, 7-nitroindazole (500 pmol), into the RVLM decreased RSNA baroreflex gain by 42+/-12%, without altering resting BP, heart rate, or RSNA. Local administration of inducible NOS (iNOS) inhibitors, S-methylisothiourea (0.25 nmol) and aminoguanidine (0.25 and 2.5 nmol), affected neither resting nor baroreflex parameters. These results suggest that nNOS-derived NO facilitates sympathetic baroreflex transmission in the RVLM at least in part via a sGC-dependent, superoxide-independent mechanism. However, local nNOS and iNOS play little role in the tonic support of BP in conscious rabbits.

Glutamate suppresses GABA release via presynaptic metabotropic glutamate receptors at baroreceptor neurones in rats

The nucleus tractus solitarii (NTS) is essential for coordinating arterial baroreflex control of blood pressure. The primary baroreceptor afferent fibres make their first excitatory synaptic contact at second-order NTS neurones with glutamate as the major neurotransmitter. Glutamate regulates its own release by activating presynaptic metabotropic glutamate autoreceptors (mGluRs) on the baroreceptor central terminals to suppress its further release in frequency-dependent manner. Gamma-aminobutyric acid (GABA) interneurones provide the major inhibitory synaptic input. It is the integration of excitatory and inhibitory inputs that shapes the NTS output of baroreceptor signals. We hypothesized that glutamate released from the primary central afferent terminals can spill over to presynaptic mGluRs on GABA interneurones to suppress GABA release at the second-order baroreceptor neurones. We assessed GABA transmission in second-order baroreceptor neurones identified by attached aortic depressor nerve (ADN) boutons. The medial NTS was stimulated to evoke GABA inhibitory postsynaptic currents (eIPSCs). Glutamate spillover, generated by brief 2 s, 25 Hz trains of stimuli applied to the tractus solitarius (TS), induced a small (10%) but significant reduction in the eIPSC amplitudes. The depression was enhanced to a 25% decrease by increasing glutamate in the cleft with a glutamate-uptake inhibitor (M-trans-pyrrolidine-2,4-dicarboxylic acid, 1 mum), blocked by a Group II mGluR antagonist (LY341495, 200 nm) and mimicked by a Group II agonist ((2S,3S,4S)-CCG/(2S,1'S,2'S)-2-carboxycyclopropyl; L-CCG-I). A presynaptic mGluR locus was established by the mGluR agonist-mediated increase in the paired-pulse ratio of two consecutive eIPSCs in conjunction with the decrease in the first eIPSC, and a decrease in the frequency (39-46% reduction at EC(50) concentration), but not amplitude, of spontaneous and miniature GABA IPSCs. The data indicate that endogenous glutamate activation of Group II presynaptic mGluRs can decrease GABA release at the first central synapses, suggesting a heterosynaptic role for the Group II mGluRs in shaping baroreceptor signal transmission.

A mathematical analysis for the cardiovascular control adaptations in chronic renal failure.

A model of baroreflex control of blood pressure (BP) is proposed in terms of a delay differential equation and this is used to predict the adaptation of short-term cardiovascular control in chronic renal failure (CRF) patients. Cardiac pump dynamics are explored by means of plots of blood flow vs. mean BP. The parameters of the model were determined from available data and from a sensitivity analysis. The model predicts stable and unstable equilibria close to the steady BP. It is shown that the unstable equilibrium point generates a quasiperiodic solution with two main harmonics for healthy subjects. We also show that the parameters for CRF patients predict solutions whose spectra exhibit a small high frequency component. This is due to the coalescence of the equilibrium points. The heart rate variability (HRV) time series and power spectra from healthy volunteers and CRF patients were compared with the model predictions. As an adequate measure of the sympathovagal balance we use the LF/HF index obtained from the power spectrum. The model allows the interpretation of the variability of the LF/HF index in terms of a specific set of cardiovascular parameters which are known to change from healthy to CRF patients. Comparisons of the changes in the LF/HF index predicted by the model are in agreement with actual observations for both the healthy and the CRF patients. These results show that the cardiac pump has a more restricted response in CRF patients. The model quantifies the cardiovascular adaptations to the CRF condition in terms of increased peripheral resistance and baroreflex delay and decreased arterial compliance, cardiac period, and stroke volume.

Anandamide content and interaction of endocannabinoid/GABA modulatory effects in the NTS on baroreflex-evoked sympathoinhibition.

Cannabinoids have been shown to modulate central autonomic regulation and baroreflex control of blood pressure (BP). The presence of cannabinoid CB(1) receptors on fibers in the nucleus tractus solitarius (NTS) suggests that some presynaptic modulation of transmitter release could occur in this region, which receives direct afferent projections from arterial baroreceptors and cardiac mechanoreceptors. This study, therefore, was performed to determine the mechanism(s) of effects of microinjection of an endocannabinoid, arachidonylethanolamide (anandamide, AEA), into the NTS on baroreflex sympathetic nerve responses produced by phenylephrine-induced pressure changes in anesthetized rats. AEA prolonged reflex inhibition of renal sympathetic nerve activity (RSNA), suggesting an increase in baroreflex sensitivity. This effect of AEA was blocked by prior microinjection of SR-141716 to block cannabinoid CB(1) receptors. To determine whether this baroreflex enhancement by AEA involved a GABA(A) mechanism, the baroreflex response to AEA was tested after prior blockade of postsynaptic GABA(A) receptors by bicuculline, which would eliminate any effects due to modulation of GABA activity. After bicuculline, which alone prolonged the baroreflex inhibition of RSNA, AEA shortened the duration of RSNA inhibition, suggesting a possible presynaptic inhibition of glutamate release previously obscured by a more dominant GABA(A) effect. To support a possible physiological role for AEA, AEA concentration in the NTS was measured after a phenylephrine-induced increase in BP. AEA content in the NTS was increased significantly over that in normotensive animals. These results support the hypothesis that AEA content is increased by brief periods of hypertension and suggest that AEA can modulate the baroreflex through activation of CB(1) receptors within the NTS, possibly modulating effectiveness of GABA and/or glutamate neurotransmission.