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Hierarchical recruitment of the sympathetic and parasympathetic limbs of the baroreflex in normotensive and spontaneously hypertensive rats.
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PMID:  17170043     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The arterial baroreflex acts to buffer acute changes in blood pressure by reciprocal modulation of sympathetic and parasympathetic activity that controls the heart and vasculature. We have examined the baroreflex pressure-function curves for changes in heart rate and non-cardiac sympathetic nerve activity (SNA, thoracic chain T8-12) in artificially perfused in situ rat preparations. We found that the non-cardiac SNA baroreflex is active over a lower range of pressures than the cardiac baroreflex (threshold 66 +/- 1 mmHg versus 82 +/- 5 mmHg and mid-point 77 +/- 3 versus 87 +/- 4 mmHg, respectively, P < 0.05, n = 6). This can manifest as a complete dissociation of the baroreflex limbs at low pressures. This difference between the cardiac and non-cardiac SNA baroreflex is also seen in end-organ sympathetic outflows (adrenal and renal nerves). Recordings of the cardiac vagal (parasympathetic) and the inferior cardiac (sympathetic) nerves identify the cardiac parasympathetic baroreflex component as being active over a higher range of pressures. This difference in the operating range of the baroreflex-function curves is exaggerated in the spontaneously hypertensive rat where the cardiac component has selectively reset by 20-25 mmHg to a higher pressure range (threshold of 104 +/- 4 mmHg and mid-point 113 +/- 4, n = 6). The difference in the pressure-function curves for the cardiac versus the vascular baroreflex indicates that there is a hierarchical recruitment of the output limbs of the baroreflex with a sympathetic predominance at lower arterial pressures.
Authors:
Annabel E Simms; Julian F R Paton; Anthony E Pickering
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-12-14
Journal Detail:
Title:  The Journal of physiology     Volume:  579     ISSN:  0022-3751     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-01     Completed Date:  2007-04-27     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  473-86     Citation Subset:  IM    
Affiliation:
Department of Physiology, Bristol Heart Institute, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK.
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MeSH Terms
Descriptor/Qualifier:
Animals
Baroreflex / physiology*
Bradycardia / physiopathology
Heart Rate / physiology
Hypertension / physiopathology
Male
Parasympathetic Nervous System / physiology*
Rats
Rats, Inbred SHR
Rats, Wistar
Sympathetic Nervous System / physiology*
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Journal Information
Journal ID (nlm-ta): J Physiol
Journal ID (publisher-id): tjp
ISSN: 0022-3751
ISSN: 1469-7793
Publisher: Blackwell Science Inc
Article Information
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? 2007 The Authors. Journal compilation ? 2007 The Physiological Society
Received Day: 07 Month: 11 Year: 2006
Accepted Day: 07 Month: 12 Year: 2006
Print publication date: Day: 01 Month: 3 Year: 2007
Electronic publication date: Day: 14 Month: 12 Year: 2006
Volume: 579 Issue: Pt 2
First Page: 473 Last Page: 486
ID: 1865002
DOI: 10.1113/jphysiol.2006.124396
PubMed Id: 17170043

Hierarchical recruitment of the sympathetic and parasympathetic limbs of the baroreflex in normotensive and spontaneously hypertensive rats
Annabel E Simms1
Julian F R Paton1
Anthony E Pickering12
1Department of Physiology, Bristol Heart Institute, School of Medical Sciences, University Walk, University of BristolBristol BS8 1TD, UK
2Department of Anaesthesia, Bristol Royal InfirmaryBristol BS2 8HW, UK
Correspondence: Corresponding author A. E. Pickering: Department of Physiology, Bristol Heart Institute, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK. Email: tony.pickering@bristol.ac.uk

The arterial baroreceptor reflex is a key buffer of acute changes in blood pressure (Sagawa, 1983). The rapid buffering of pressure is predominantly mediated by a reciprocal modulation of the sympathetic and parasympathetic nervous systems. This reciprocity is generated in the brainstem processing of the excitatory baroreflex afferent information (reviewed in Spyer, 1990; Pilowsky & Goodchild, 2002) whereby the sympathetic component undergoes a change of sign, mediated by an inhibitory interneurone in the caudal ventrolateral medulla. Other than this change of sign, it has been thought that these major output limbs of the baroreflex are governed by similar arterial pressure transfer functions.

It is therefore interesting that in human disease states such as hypertension there can be isolated, specific deficits in either the vascular sympathetic (Jordan et al. 2000) or cardiac parasympathetic components of the baroreflex (Mancia & Mark, 1983; Grassi et al. 1998). The specificity of these deficits is mirrored in both the spontaneously hypertensive rat (SHR; Head & Adams, 1988; Dickhout & Lee, 1998) and the renal wrap model of hypertension (Vitela et al. 2005) which exhibit a selective attenuation of the parasympathetic limb of the baroreflex. Furthermore, under normal physiological circumstances, there is evidence for separate regulation of the baroreflex limbs, for example during exercise (Raven et al. 2006). The forgoing suggests that the efferent limbs of the baroreflex can be independently controlled, presumably through alterations in brainstem processing.

This study was triggered by our observation that it is possible to fully dissociate the non-cardiac sympathetic and cardiac baroreflex components in a decerebrate, artificially perfused rat (DAPR) preparation (Simms et al. 2004). This in situ approach allows the effect of precise, pressure stimuli to be examined on a range of sympathetic and parasympathetic nerve and end-organ responses without the need for anaesthesia, artificial ventilation or vagotomy (Pickering & Paton, 2006). The aim of this study was to explore this apparent difference in the pressure sensitivity of baroreflex regulation of sympathetic and parasympathetic activity in both normotensive and spontaneously hypertensive rat strains. Some of these data have been communicated previously in abstract form (Simms et al. 2004).


Methods

All procedures conformed to the UK Animals (Scientific Procedures) Act 1986 and were approved by the University of Bristol ethical review committee. Two in situ preparations were used according to previously described methods: the working heart brainstem preparation (WHBP; Paton, 1996) and the decerebrate artificially perfused rat (DAPR) preparation (Pickering et al. 2003; Pickering & Paton, 2006). In brief, male Wistar (n = 54) or spontaneously hypertensive (n = 6) rats (60?100 g, postnatal days 28?35) were deeply anaesthetized with halothane, until loss of withdrawal to paw pinch, before undertaking the following surgical procedures.

WHBP

The rat was bisected subdiaphragmatically, immersed in carbogenated Ringer solution at 10?C, and suction-decerebrated precollicularly. After transfer to the recording chamber a double lumen cannula was inserted into the descending aorta for retrograde perfusion.

DAPR preparation

The stomach, intestines and spleen were ligated and removed via a midline laparotomy. After sternotomy the ribcage was retracted to allow access to the mediastinum. The animal was cooled by immersion in carbogenated Ringer solution at 10?C and decerebrated precollicularly. Once in the recording chamber a double lumen perfusion cannula was introduced into the ascending aorta, via an incision in the left ventricle, for anterograde perfusion.

In both preparations, after decerebration, anaesthesia was discontinued as the animal was insentient. Perfusion was reinstated using a peristaltic roller pump (Watson Marlow 505D) with a carbogenated Ringer solution at 32?C (for constituents, see below). The second lumen of the cannula was used to monitor aortic perfusion pressure. The pump head speed was controlled using custom-written scripts (Spike2 driving micro1401, Cambridge Electronic Design, Cambridge, UK) allowing the generation of flexible flow change protocols to alter perfusion pressure.

The phrenic nerve activity (along with ECG) was recorded via a suction electrode (filtered 80 Hz to 3 kHz). The baseline perfusate flow was adjusted until the respiratory motor pattern consisted of an augmenting burst discharge indicating eupnoea (Paton, 1996). In addition, vasopressin (200?400 pM) was added to the perfusate, as required, to increase vascular resistance and hence baseline perfusion pressure (Pickering & Paton, 2006). Instantaneous heart rate (HR) in beats per minute (bpm) was derived by triggering from the R wave of the ECG with a window discriminator.

Cardiorespiratory afferent stimulation

The baroreflex was activated by perfusion pressure challenges (generated by altering the perfusate flow). Initial studies used flow steps to increase perfusion pressure (by 30 mmHg over 1 s) from a range of different baseline pressures (30?80 mmHg, by adjusting the baseline flow). We also used flow ramps (typically from 0 to 3 ? basal flow over 15?60 s) to change flow linearly and thus produce biphasic perfusion pressure challenges.

The peripheral chemoreceptors were stimulated with NaCN (0.01% solution; 100 ?l intra-aortic bolus) to produce a submaximal bradycardia (Paton & Kasparov, 1999). Such activation of the peripheral chemoreceptor reflex produced an increase in central respiratory drive accompanied by bradycardia and an increase in sympathetic nerve activity. The activation of the peripheral chemoreflex provided a method to check that a vagal bradycardia could be evoked; this was particularly pertinent on the occasions when there was an absence of baroreflex bradycardia.

Nerve recordings

Nerve recordings were made using suction electrodes from the lower thoracic (non-cardiac) sympathetic chain (T8?13), renal, adrenal, inferior cardiac (ICN) and cardiac vagal (CVN) nerves. The identity of the latter two nerves was confirmed by electrical stimulation (1?4 s train at 30?50 Hz; pulses 1 ms ? 10?20 V) of the distal end of the nerve to obtain tachycardia (ICN, see Boscan et al. 2001) or bradycardia (CVN, see Pickering et al. 2003). All the sympathetic nerves exhibited marked respiratory modulation of their activity and this was profoundly attenuated by an increase in perfusion pressure (to stimulate arterial baroreceptors). The CVN also exhibited respiratory modulation with bursts of activity in the post-inspiratory period. However, by contrast with the sympathetic outflows, the CVN showed increased discharge in response to pressor stimuli (see Pickering et al. 2003). Nerve recordings were AC amplified (custom built), filtered (100?2000 Hz), rectified and integrated.

Data analysis

The baroreflex response to perfusion pressure challenges was quantified using two different methods. For the transient pressor challenges (1 s), applied from a range of baseline pressures, the cardiac baroreflex gain was calculated from the ratio of ?Heart rate/?Perfusion pressure (bpm mmHg?1; see Paton & Kasparov, 1999). Because the SNA showed respiratory modulation, the pressor challenges were applied during the same phase of the respiratory cycle (end-inspiration). The sympathetic baroreflex gain was calculated by ratioing the change in ?SNA during the perfusion pressure ramp against the average of two equivalent control periods of ?SNA taken from the corresponding phase of preceding respiratory cycles (expressed as percentage sympathoinhibition per millimetre of mercury; see Pickering et al. 2003).

In contrast, for the dynamic biphasic pressure ramps (over 30 s) a baroreflex?function curve (Kent et al. 1972) was constructed (for the heart rate (HR), SNA and/or CVN activity (CVNA)) by fitting a logistic sigmoid (Prism4, Graphpad, CA, USA):

[Formula ID: e1]
(1) 
where y= SNA, CVNA or HR; P1= range; P2= slope coefficient; P3= perfusion pressure at 50% (PP50%); P4= minimum; x= perfusion pressure. The curves were fitted to HR or integrated SNA/CVNA (time constant of 1 s) averaged into 1 s bins (n = 30), measured over the extent of the ramp. The peak baroreflex gain was calculated from the first derivative and the pressure threshold and saturation (Pth and Psat) were obtained from the third derivative of these function curves.

Significance of data was assessed using Student's two-tailed t test, ANOVA or Wilcoxon signed rank test as appropriate (Prism4). All values quoted are the mean ?S.E.M. and differences were considered significant at the 95% confidence limit.

Drugs and solutions

The composition of the modified Ringer solution was (mM): NaCl (125); NaHCO3 (24); KCl (5); CaCl2 (2?5); MgSO4 (1?25); KH2PO4 (1?25); dextrose (10); pH 7?35?7.4 after carbogenation. The perfusion solution also contained Ficoll 70 (1?25%) as an oncotic agent, and heparin (1 i.u. ml?1). All chemicals were from Sigma (UK).


Results
Dissociation of baroreflex sympathoinhibition and bradycardia in DAPR

In the DAPR preparation it was possible to evoke baroreflex sympathoinhibition, in response to a pressor challenge, without an associated baroreflex bradycardia (Fig. 1Aa, seen in 6/20 DAPR preparations). These preparations had relatively low baseline perfusion pressures (less than 60 mmHg) but were otherwise functionally normal with eupnoeic patterns of phrenic discharge, respiratory sinus arrhythmia and robust peripheral chemoreflex bradycardia (Figs 1 and 2) indicative of intact cardiac vagal reflex function. Importantly, by increasing the baseline pressure (by the addition of vasopressin to the perfusate at 200?400 pM) the baroreflex bradycardia could be reinstated (n = 4, Fig. 1B).

Conversely in the DAPR (14/20 preparations) that showed baroreflex bradycardia and sympathoinhibition in response to pressure ramps from the baseline, it was possible to observe a similar phenomenon (Fig. 2, n = 4/4 DAPR tested). By decrementally lowering the baseline pressure (by reducing perfusate flow) and applying transient pressor ramps, it was possible to show a dissociation of the baroreflex sympathoinhibition (preserved and even enhanced) and the baroreflex bradycardia (lost, Fig. 2Ad). The peripheral chemoreflex bradycardia was still present at the lowest perfusion pressures, again indicating that cardiac vagal function was preserved (data not shown). It was also notable that lowering the baseline perfusion pressure by 30 mmHg caused a marked increase in baseline SNA but comparatively little change in heart rate (Fig. 2A).

Distinct pressure operating ranges of baroreflex sympathoinhibition and bradycardia

To guard against the possibility that this ability to dissociate the limbs of the baroreflex might be an anomalous feature of the DAPR preparation these experiments were systematically repeated in the WHBP where the ability to manipulate the perfusion pressure is facilitated by the smaller remaining vascular tree. The baroreflex was challenged with pressure ramps (30 mmHg ? 1 s) from a series of different baseline perfusion pressures (30?80 mmHg, n = 9) and the associated baroreflex gains were derived. Baroreflex sympathoinhibition was observed from all of the baseline pressures. However, like the DAPR experiments, the cardiac component of the baroreflex was typically only seen with pulses from a baseline pressure of greater than 50 mmHg. This appeared to reflect a pressure threshold for activation of the cardiac baroreflex with pressure pulses peaking between 75 and 90 mmHg across different preparations (mean 83 ? 3 mmHg, n = 9). The cardiac baroreflex gain increased by over 6-fold when the pressure ramp crossed this apparent threshold (?0.3 ? 0.04 to ?2.0 ? 0.3 bpm mmHg?1, P < 0.0005, n = 9). In contrast, the baroreflex sympathetic gain only increased by ?50% (?1.3 ? 0.1 to ?2.0 ? 0.3% sympathoinhibition mmHg?1, P < 0.01).

Detailed examination of the arterial pressure?baroreflex gain relationship in the WHBP (Fig. 2B) showed that the cardiac baroreflex was right-shifted by ?15?20 mmHg to a higher pressure range compared to the baroreflex sympathoinhibition. Hence the perfusion pressure at 50% of the maximum gain was 67 mmHg for sympathoinhibition versus 85 mmHg for the bradycardia. However, using this approach with static changes in baseline pressure, it was not possible to define the low pressure end of the baroreflex sympathoinhibition curve. This was because at baseline perfusion pressures of less than 30 mmHg (for periods of more than about 30 s) the phrenic and cardiorespiratory reflex activity in the WHBP was compromised, indicating inadequate perfusion of the brainstem.

Dynamic biphasic pressure ramps separate the parasympathetic and sympathetic baroreflex limbs

To explore the low-pressure end of the sympathetic baroreflex curve, we devised a biphasic flow protocol allowing pressure to be transiently lowered to 20?30 mmHg then ramped up over 30 s at a rate of 2?3 mmHg s?1 (Fig. 3A). This dynamic ramp protocol produced a graded activation of the sympathetic and cardiac baroreflex. By fitting baroreflex function curves to the data (Fig. 3C and D, Table 1) it was apparent that the non-cardiac sympathetic baroreflex is active over a lower-pressure range than the cardiac baroreflex (Pth 66 ? 1 versus 82 ? 5 mmHg, P < 0.02; PP50% 77 ? 3 versus 87 ? 4 mmHg, P < 0.001, n = 6).

Furthermore, equivalent biphasic pressure ramps from lower baseline perfusion pressure show that the bradycardia was again completely dissociable from the sympathoinhibition (Fig. 3A and B, n = 4). Note the chemoreflex bradycardia was still present at the lowest baseline perfusion pressure (not shown). The ability to dissociate the bradycardia and sympathoinhibition makes it unlikely that our observed differences in pressure responsiveness stem from a temporal delay in the heart rate response to baroreflex activation as compared to a more rapid response of the change in SNA. However, this does raise the question of whether the difference in the baroreflex function curves is a result of the comparison between nerve activity and an end-organ response (heart rate), where a large change in the neural activity may be required to produce a detectable change in end-organ activity, i.e. vagally mediated reflex bradycardia.

Cardiac parasympathetic versus cardiac and non-cardiac sympathetic baroreflex limbs

To address this issue, recordings were made from the CVN during pressure challenges. The evoked, graded bradycardia was mirrored by a ramp increase in the CVN activity (Fig. 4A, n = 4). The increase in CVN activity was well described by the logistic sigmoid baroreflex function curve and the Pth was similar to that for the cardiac baroreflex (Fig. 4B). This indicates that the graded heart rate changes are consequent upon similar changes in CVN activity.

We extended these observations with dual-nerve recordings of CVN activity and non-cardiac sympathetic activity. By applying a series of pressure pulses of increasing amplitude (Fig. 5) it was possible to show baroreflex inhibition of SNA before there was any activation of the CVN (n = 3). Similarly using pressure ramps (Fig. 6A) we found that the Pth of the CVN was significantly higher than that of the non-cardiac sympathetic (82 ? 3 versus 64 ? 2 mmHg, P < 0.01, n = 5). Furthermore this threshold value for cardiac vagal activation was similar to the baroreflex threshold for heart rate change (82 ? 3 versus 90 ? 5 mmHg, not significant). By contrast, the threshold for baroreflex inhibition of the cardiac sympathetic (Fig. 6B) was similar to that of the non-cardiac sympathetic rather than that of the cardiac vagal nerve (n = 3). These data indicate that it is the cardiac parasympathetic component of the baroreflex that is activated over a higher range of pressures.

Pressure operating range of the sympathetic baroreflex to different end-organs

Having shown a difference in the function curves between the cardiac and non-cardiac sympathetic baroreflex we were interested to extend the comparison to end-organ sympathetic nerves. Therefore, we made simultaneous recordings of adrenal and renal nerves in the DAPR (Fig. 7, n = 4). These recordings showed similar patterns of baroreflex pressure sensitivity to the low thoracic chain with both the adrenal and renal SNA being strikingly inhibited prior to a significant change in heart rate (Fig. 7).

It is also interesting that, in the DAPR, the biphasic pressure ramp had a marked inflection during the rising phase (Fig. 7). As there was a linear increase in the flow rate during this ramp, then the inflexion must result from a dramatic change in the vascular resistance of the preparation following baroreflex sympathoinhibition. Note that this vascular end-organ response occurred before there was significant change in heart rate.

Changes in parasympathetic and sympathetic baroreflex function curves in spontaneously hypertensive rats

It has previously been reported that the baroreflex resets to a higher pressure range in hypertension (Head & Adams, 1988; Dickhout & Lee, 1998; Grassi et al. 1998). Therefore we were interested to see if the sympathetic and parasympathetic components of the baroreflex were reset to an equal degree in WHBP of SHR. Compared to Wistar rats, the SHR showed a higher baseline perfusion pressure (80 ? 4 versus 56 ? 3 mmHg, P < 0.002, n = 6) and heart rate (347 ? 8 versus 293 ? 19, P < 0.05, n = 6) at the same perfusate flow (17 ml min?1, Table 1). The higher pressure in the SHR therefore reflects a greater baseline vascular resistance.

Like the Wistar rats, there were differences in SHR in the non-cardiac sympathetic compared to the cardiac baroreflex (respectively, Pth 70 ? 3 versus 104 ? 4 mmHg, P < 0.002; PP50% 84 ? 4 versus 113 ? 4 mmHg, P < 0.01, n = 6, Fig. 8). Interestingly, when compared to the Wistar rats, both the sympathetic and cardiac baroreflex function curves in the SHR showed a trend towards a higher pressure range (Wistar PP50% values of 77 ? 3 and 87 ? 4 mmHg versus SHR 84 ? 4 and 113 ? 4 mmHg, respectively). However, only the increase in the cardiac baroreflex reached statistical significance (P = 0.005, Tables 1 and Fig. 8C) indicating that the cardiac component of the baroreflex has reset to a higher pressure range in the juvenile SHR. It was also notable that the cardiac baroreflex gain was reduced 4-fold in the SHR (Table 1).


Discussion

In this study we have shown that the non-cardiac sympathetic limb of the baroreflex is active over a lower range of pressures than the cardiac baroreflex. This difference originates from the higher pressure range over which the baroreflex modulates the parasympathetic outflow to the heart. In contrast the cardiac sympathetic outflow shows similar pressure responsiveness to the non-cardiac sympathetic outflow. This difference is strikingly illustrated by the dissociation of the cardiac limb from the non-cardiac sympathetic limb of the baroreflex using pressor stimuli from low baseline pressures. Thus, there is a pressure hierarchy of recruitment of these two limbs of the baroreflex with the sympathetic component being engaged before the cardiac parasympathetic component. These differences between the cardiac and the non-cardiac baroreflex are exaggerated in the SHR model of hypertension as the cardiac component is selectively reset to a higher pressure range.

The arterial baroreflex has been extensively investigated since its description (Cyon & Ludwig, 1866) (> 2300 animal studies indexed in Medline), and it is surprising that the ability to disengage the two limbs has not been observed. This may reflect the fact that only a small proportion of studies have examined the input (arterial pressure) and output function (nerve activity or end-organ response) of both the parasympathetic and sympathetic baroreflex limbs simultaneously. This has often been because the in vivo approaches employed to study the baroreflex have been done in ?open loop? vagotomized animals, or in the presence of anaesthesia (see Shimokawa et al. 1998) or neuromuscular blocking agents that obtund the cardiac limb of the baroreflex. Consequently many studies have appeared to make an underlying assumption that monitoring a single baroreflex efferent limb allows inferences to be made about the global function of the baroreflex, despite previous cautions to the contrary (Sagawa, 1983).

Notwithstanding, several recent studies (Ling et al. 1998; Foley et al. 2001; Vitela et al. 2005; McDowall et al. 2006) in anaesthetized rodents have examined baroreflex sympathetic and heart rate responses and have shown no differences in the baseline baroreflex function parameters. Curiously, these same studies have shown a variety of physiological, pharmacological and genetic interventions to differentially modulate the limbs of the baroreflex (Ling et al. 1998; Foley et al. 2001; Vitela et al. 2005; McDowall et al. 2006) raising the issue of why, under baseline conditions, the two limbs are operating within similar parameters.

However, a recent study in conscious rats has indicated that the baroreflex function curve threshold and midpoint pressures were approximately 20 mmHg lower for renal sympathetic nerve activity compared to heart rate (Miki et al. 2003), although these authors did not comment or elaborate on the potential significance of this observation. These findings can also be tied in with earlier studies on dogs and humans (Glick & Braunwald, 1965) and rats (Stornetta et al. 1987) that have shown pharmacologically that the baroreflex heart rate response is predominantly vagal in the pressor direction and predominantly sympathetic in the depressor direction. This qualitative asymmetry may be explained by our observed differences in the pressure range of the baroreflex function curves with the sympathetic system operating over a lower range. Hence an interesting possibility is raised by our findings; in baroreflex studies in humans SNA correlates best with diastolic pressure whereas heart rate changes correlate with the systolic or mean pressures (Sundlof & Wallin, 1978; Eckberg et al. 1988; Ebert & Cowley, 1992). This finding may result from differences in the respective pressure operating ranges of the baroreflex limbs.

Previous human studies suggest that muscle vasoconstrictor SNA is sensitive to increases in arterial pressure that are without effect on heart rate (Eckberg et al. 1988; Rudas et al. 1999). This is mirrored by our ability to produce striking sympathoinhibition with small changes in perfusion pressure (10 mmHg pressor challenge from baseline ? 50% less SNA). It is noteworthy that our pressure stimuli were generated by altering the perfusate flow, thus exposing the barosensors to increases in pressure and flow (a situation commonly seen in vivo). The carotid sinus baroreceptors in dogs are sensitized under conditions of increased flow and pressure (Hajduczok et al. 1988) such that they exhibit lower thresholds for discharge. Also, it has recently been reported that the long-term level of human SNA may be better related to the cardiac output rather than to arterial pressure (Charkoudian et al. 2005) suggesting that the SNA is regulated by a cardiac output-sensitive mechanism. Thus it could be hypothesized that our approach may detect a difference between the baroreflex limbs because the sympathetic system is sensitive to both pressure and flow (this intriguing possibility could be tested using in situ preparations as flow and pressure can be independently controlled).

Our use of artificially perfused preparations has afforded the ability to explore the low-pressure end of the baroreflex relationship in detail. By comparison, the commonly used in vivo approach to assess the baroreflex employs administration of vasodilator followed by vasoconstrictor to manipulate arterial pressure and explore the operating range of the baroreflex (e.g. Ebert & Cowley, 1992). However, there are limits as to how far the systemic pressure can be lowered because of the unwanted effects of CNS/cardiac ischaemia. There may also be direct drug effects on the vessels at the baroreceptor sites and on the heart/brain that may alter the response. An alternative approach isolates and exposes a single baroreceptor region (e.g. carotid sinus) to a wide range of pressures without interference from the other baroreceptors (?open loop? following denervation, see Shoukas et al. 1991). However, such isolated carotid sinus experiments allow the effects to be measured from only one of the baroafferent sites and it is known that the effect of each of these afferent sites can be different (Dworkin et al. 2000) and can sum in a non-linear fashion (Sagawa, 1983). Our in situ approach allows precise control of both baseline and stimulus pressures, independent of the cardiac output, and we are able to compensate for changes in the vascular resistance by altering perfusate flow. Thus, we can repeatedly apply defined stimuli to all four barosensor sites and quantify the parameters of the baroreflex response in terms of nerve activity and end-organ responses (heart rate and vascular resistance). Furthermore, because we continuously monitor phrenic nerve activity we can detect (and rectify) signs of brainstem ischaemia

In our in situ preparations, it should be noted that there is almost no arterial pulse wave as the preparation is perfused independently, from a peristaltic pump, bypassing the cardiac output. The pressure pulse wave in vivo phasically activates the baroreceptors and there is evidence that it augments baroreflex-mediated sympathoinhibition (Ead et al. 1952; James & Daly, 1970; Chapleau et al. 1989) (but not heart rate changes: Ead et al. 1952). Furthermore, the sympathetic outflow shows a pulse-related modulation of activity that is a manifestation of this phasic baroreflex activation by the pressure pulse (Adrian et al. 1932; Habler et al. 1994; Malpas, 1998). This raises the issue of whether the pulselessness of the artificially perfused in situ preparation is leading to non-physiological stimulation of the baroafferents and hence producing misleading results. In addressing this issue it is important to emphasize that in our study we have obtained similar results using both brief, phasic pressure pulses (rising phase 1?2 s) and also slower pressure ramps (over 30 s) and in both cases have shown clear differences in the pressure sensitivity of the cardiac and non-cardiac sympathetic baroreflex limbs under both conditions. It is also worth noting that previous studies of the baroreflex in vivo have obtained baroreflex function curves using averaged changes in mean pressure rather than instantaneous pulsatile pressure, thus they have taken little account of the variation in pressure pulsatility (Ling et al. 1998; Foley et al. 2001; Vitela et al. 2005; McDowall et al. 2006). In support of our findings, a recent study in conscious rats has described a similar difference in the operating range of the renal sympathetic and heart rate baroreflex (Miki et al. 2003), suggesting that our in situ observations are indeed comparable with those seen in vivo.

In SHR WHBP (4?6 weeks of age) the baseline perfusion pressure and resting heart rate were elevated (compared to Wistars). Similar findings have been reported with SHR in vivo showing significant increases in arterial pressure from 4 weeks of age and heart rate from 2 weeks of age (Dickhout & Lee, 1998). We show that in the juvenile SHR there is an exaggerated difference in the pressure operating range of the limbs of the baroreflex as the cardiac limb has selectively reset to higher pressures. This is somewhat surprising given the well-known resetting of the peripheral baroafferents seen in the SHR (Andresen et al. 1978; Chapleau et al. 1988). However, our findings agree with previous studies in SHR that show a selective change in the cardiac parasympathetic component of the heart rate response with preservation of the sympathetic baroreflex (Head & Adams, 1988, 1992; Salgado et al. 2006). Thus these juvenile SHR in situ show increased vascular resistance, heart rate and an underlying resetting of the cardiac baroreflex to higher pressures. It is interesting to speculate that this selective resetting of the cardiac baroreflex may permit the increase in heart rate that precedes (and predicts) the development of hypertension in SHR (Dickhout & Lee, 1998). These data also further demonstrate the similarity between the SHR and human hypertension with selective alterations of the cardiac (parasympathetic) component of the baroreflex with a shift to higher pressures, a decreased gain and a reduced range (Mancia & Mark, 1983; Grassi et al. 1998).

The location within the baroreflex arc where the differential control of the baroreflex limbs originates remains to be determined. In particular, it is interesting to consider whether the two limbs of the reflex receive the same information from the baroreceptors or if there is segregation and differential processing of this afferent traffic before the split downstream of the nucleus tractus solitarii (NTS). One plausible explanation of our findings is that the processed baro-output from the NTS may be more effective at exciting the neurones of the caudal ventrolateral medulla (sympathetic limb) than the cardiac vagal preganglionic neurones (parasympathetic) and thus the different thresholds reflect the differences in the integrative properties of these groups of neurones. Under this model, both limbs of the reflex would receive the same information from the NTS. However, there are indications that differential processing of the baroreflex information may originate in the periphery, such as the observation of differences in the pressure responsiveness of the aortic versus the carotid baroreceptors in dogs (Donald & Edis, 1971) and the observation of a dominant role for the aortic baroreceptors in the cardiac component of the reflex in conscious rats (Dworkin et al. 2000). There are also differences in the heart rate and vascular responses to selective A- and C-fibre stimulation of baroreflex afferents such that A-fibres appear critical in the generation of baroreflex heart rate responses (Fan et al. 1999). Additionally, within the nucleus of the solitary tract, barosensitive neurones exhibit different single cell responses (Zhang & Mifflin, 2000; Paton et al. 2001) and the demonstration that the limbs of the baroreflex have differential pharmacological sensitivity (e.g. Pickering et al. 2003; Simms et al. 2006). These lines of evidence suggest that the transduced pressure information may be specifically tailored for the output limbs of the baroreflex by the NTS, or perhaps even earlier in the reflex arc, in the organization and functional properties of the baroafferents.

Through the use of in situ artificially perfused rat preparations we have shown clear differences in the pressure operating ranges of the sympathetic and parasympathetic limbs of the baroreflex, with the sympathetic limb being active at lower pressures. This is exaggerated in the SHR model of hypertension with a selective increase in the pressure range of the cardiac baroreflex. These observations indicate that there is a functional pressure hierarchy for recruitment of the sympathetic and parasympathetic baroreflex limbs that extends the previous observation of the non-uniform baroreflex effects on the sympathetic outflows to different vascular beds (Ninomiya et al. 1971). Given the ability to independently modulate the limbs of the baroreflex under a range of physiological and pathological conditions (Mancia & Mark, 1983; Grassi et al. 1998; Ling et al. 1998; Jordan et al. 2000; Foley et al. 2001; Miki et al. 2003; Vitela et al. 2005; McDowall et al. 2006; Raven et al. 2006) it seems likely that it is possible to dynamically restructure this functional hierarchy. This provides considerable flexibility of baroreflex response pattern with the ability to favour changes in flow or pressure to particular vascular beds according to the specific physiological circumstance.


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This study was supported by the British Heart Foundation and by the British Journal of Anaesthesia/Royal College of Anaesthetists. A.E.S. is in receipt of the British Heart Foundation Dr W. E. Parkes PhD Studentship. A.E.P. is a Wellcome Trust Advanced fellow. J.F.R.P. was in receipt of a Royal Society Wolfson Research Merit Award. We are grateful to Simon Lishman and Jeff Croker for technical support.


Figures

[Figure ID: fig02]
Figure 2  Differential sensitivity of the baroreflex limbs to perfusion pressure

A, this continuous record, from a DAPR, shows the effect of sequential lowering of baseline PP, by reducing flow, on the baroreflex responses (heart rate and T12 SNA) to pressor challenges. From the initial baseline pressure the pressor challenge evokes a baroreflex bradycardia and sympathoinhibition (a). Subsequent equivalent perfusion ramps from the lowered baselines (b?d) produce baroreflex sympathoinhibition but a progressive attenuation (b and c) followed by complete loss of the baroreflex bradycardia (d). Note that the progressive reductions in baseline pressure were associated with a marked increase in the SNA but little change in heart rate. B, in the WHBP, the cardiac and non-cardiac sympathetic baroreflex gains were systematically examined using a similar approach with pressor stimuli (30 mmHg, 1 s) from different baseline pressures (30?80 mmHg, by adjusting flow). The derived cardiac (?) and sympathetic (?) gains were normalized against the maximum within each preparation (n = 9) and the pooled data were plotted against the peak perfusion pressure (mean ?S.E.M., n > 4 for each point). This showed that the normalized sympathetic gain was larger than the cardiac gain over the range 60?95 mmHg (*P < 0.05, **P < 0.01) and the degree of shift in the pressure?gain relationship was indicated by the pressure at 50% maximum gain (sympathoinhibition 67 mmHg versus bradycardia 85 mmHg, dotted lines).



[Figure ID: fig01]
Figure 1  Dissociation and recovery of baroreflex bradycardia in DAPR

Recording of SNA (T12 chain; integrated SNA ?-200 ms). Aa, application of a pressor challenge (bar) evoked baroreflex sympathoinhibition without a bradycardia. Ab, by contrast, activation of the peripheral chemoreflex (NaCN 0.01%, 0.1 ml) evoked an increase in respiratory frequency, sympathetic nerve activity and pertinently a bradycardia, indicating that the reflex cardiac vagal outflow to the heart was intact (note change of scale in heart rate trace). B, the addition of arginine-vasopressin (AVP, 400 pM) to the perfusate increased the baseline perfusion pressure by 20 mmHg (arrow). From this higher baseline (10 min later) an equivalent pressor challenge produced a marked bradycardia associated with a similar degree of sympathoinhibition to that in Aa.



[Figure ID: fig03]
Figure 3  Dynamic biphasic pressure ramps demonstrate differences in the cardiac and non-cardiac sympathetic baroreflex function curves

Recording of SNA (T10; integrated ?-500 ms) from WHBP. A, a biphasic perfusion pressure stimulus (covering 60 mmHg over 30 s) evoked a reproducible baroreflex sympathoinhibition and bradycardia. B, from a lower baseline perfusion pressure (40 versus 60 mmHg, dotted) a ramp of equivalent magnitude produces baroreflex sympathoinhibition but now without the bradycardia. C, logistic sigmoid baroreflex function curves were fitted to the sympathetic (?) and heart rate (?) data (from A). The cardiac baroreflex function curve was right-shifted to a higher pressure range than the non-cardiac sympathetic function curve. (R2 > 0.95, 95% confidence intervals dotted; sympathetic function curve parameters: Pth 66 mmHg, PP50% 76 mmHg, Psat 86 mmHg; gain 0.14 ?V mmHg?1; cardiac function curve parameters: Pth 78 mmHg; PP50% 83 mmHg; Psat 88 mmHg; gain 14 bpm mmHg?1.) D, graph of function curve parameters (Pth and PP50%) for the cardiac and non-cardiac sympathetic (shaded) baroreflex (n = 6 WHBP). The Pth and PP50% were significantly higher for the cardiac compared to the non-cardiac sympathetic baroreflex (*P < 0.05, **P < 0.01).



[Figure ID: fig04]
Figure 4  Baroreflex activation of the cardiac vagal nerve parallels the bradycardia

A, recording of the cardiac vagal nerve (integrated ?-100 ms) in the WHBP shows characteristic respiratory modulation of discharge. The biphasic perfusion pressure challenge produced an incremental bradycardia that is mirrored by a graded increase in CVN activity. B, logistic sigmoid baroreflex function curves were fitted to the integrated cardiac vagal activity (?) and heart rate (?) data (from A). The threshold for the cardiac baroreflex (79 mmHg) was similar to that of the CVN (80 mmHg). (R2 > 0.90, 95% confidence intervals dotted; parasympathetic function curve parameters: Pth 80 mmHg, PP50% 90 mmHg, Psat 101 mmHg, gain 0.14 ?V mmHg?1; cardiac function curve parameters: Pth 79 mmHg, PP50% 84 mmHg, Psat 89 mmHg, gain 22 bpm mmHg?1.)



[Figure ID: fig06]
Figure 6  Comparison of cardiac vagal, cardiac sympathetic and non-cardiac sympathetic responses to a perfusion pressure ramp

A, recordings of CVN and sympathetic chain (T12) showing the response to a ramp increase in perfusion pressure. The resulting baroreflex bradycardia (note only one CVN intact) followed the increase in firing on the cardiac vagal nerve. By fitting baroreflex function curves to the data it was apparent that the thresholds for activation of the cardiac vagal nerve (81 mmHg, dashed line, similar to the bradycardia) was higher than the threshold for inhibition of the sympathetic chain (67 mmHg, continuous line). B, later, recordings of the cardiac sympathetic nerve and the non-cardiac sympathetic chain showed similar baroreflex pressure sensitivity (same preparation as A). Fitting baroreflex function curves showed the Pth of the cardiac and non-cardiac sympathetic to be similar (62 mmHg, dotted line versus 68 mmHg, continuous line, respectively).



[Figure ID: fig05]
Figure 5  Baroreflex inhibition of non-cardiac sympathetic without cardiac vagal activation

Simultaneous recordings of cardiac vagal nerve and non-cardiac, thoracic sympathetic chain in the WHBP. With a small perfusion pressure pulse it was possible to demonstrate clear baroreflex sympathoinhibition without cardiac vagal activation (A). Subsequent larger pulses produce graded activation of the cardiac vagal and sympathoinhibition (B and C). Note also that the time course of the sympathoinhibition was more prolonged than the period of vagal activation.



[Figure ID: fig07]
Figure 7  Comparison of baroreflex function curves for heart rate versus renal and adrenal sympathetic nerves

A, dual renal and adrenal sympathetic nerve recordings in the DAPR showed striking sympathoinhibition early in the biphasic perfusion pressure ramp (continuous line marks Pth). The inflection in the profile of the perfusion pressure ramp (arrow) follows this loss of sympathetic tone. The onset of the baroreflex bradycardia (Pth, dotted line) followed after the sympathoinhibition (and pressure inflection point). B, baroreflex function curves were fitted to the sympathetic nerve recordings and heart rate data (R2 > 0.95, 95% confidence intervals dotted). Again the cardiac function curve (?) was operative over a higher pressure range (Pth= 94 mmHg) than either the renal (?) or adrenal (?) sympathetic function curves (both Pth= 73 mmHg). (Renal function curve parameters: Pth 73 mmHg, PP50% 78 mmHg, Psat 84 mmHg, gain 2.5 ?V mmHg?1; adrenal function curve parameters: Pth 73 mmHg, PP50% 78 mmHg, Psat 82 mmHg, gain 1.6 ?V mmHg?1; cardiac function curve parameters: Pth 94 mmHg, PP50% 103 mmHg, Psat 112 mmHg, gain 4 bpm mmHg?1.)



[Figure ID: fig08]
Figure 8  Baroreflex function curves in spontaneously hypertensive rats

A, response to biphasic pressure ramp stimulus in SHR WHBP (postnatal day 28) showing baroreflex inhibition of the non-cardiac sympathetic chain and bradycardia. Note that the amplitude of the ramp in the SHR was larger for an equivalent flow change (compared to Wistar WHBP) and in turn, this larger pressure change was necessary to activate the baroreflex bradycardia. B, baroreflex function curves (from data in A) demonstrate a clear difference in the pressure sensitivity of the non-cardiac sympathetic and cardiac baroreflex. (Sympathetic function curve parameters: Pth 76 mmHg, PP50% 94 mmHg, Psat 113 mmHg, gain 0.11 ?V mmHg?1; cardiac function curve parameters: Pth 101 mmHg, PP50% 109 mmHg, Psat 118 mmHg, gain 10 bpm mmHg?1.) C, comparison of the baroreflex function parameters of SHR and Wistar rats. The pooled analysis (n = 6) shows that the cardiac baroreflex in the SHR (like the Wistar) was active over a significantly higher pressure range than the sympathetic. Furthermore, when compared to the Wistar, the SHR cardiac baroreflex was reset to a significantly higher pressure range whereas there was a smaller, non-significant, trend towards higher values for the non-cardiac sympathetic baroreflex. **P < 0.01.



Tables
[TableWrap ID: tbl1] Table 1 

Baseline cardiovascular and baroreflex parameters for Wistar and spontaneously hypertensive rats (SHR)


Parameter Wistar SHR P
Perfusion pressure (mmHg) 56 ? 4 80 ? 4 < 0.002
HR (bpm) 293 ? 19 347 ? 8 < 0.05
Sympathetic
?Pth (mmHg) 66 ? 1 70 ? 3 NS
?PP50% (mmHg) 77 ? 3 84 ? 4 NS
?Psat (mmHg) 88 ? 6 97 ? 5 NS
?Gain (?V mmHg?1) 0.49 ? 0.1 0.26 ? 0.06 NS
?Minimum SNA (?V) 0.67 ? 0.27 1.12 ? 0.47 NS
?SNA range (?V) 9.7 ? 3.4 5.8 ? 1.4 NS
Cardiac
?Pth (mmHg) 82 ? 5 104 ? 4 = 0.005
?PP50% (mmHg) 87 ? 4 113 ? 4 = 0.001
?Psat (mmHg) 92 ? 4 123 ? 4 < 0.001
?Gain (bpm mmHg?1) 22 ? 5 5.5 ? 1.5 < 0.01
?Minimum HR (bpm) 150 ? 24 255 ? 23 = 0.01
?HR range (bpm) 149 ? 18 87 ? 24 = 0.06

All data from WHBP with the same basal perfusate flow rate (17 ml min?1, n = 6 per group, unpaired t test). Parameters derived from the baroreflex function curve. Pth, pressure threshold; PP50%, perfusion pressure at 50% of maximum baroreflex activation; Psat, saturation pressure; SNA, sympathetic nerve activity; HR, heart rate; NS, not significant.



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