While there is no disputing the critical role of baroreflexes in buffering rapid changes in arterial pressure, their role in long-term pressure control has become an area of controversy. Recent experiments using novel techniques have challenged the traditional view that arterial baroreflexes are not involved in setting chronic arterial pressure levels. Resetting of the arterial baroreflex, often used as an argument against the arterial baroreflex playing a role in long-term pressure control is rarely complete. The arterial baroreflex is just one of the many neural, hormonal, and intrinsic mechanisms involved in arterial pressure control and while the removal of the arterial baroreflex alone has little effect on mean arterial pressure it is too simplistic to suggest that the baroreflex has no role in long-term pressure control. Renal sympathetic nerve activity appears to be particularly resistant to resetting in response to ANG II-induced hypertension. Given the important role of the kidneys in long-term pressure control, we suggest there is a clear need to develop experimental techniques whereby sympathetic nerve activity to the kidneys and other organs can be monitored over periods of weeks to months.
- baroreflex resetting
- sinoaortic denervation
- renal sympathetic nerve activity
despite much research on the neural, hormonal, and intrinsic mechanisms involved in the control of arterial pressure, our understanding of how arterial pressure is controlled over the long term is limited. The classic experiments illustrating the ability of the arterial baroreflex to rapidly reset (25, 36) and showing that there is no change in the arterial pressure after chronic baroreceptor denervation (12) relegated the arterial baroreflex to only being important in short-term pressure control, suggesting other mechanisms were involved in the control of blood pressure over longer time scales. Recently a number of studies, using novel approaches (32, 33, 54), seem to indicate that this “relegation” was premature. The aim of this review is not to suggest we begin back at square one and dismiss the early studies, but rather to attempt to put the results of the previous studies and recent research into context and thus assist in plotting the roadmap ahead for delineating how blood pressure is controlled.
FIRST ARGUMENT AGAINST ARTERIAL BAROREFLEXES PLAYING A ROLE IN THE LONG-TERM CONTROL OF ARTERIAL PRESSURE: THE RESETTING PHENOMENA
Perhaps one of the strongest arguments for arterial baroreflex to not play a role in the long-term control of arterial pressure is the fact that the reflex can adapt or “reset” in response to maintained changes in pressure. The possibility that the receptors may reset was first suggested by McCubbin et al. (36) when they found that the receptor firing rate was much lower at equivalent pressures in chronically hypertensive than in normal dogs. It has since been shown that resetting is not necessarily a chronic phenomenon and may occur in response to brief exposure to a high or low conditioning pressure. Shifts in the operating range of the receptors in the direction of the prevailing pressure have been reported within seconds to minutes after a change in pressure activity (8). Munch et al. (37), using an in vitro preparation of the rat aortic arch, showed that when a step rise in arterial pressure was maintained, single-fiber baroreceptor activity declined exponentially with a time constant of 3–4 min. Reports of resetting over an even shorter time frame have been reported (6). Resetting of the arterial baroreceptors is also observed in chronic hypertension, although it should be noted that the shift in the arterial pressure-baroreceptor activity relationship is rarely found to be complete (see Ref. 37), suggesting that even in established hypertension the arterial baroreflex may still to some extent be opposing the elevated pressure. Resetting of the reflex is not limited to resetting of the arterial pressure-afferent baroreceptor activity relationship. Alterations in the input-output response can occur as a result of changes at the level of the afferent, central, or efferent component of the arterial baroreflex.
Differential Baroreflex Resetting
A common assumption made is that if one component of the baroreflex resets, all components must; e.g., if heart rate control is reset then so must sympathetic activity to the kidneys, muscle, skin, etc. In reality it is entirely possible that different components of the baroreflex may be more or less sensitive to sustained changes in pressure. Even at the level of the baroreceptor endings themselves there is evidence that the baroreceptors are capable of providing information about both the absolute and relative level of pressure. The baroreceptor afferents are composed of both A and C fibers. Typically, C fibers have a much lower firing frequency and higher pressure threshold than A fibers (53). Even at normal resting arterial pressures it appears that, while most A fibers are active, many C fibers are still below threshold (9). One possibility is that the A fibers are important in buffering rapid changes in pressure, and reset readily whereas the C fibers are more important in preventing high pressures and are less likely to reset (48). In explaining the greater shift in the response curve at threshold pressures than at higher pressures seen in whole nerve recordings, both Undesser et al. (55) and Heesch et al. (19) speculated that the low-threshold receptors may reset more readily than high-threshold baroreceptors.
There is also evidence to suggest that the different subtypes of baroreceptor afferents may project to different regions of the nucleus tractus solitarius (13) and ultimately have control over different reflex pathways (14). Sympathetic nerve activity (SNA) to the renal, muscle and heart is strongly baroreflex modulated yet SNA to the skin and gut much less so (23, 38–40). It is perhaps not surprising then that just because one branch of the efferent baroreflex pathway may reset, this does not necessarily mean all reflex pathways will be reset similarly. Even in acute experiments where the baroreceptor afferents have been stimulated electrically it has been shown that when the stimulation stops arterial pressure returns to resting levels much quicker than renal sympathetic nerve activity (26). Disparities in the way in which heart rate and renal SNA reset in response to a two-kidney, one-clip model of hypertension have also been observed, with an attenuation of the arterial baroreflex control of renal SNA at 3 wk postclip but not 6 wk, whereas baroreflex control of heart rate was attenuated at both time points (18). Clearly, one cannot assume that just because baroreflex control of heart rate has reset that baroreflex control to other vascular beds will also have reset.
SECOND ARGUMENT AGAINST ARTERIAL BAROREFLEXES PLAYING A ROLE IN THE LONG-TERM CONTROL OF ARTERIAL PRESSURE: BARORECEPTOR DENERVATION STUDIES
A traditional method of examining the role of the arterial baroreflexes in long-term pressure control has been to simply eliminate the baroreceptor afferents, by cutting the aortic depressor and carotid sinus nerves (sinoaortic denervation, SAD). Cowley and colleagues (12) established the need for continuous recording under undisturbed conditions to see “nearly normal” arterial blood pressures in SAD dogs. Similar findings have since been reported in a range of species including cats (44), rats (41), rabbits (46), and monkeys (10). The baroreceptor denervation studies have lead to the conclusion that given mean arterial pressure, when averaged over a period of time, is not significantly affected by baroreceptor denervation, the baroreceptors cannot be setting the long-term level of arterial pressure.
It should be not be forgotten that pressure in the SAD animals is much more variable than in baroreceptor-intact animals, with the frequency distribution curves often having long tails, indicating extremes in pressure in the SAD animals, emphasizing the importance of the arterial baroreflex in buffering rapid changes in arterial pressure. If we closely examine the frequency distribution curves of the mean arterial pressure in the SAD dogs presented by Cowley et al. it is apparent that, not only is the distribution of the pressures wider than in the intact dogs, but in 8 of the 12 SAD dogs the peak of the distribution curve (mode) is much higher than we would expect (well above 125 mmHg, whereas in the intact dogs no peak was above 125 mmHg, Figure 1 ), suggesting that in any one animal at a given time the arterial pressure is hardly “normal” in the SAD animals. We should keep in mind why it is so important that arterial pressure is tightly regulated; there is a fine line between organs receiving sufficient perfusion to meet their metabolic needs and being exposed to too low or too high pressures resulting in end-organ damage. While the mean pressure, when averaged over many days may be the same in intact and SAD animals, this does not mean that pressure is normal, with evidence that impaired baroreflex control, with increased pressure variability is associated with significant end-organ damage in the heart (52, 56) and kidneys (49, 50).
Immediately following baroreceptor denervation, arterial pressure is elevated, with pressure recovering to baseline with time; the general assumption has been that this recovery represents a resetting of the central control of sympathetic activity. However, an alternate hypothesis is that in the absence of afferent information there is central remodeling, with changes in the central pathways to compensate for the loss of afferents. It has been suggested that the cardiopulmonary and arterial baroreceptors have a “nonadditive attenuation effect on the central structures responsible for efferent cardiovascular control” so that as soon as one of these receptor areas is lost the function is taken over by the remaining receptor areas (43). Elimination of either the arterial or cardiopulmonary afferents does not change mean pressure, but a combined denervation of both cardiopulmonary and arterial receptors does results in chronic hypertension, at least in dogs (43). A species difference in cardiopulmonary baroreceptor afferent function may exist, as no effect on arterial pressure is seen when the cardiopulmonary afferent pathway is interrupted in SAD rats (47). While the arterial baroreflex cannot be ignored when considering long-term pressure control, we must remember that the arterial baroreflex does not work in isolation. Denervation of the arterial baroreflexes alone is not sufficient to chronically change mean arterial pressure, because other neural and hormonal systems are capable of compensating for their loss.
WHAT ARE THE IDEAL CONDITIONS IN WHICH TO STUDY THE ROLE OF THE BAROREFLEX IN LONG-TERM PRESSURE CONTROL?
While baroreflex resetting has been well described in acute experiments in which the conditions the baroreceptor afferents are exposed to have been tightly controlled, examining resetting in conscious freely moving animals is much more difficult. Two common approaches used in the literature are simply examining baroreflex control of heart rate, or if SNA is measured it is typically within 48 h of surgery to implant the electrodes. Recording SNA so soon after surgery raises the question of whether the effect of surgery and associated fluid balance confounds the SNA recordings. In our own laboratory we have found that SNA in rabbits is often high for up to 5 days postsurgery, with the normal circadian rhythm only observed once SNA has stabilized (1). This raises the issue as to not only when, but also which, index of baroreflex control should be measured, as using heart rate as the only indexes of baroreflex control will likely not tell the whole story.
Studies in the conscious baroreceptor-denervated animals are also often conducted under conditions in which the measurement environment was tightly constrained; for example in the studies by Cowley et al. (12) the dogs were tethered, preventing them from turning more than 360° or rolling onto their back. Given the human situation is one where the environmental inputs constantly change why should we study animal models in which we tightly control the inputs? One reason the inputs are tightly controlled is because we wish to hold constant as many of the factors liable to influence our experimental data as possible. In principle this gives the highest likelihood of seeing a significant effect. Yet the converse argument is also true: that we may see different effects when we let the inputs vary and thus we may see the sum of the different factors involved in pressure control. Howe and colleagues (22) reported that increasing dietary salt intake resulted in hypertension in SAD but not baroreceptor-intact rats. Similarly, Osborn and Hornfeldt (42) recorded arterial pressure via telemetry in Sprague-Dawley rats fed three levels of dietary salt, 0.4, 4.0 and 8.0%. By the third week of 4.0% salt, arterial pressure was elevated significantly in SAD but not sham-operated rats. By the end of the third week of 8.0% salt diet, 24-h arterial pressure was elevated 15 ± 2 mmHg above control in SAD rats compared with a 4 ± 1 mmHg increase in sham-operated rats. Hourly analysis of the final 72 h of each level of dietary salt revealed a marked effect of dietary salt on arterial pressure in SAD rats, particularly during the dark cycle when animals were active. Arterial pressure increased ∼20 and 30 mmHg in SAD rats over the 12-h dark cycle for 4.0 and 8.0% NaCl diets, respectively. In contrast, increased dietary salt had no effect on arterial pressure during any phase of the light or dark period in sham-operated rats. These results not only reveal the importance of the baroreceptors in modulating arterial pressure in the presence of a high salt intake but also show how important it is to record arterial pressure over 24 h.
We believe that if we are going to fully understand the role baroreflexes play in setting the mean level of blood pressure over the long-term, we need to examine the factors involved in blood pressure control for periods of weeks if not months, with 24 h/day recordings in an environment where the arterial baroreceptors are exposed to the fluctuations in pressure that accompany everyday life. While such fluctuations illustrate the ability of baroreflexes to buffer acute pressure stimuli, it is worth considering that it may be this very nature of arterial pressure that allows the baroreflexes to continue to play a role in long-term pressure control. While there is clear evidence that the arterial baroreflex resets when faced with a sustained change in arterial pressure, the question arises if this is really the type of stimuli that the arterial baroreflex is exposed to in vivo. Everyday activities such as sleeping, exercise, and eating, produce considerable changes in arterial pressure, and thus the input to the baroreceptors is never really constant. Recently, Lohmeier et al. (30) applied electrical stimulation to the carotid baroreceptors in dogs for 7 days and observed a sustained reduction in arterial pressure, suggesting that the arterial baroreflex was not resetting. It is important to note the stimulus used was not in fact constant but rather a train of stimuli for 9 min followed by a 1-min off period. Thus it is possible that the baroreflex was never in a position to be able to reset because their input was being adjusted every 9 min. Rather than criticize this approach as one that could not ascertain whether baroreflex resetting occurs, one could suggest that it better reflects the fluctuating nature of the stimuli that the arterial baroreflex would be exposed to in daily life. It is noted that Lohmeier et al. bypassed the pressure-encoding step of the arterial baroreflex by direct stimulation of the baroreceptors, and thus we can only conclude that the central component of the arterial baroreflex does not reset under such conditions of intermittent stimuli. It remains unclear whether the afferent limb of the arterial baroreflex, the baroreceptors themselves, would reset when exposed to a pressure which on average was raised, but showed continuous fluctuations.
What Variable Should We Be Studying?
If arterial baroreflexes do exert a long-term action over SNA and arterial pressure, it is possible that the mechanisms involved are quite different from those involved in the short term. Currently many researchers lump the changes in SNA into a single response and forget that the ability of the arterial baroreflex to regulate SNA is differentially controlled. One important area for future study is to determine the relative role in long-term pressure control of each the various efferent pathways under baroreflex control. It has been argued that in order for baroreflexes to exert a long-term action on arterial pressure it must be via an alteration in the renal pressure diuresis/natriuresis relationship (28). The importance of the renal nerves in long-term pressure regulation is illustrated by the point that renal denervation alone lowers arterial pressure, at least in part due to neurally mediated release of rennin (24). Similarly, our own studies in anesthetized rabbits show that low-level electrical stimulation of the renal nerves to a single kidney produces increases in arterial pressure, a response dependent on ANG II (27). Given the kidney's central role in the long-term control of arterial pressure, a key question must therefore be what is the role of the arterial baroreflex regulation of SNA to the kidney vs. other vascular beds? Only by directly recording SNA to various vascular beds are we going to be able to unravel the relative importance of each of the vascular beds in blood pressure control.
ANG II MODELS OF HYPERTENSION: WHAT CAN WE LEARN FROM THEM?
To study the long-term effects of a change in pressure we need to manipulate pressure. The majority of methods that increase arterial pressure rely on altering the renin-ANG II system. The ability of ANG II, whether by infusing the peptide, or altering kidney production of renin, to shift the renal function curve, and thus systemic arterial pressure offers a convenient tool when studying the effect of maintained changes in pressure.
Our own studies in conscious animals using ANG II infusions to induce hypertension have shown clear differences in the ability of baroreflex control of heart rate and SNA to reset. Importantly these are the first studies in which within-animal long-term recordings of SNA been described. Using direct long-term recordings of renal SNA and blood pressure in rabbits, we explored the relationship between increased ANG II levels, SNA and baroreflexes (2). A 1-wk period of ANG II infusion (50 ng·kg−1·min−1) caused a sustained increase in arterial pressure (∼18 mmHg). While ANG II is thought to act centrally to cause sympathoexcitation (60), we found ANG II caused a sustained decrease in renal SNA throughout the whole infusion (Fig. 2). Cessation of the ANG II caused blood pressure and SNA to return to control levels. The observation of sympathoinhibition during ANG II infusions is also supported by Carroll et al. (7) who measured renal norepinephrine overflow as an indirect index of renal sympathetic nerve activity. Six days of ANG II hypertension was associated with marked reductions in renal norepinephrine spillover. Our results suggest that ANG II-induced hypertension results in a sustained reduction in renal SNA that is likely to be baroreflex dependent. The heart rate to arterial pressure baroreflex response displayed evidence of the classical resetting with a rightward shift in the curve (Fig. 3). However, in the arterial pressure to SNA relationship there was no evidence of resetting (Fig. 3). There was an obvious decrease in the range of the reflex at days 2 and 7 of ANG II infusion. Significantly before the ANG II infusion the resting point of the arterial baroreflex curve lay near the steepest point of the arterial pressure-renal SNA curve, whereas during the ANG II infusion the resting point lay close to the lower plateau; thus producing an increase in arterial pressure from this point using a rapid phenylephrine infusion did not result in any further decrease SNA. The arterial pressure at half the reflex range was not altered during the ANG II infusion; in other words the overall curve was not shifted to the left or right. The gain of the curve was also unaffected, despite the decrease in range. Upon ANG II cessation, all baroreflex parameters had returned to control values when measured 3 days after stopping ANG II (Fig. 3). It was proposed that the lack of resetting of the arterial pressure to SNA curve, with the resting point lying near the lower plateau, suggests the sustained decrease in SNA during ANG II is baroreflex mediated.
Studies by Lohmeier and colleagues, where sympathetic activity has been inferred from measuring sodium excretion in a dog split bladder preparation with one denervated kidney, also suggest that renal sympathetic activity is chronically inhibited in response to ANG II infusion (29, 31, 32). The elevation in sodium excretion from the intact kidney relative to the denervated kidney was prevented by cardiopulmonary denervation and reversed after sinoaortic denervation, suggesting that cardiac and/or arterial baroreflexes chronically inhibit renal SNA during ANG II-induced hypertension (31). Preliminary experiments from our own laboratory have shown that in rabbits with sinoaortic denervation there is no change in renal SNA in response to ANG II infusion (Barrett and Malpas, unpublished observation). Together these findings suggest the arterial baroreflexes are necessary for the sustained inhibition of renal SNA in response to an ANG II-mediated increase in arterial pressure.
The effect of ANG II-induced hypertension in baroreceptor-denervated animals also offers some interesting insights. One would predict that if the arterial baroreceptors are playing a role in buffering the increase in arterial pressure in response to ANG II, then the increase in arterial pressure in response to ANG II infusion would be greater in SAD than intact animals. Cowley and DeClue (11) were the first to test this hypothesis and found that ANG II infusion in SAD dogs caused an abruptincrease in arterial pressure, with a slower rise in pressure in the arterial baroreflex-intact dogs. However, after 28 h the mean arterial pressure was not different between the two groups of animals, leading them to conclude that while initially the arterial baroreflexes helped prevent the rise in pressure, they reset in response to the maintained infusion. Our own observations suggest that this conclusion is too simplistic. We examined the responses in intact and SAD rabbits to a 7-day infusion ANG II (50 ng·kg−1·min−1 iv via a miniosmotic pump). Baseline arterial pressure was not significantly different between the intact and SAD rabbits (76.0 ± 3.1 mmHg in the sham operated and 80.6 ± 1.5 mmHg in the SAD), although as expected the variability of the pressure was greater in the denervated rabbits. ANG II infusion significantly increased arterial pressure in both groups of animals. Like Cowley and DeClue (11), we found that the increase in arterial pressure tended to occur more rapidly in the SAD rabbits (Fig. 4); however, the mean increase over the 7-day infusion period was not different between the sham-operated and SAD rabbits (95.5 ± 3.2 mmHg and 96.2 ± 2.9 in the sham-operated and SAD rabbits, respectively, P = 0.79, Fig. 4). It should be pointed out that while arterial pressure in the control animals reached the same mean level as the SAD rabbits, we have already shown that ANG II causes a sustained decrease in renal SNA throughout the 7 days of infusion (2). This raises an interesting scenario: for the first 24 h of ANG II infusion arterial pressure is lower in the intact than denervated rabbits, presumably due to the buffering effects of the arterial baroreflex; however, long term there is no difference in the mean arterial pressure between the two groups of animals. What has happened? Given that renal SNA is still suppressed by ∼50% in the intact animals (Fig. 2), we cannot conclude that the arterial baroreflexes have reset, at least not baroreflex control of renal SNA. Does the fact that the arterial pressure in the intact and denervated rabbits is the same after 7 days of ANG II infusion suggest that the changes in renal SNA are irrelevant in long-term pressure control? Or does the slow increase in arterial pressure reflect the multitude of actions ANG II has, i.e., while the systemic vasoconstrictor actions of ANG II may cause a baroreflex-mediated decrease in SNA, these are opposed over time by the ANG-induced increase in aldosterone, sodium reabsorption, and shift in the renal fluid balance relationship (17). These results illustrate the difficulty in making assumptions about one component when we are studying a system where there are multiple effectors playing a role in the long-term pressure control.
Perhaps one of the most interesting observations seen in response to ANG II-induced hypertension in the SAD animals is the effect ANG II infusion has on the arterial pressure variability. While the mean pressure in the SAD and baroreceptor-intact animals may not differ in the long term with ANG II infusion, we have found that ANG II infusion results in the arterial pressure becoming even more variable in the SAD rabbits. The frequency distribution of pressures shows that during ANG II infusion in the SAD rabbits the peak in the frequency distribution curve (mode) was well above that observed in the control animals (Fig. 5). It appears that the extreme hypotensive periods of pressure observed in SAD animals in effect balance the extreme hypertensive periods, such that while arterial pressure is generally higher in the SAD animals during the ANG II infusion, the mean pressure over days is not different because of the extreme hypotensive periods. This increased pressure variability during the ANG II infusion in the SAD animals illustrates the point that while there are multiple mechanisms involved in long-term pressure regulation, it is often necessary to disturb more than one of these mechanisms to have any noticeable affect on arterial pressure regulation.
When observing the sustained decrease in renal SNA during the 7 days of ANG II infusion, we suggested that in conscious animals, where the baroreceptors are exposed to natural variations in arterial pressure as the animal goes about its daily activities, the arterial baroreflexes may play a significant role in the control of SNA and arterial pressure in the long-term (2). These results support previous studies where a sustained decrease in renal SNA was inferred (7, 29). However, we recognize that the SNA suppression may be specific to ANG II. It is unclear whether the same changes in SNA would have occurred if a non-ANG II-based form of hypertension had been used. While ANG II does not appear to affect the arterial pressure-baroreceptor afferent activity relationship (21), there is evidence that ANG II can act within the central nervous system in a pressure-independent manner to alter the arterial baroreceptor reflex output relationship (34). Brooks and colleagues (3–5) have shown that the shift in the baroreflex control of heart rate and plasma norepinephrine levels they observe with ANG II infusion is largely reversed even when arterial pressure is maintained at the hypertensive level by replacing ANG II with phenylephrine. It is also worth considering what would have happened if we had used a lower dose of ANG II; would we then have seen sympathoexcitation as has been often reported (20, 45). Finally, many of the studies have followed baroreflexes and/or SNA for only a modest period of time (5–10 days), and it remains unclear whether baroreflex control of renal SNA would eventually reset if the administration of ANG II had been for longer. The evidence from a renal clip form of hypertension, and thus high ANG II levels, is that resetting does occur after 6 wk (18). It is also worth remembering the differential nature of sympathetic nerve activity as it does appear that the action of ANG II on renal SNA may be specific to the renal component of SNA. In our own study while we saw a sustained sympathoinhibition of renal SNA, the arterial pressure-to-heart rate relationship clearly did reset by day 2 of the ANG II infusion (2). Similarly, May and colleagues have shown that the acute intracerebroventricular administration of ANG II in sheep results in an increase in cardiac SNA (59) but a decrease in renal SNA (35). Given the importance of renal SNA in long-term pressure control, a better understanding of this differential control of renal SNA is clearly required. Such questions and caveats may in some way help to explain the apparent major discrepancy between the early studies (12) indicating the arterial baroreflexes weren't important for long-term blood pressure control from more recent studies indicating nonresetting of the arterial baroreflex (2, 33) and therefore a possible role in long-term blood pressure control.
NEW APPROACHES NEEDED
Anesthetized studies are useful in illustrating important features such as the firing properties of receptors, cell groups involved in the pathways and the neurotransmitters involved in the arterial baroreflex; however, they are limited in their ability to provide quantitative information on long-term blood pressure control. Given the long-term control of arterial pressure is the product of a host of hormonal, neural, and intrinsic factors, the ability to determine the relative importance of one component vs. another component is crucial. The question becomes if the arterial baroreflex is not important for setting the mean level of SNA and thus the mean level of blood pressure, then what is? While renal function is attributed to being the crucial factor in long-term pressure regulation (16), even our knowledge of how nonbaroreflex mechanisms regulate renal SNA is poor. In part this may be explained by a lack of tools to approach this question as direct long-term recordings of SNA have, until recently (2), not been possible.
Currently, the most common approach for examining the role of the arterial baroreflexes in long-term pressure control is to remove one component of the reflex, using techniques such as SAD, renal denervation, sympathectomy, and ganglionic blockade. While such techniques may offer some information as to the importance of the arterial baroreflex, they are limited in their ability to allow changes to be monitored with time and they do not allow quantitative data to be collected. The drive to understand the role of baroreflexes in long-term pressure regulation is generated by the interest in understanding pathologies where it appears the arterial baroreflex is disrupted in some sense, e.g., heart failure, sleep apnea, obesity, early-stage hypertension; in each of these cases SNA tends to be increased (15, 51, 57, 61). Given that we are interested in understanding pathologies in which SNA appears to be increased, it seems a critical flaw is to assume that the responses to decreasing or removing SNA will simply be the opposite of increasing SNA. There is a clear need to focus on developing experimental paradigms/stimuli that increase arterial pressure via increasing SNA. The “chronic baroreceptor unloading” method developed by Thrasher (54) whereby a decrease in carotid sinus pressure is achieved by isolating the sinus is an excellent attempt at inducing a reflex increase in SNA and systemic arterial pressure. A disadvantage of this chronic baroreceptor unloading technique is that the preparation may not be stable, with increased flow to the carotid region with time making changes in systemic arterial pressure difficult to interpret. Measurements of blood flow above the carotid sinus, and SNA may help answer the questions as to the stability of the method.
To determine exactly the long-term roles of different pathways within the central nervous system, it is perhaps a combination of tools that is required. With the advent of the revolution in genetic manipulation, a number of new avenues for investigating the mechanisms of cardiovascular control are opened up. The use of viral vectors for gene transfer to alter the regulation of specific peptides within the brain stem is one such technique that allows the action of specific components of cardiovascular control to be studied. The use of viral vectors is promising because of its ability to locally regulate gene expression. Such tools have already shown that endothelial nitric oxide synthase acts within the nucleus of the solitary tract to chronically attenuate the gain of the arterial baroreflex (58). The use of such tools in combination with long-term recordings, whether it is of just blood pressure or in combination with SNA recordings, offers potential for a wealth of information to be determined about the effects of various peptides within specific areas of the central nervous system.
In summary, the question remains, do the arterial baroreflexes play a role in long-term pressure regulation? We suggest that the answer is yes, although we do not believe that this necessitates a radical new thinking of the role of the arterial baroreflexes. Their role predominantly is to buffer rapid changes in arterial pressure. Removal of the arterial baroreceptors alone increases the variability of arterial pressure but has no long-term effect on arterial pressure (12), in part because other neural, hormonal, and intrinsic mechanisms are available to regulate the mean level of arterial pressure. In the conscious animal, where the arterial baroreceptors are continually exposed to fluctuations in pressure associated with daily activity, it is unlikely that a sustained change in pressure will result in complete resetting of the arterial baroreflex (37), and thus the arterial baroreflexes will continue to oppose the change in pressure to some degree. Our own recent work has shown that in response to ANG-induced hypertension, renal SNA is likely to be inhibited for a period of at least 7 days (2). While this inhibition may be a specific ANG II effect, and not necessarily directly pressure dependent, it does appear to be dependent on an intact arterial baroreflex pathway (31). The inhibition of SNA may be limited to the renal bed (2, 59); however, given the crucial role of the kidneys in long-term pressure control (17), changes in renal SNA cannot be overlooked. There is a clear need to develop experimental paradigms whereby arterial pressure is manipulated and SNA monitored to a range of organs continuously over a time period of weeks to months.
- Copyright © 2005 the American Physiological Society