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This Article Abstract Full Text (PDF) All Versions of this Article: 89/4/331    most recent expphysiol.2004.027441v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thrasher, T. N. Search for Related Content PubMed PubMed Citation Articles by Thrasher, T. N. Related Collections Exchange of Views Cardiovascular control Hot Topic Reviews

Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA

Abstract

The current consensus is that arterial baroreceptors are vitally important in the short term (seconds to minutes) control of mean arterial pressure (MAP) but are unimportant in determining the long-term level of MAP. The latter statement is based primarily on two observations: first, that baroreceptors rapidly reset to the prevailing level of MAP and second, that total baroreceptor denervation has no lasting effect on the average daily MAP, although the variability of MAP is increased dramatically. However, recent studies in intact experimental animals have produced results that suggest baroreceptor resetting may not be as rapid or complete as previously thought. Furthermore, reconsideration of the responses to baroreceptor denervation suggest that the condition may accurately represent responses to short-term baroreceptor unloading but not long-term unloading. Results obtained using a new model of chronic baroreceptor unloading indicate that the condition results in a sustained increase in MAP. These results strongly suggest that the role of baroreceptors in the long term control of MAP needs to be revisited.

(Received 16 February 2003; accepted after revision 4 May 2004; first published online 6 May 2004)
Corresponding author T. N. Thrasher, Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD21201, USA. Email: tthrasher{at}smail.umaryland.edu

Arterial baroreceptors provide the afferent input to a medullary circuit that controls sympathetic drive to the heart and peripheral vasculature. As baroreceptor activity is related directly to the level of arterial pressure and the response to baroreceptor activation leads to reciprocal changes in sympathetic outflow, it was quickly recognized that baroreceptors constitute an important mechanism in the control of arterial blood pressure (Heymans & Neil, 1958). There was no controversy about whether baroreceptors play a role in the control of MAP, rather the controversial issue was the time frame involved. The current consensus is that baroreceptors play a crucial role in the short term (i.e. seconds to minutes) control of MAP but no role in the long term control of blood pressure. It has proven relatively easy to demonstrate that baroreceptor input is important in short-term control. For example, the technique of severing baroreceptor afferents, commonly referred to as sino-aortic denervation (SAD) results in huge swings in MAP in response to physical movement and environmental stimuli (Cowley et al. 1973). Furthermore, the ability to maintain blood pressure in response to a challenge such as haemorrhage is markedly reduced following SAD (Thrasher & Keil, 1998). In contrast, it has proven remarkably difficult to show that baroreceptors are involved in the long term control of blood pressure. The aim of the present article is to briefly review the data that argue strongly against baroreceptor involvement in long-term control and present some new observations that suggest the need to reconsider the consensus described above.

There are two well-established arguments against a role for baroreceptors in the long term control of MAP. Baroreceptors adapt or ‘reset’ in response to maintained changes in pressure as first demonstrated by McCubbin et al. (1956). They recorded from multifibre preparations of baroreceptor nerves in control and dogs with established renal hypertension. At a MAP of 60 mmHg, firing was phasic and synchronous with a rising pressure wave in control but absent in hypertensive dogs. At a MAP of 120 mmHg, phasic firing was observed in both groups. At a MAP of 240 mmHg, nerve activity was continuous in normal dogs but still phasic in the hypertensive dogs. Thus, in the hypertensive dogs, the baroreceptors reset to a higher operating range of MAP. Subsequent studies in the rat demonstrated that baroreceptor resetting in response to either hypotension or hypertension is complete within 48 h (Krieger, 1986). If baroreceptors adapt to sustained increases or decreases in MAP, the only obvious conclusion is that they are functioning to maintain the new level of MAP rather than a mechanism to restore MAP to control. The other argument against baroreceptor involvement in long-term control of MAP was provided by Cowley et al. (1973). They made continuous measurements of MAP in SAD dogs that had fully recovered from the surgical stress to produce the condition. When averaged over 24-h periods, the MAP in the SAD dogs was not different from baroreceptor intact dogs whereas the lability of MAP was much higher in the SAD condition. As SAD did not cause a chronic increase in the MAP, Cowley et al. (1973) concluded that baroreceptor input could not regulate MAP over the long-term. Numerous studies in a variety of species have validated the lack of effect of SAD on the long-term level of MAP (Cowley, 1992). These two observations, together with numerous additional supporting studies (for review, see Cowley, 1991) provide the basis for dismissing a role for baroreceptors in the long term control of MAP.

Recently a number of studies in different species have been published with results that are incompatible with the arguments presented above. Lohmeier et al. (2000) have used a split bladder preparation combined with unilateral renal denervation that allows simultaneous determination of sodium excretion from the innervated and denervated kidneys. Differences in excretion provide an indirect means of gauging the level of renal sympathetic nerve activity (RSNA). They infused angiotensin II (Ang II) continuously for 5-days in dogs sufficient to increase the MAP to 30–35 mmHg above control levels. During the control period, sodium excretion from the innervated and denervated kidneys was nearly identical. In contrast, sodium excretion increased in the innervated kidney compared to the denervated side during Ang II infusion. As both kidneys were exposed to the same increase in MAP and plasma Ang II concentration, the only explanation for the increased sodium excretion in the innervated kidney is chronic suppression of RSNA. To determine the role of cardiovascular afferents in the response, they denervated cardiopulmonary receptors and baroreceptors and repeated the experiment. In contrast to the intact response, sodium excretion in the innervated kidney decreased during infusion of Ang II, suggesting that in the absence of cardiopulmonary and baroreceptor afferents, Ang II causes a sustained increase in RSNA. Unfortunately, because of the way they performed the denervations, it is not possible to determine the relative importance of baroreceptor and cardiopulmonary input in the suppression of RSNA during Ang II infusion. In a subsequent study, Lohmeier et al. (2001) repeated the Ang II infusion for a 10-day period in intact dogs and observed an increase in sodium excretion in the innervated kidney that was sustained over the entire protocol. Both studies provide evidence that suggests baroreceptor resetting is not complete, at least in terms of the RSNA–MAP relationship in the 5 and 10-day time frames examined.

Barrett et al. (2003) performed similar experiments in rabbits except that they were able to measure RSNA via an implanted telemetry system. Ang II was infused systemically for 7 days leading to a rise in MAP of about 18 mmHg and was accompanied by a sustained 50% reduction in RSNA. By the seventh day of Ang II infusion there was clear evidence of a rightward shift in the heart rate–MAP relationship or classical resetting; in marked contrast, there was no change in the RSNA–MAP relationship. These results also challenge the notion that baroreceptors rapidly reset to the prevailing MAP. Furthermore, they indicate that evidence of resetting in terms of the heart rate–MAP relationship cannot be generalized to other vascular beds.

Osborn & Hornfeldt (1998) compared responses to chronic increases in dietary sodium on MAP (measured continuously via telemetry) in baroreceptor intact and SAD rats. Increases in sodium intake that had no effect on MAP in intact rats caused increases in MAP in the SAD animals. This observation is consistent with the suggestion that baroreceptor reflexes were buffering the effects of large increases in sodium intake on MAP. This study with the others cited above all suggest that baroreceptor-mediated suppression of sympathetic outflow is sustained during sustained increases in MAP or sodium intake.

Neuroanatomical studies have also provided evidence to support the existence of sustained baroreceptor activation in experimental hypertension. Lohmeier et al. (2002) infused a hypertensive dose of Ang II chronically (5 day duration) in dogs and then examined medullary neurones involved in the baroreflex pathway. They stained the sections immunohistochemically for Fos-like protein, a marker for cell activation. They reported a two- to threefold increase in Fos-like protein in the nucleus of the solitary tract (NTS) and caudal ventrolateral medulla (CVLM) in dogs infused with Ang II compared to control dogs but no change in the rostral ventrolateral medulla (RVLM). An increase in activity of NTS and CVLM neurones would be predicted in response to activation of baroreceptors, if baroreceptor resetting is not complete during Ang II-induced hypertension. In a different model of hypertension, dogs made obese by supplementing their normal diet with excess fat for 6 weeks, developed a 14 mmHg increase in MAP (Lohmeier et al. 2003). Immunohistochemical processing of medullary neurones revealed a three- to fivefold increase in Fos-like protein in NTS and CVLM neurones compared to control normotensive animals. Surprisingly, Fos-like protein was also increased in the RVLM in the obese dogs suggesting that other excitatory inputs were dominant to baroreceptor-mediated suppression of RVLM neurones. Results from both of these studies are compatible with sustained activation of the baroreflex pathway during hypertension.

The examples cited above provide functional evidence that baroreceptor resetting in response to increased load may not always be complete. It is known that there are two populations of baroreceptors, i.e. type 1 receptors with A-fibre afferents and type 2 with C-fibre afferents; and that the properties of the two receptors differ substantially (Seagard et al. 1992). Most importantly, whereas type 1 receptors undergo acute resetting, type 2 receptors do not. Therefore, the dogma that baroreceptor resetting is rapid and complete may not be entirely correct. If in fact the type 2 receptors do not reset, they have the capability to maintain a functionally important input signal relating systemic pressure to firing rate. In other words, they could signal longer-term changes in the level of the MAP to reflex mechanisms in the medulla that control sympathetic outflow.

If one is willing to accept the notion that baroreceptor resetting may not be complete, there is still the problem that complete baroreceptor denervation has no sustained effect on MAP. At the time when Cowley et al. (1973) reported the lack of effect of SAD on continuously recorded MAP, SAD was considered the ultimate model of baroreceptor unloading. More recent studies have revealed the enormous plasticity of the nervous system (Kandal et al. 2000). The most probable explanation for baroreceptor denervation not causing a sustained increase in MAP is due to the fact that neuronal remodelling begins soon after loss of afferent input from baroreceptor to NTS neurones in the baroreflex pathway. There are many examples of this process in other neuronal systems. For example, lesions that encompass the so-called anteroventral third ventricle (AV3V) in the rat render supraoptic neurones (SON) acutely silent electrophysiologically (Leng et al. 1988). However, recordings made 2 weeks after AV3V lesions show that the level of spontaneous activity in SON neurones has returned to normal (Chaudhry et al. 1989). Thus, the original concept that baroreceptor denervation is a model of chronic baroreceptor unloading is most probably wrong.

Work in the author's laboratory has focused on developing a new model for chronic baroreceptor unloading in the dog. Aortic baroreceptors are denervated bilaterally (in the dog this requires intrathoracic stripping of the aortic arch and major branches as aortic baroreceptor fibres run with vagal afferents) and carotid baroreceptors unilaterally (Thrasher, 2002). These procedures leave the animal with one functional set of carotid baroreceptors. The baroreceptors are chronically ‘unloaded’ by ligating the common carotid below the innervated receptors.

The response to unloading the remaining set of baroreceptors is shown in Fig. 1. A significant increase in MAP was observed that lasted for 7 days, after which the ligature occluding the common carotid was removed and MAP returned to control levels. In each dog, the increase in MAP during common carotid occlusion was sufficient to restore pressure in the innervated sinus to within a few percentage points of the control level. In fact, the pressure in the sinus was not statistically different from control, although there was a sustained decrease in pulse pressure in the blind sinus sac. These results are not due to disruption of cerebral blood flow because in some of the dogs, the common carotid on the opposite side below the denervated sinus was ligated after complete recovery from the first procedure. There was no sustained increase in MAP and pressure in the carotid sinus region fell significantly (Fig. 2). The increase in MAP that resulted from unloading carotid baroreceptors was accompanied by a sustained increase in heart rate. Surprisingly, plasma renin activity was not suppressed by the increase in MAP but instead increased significantly by day two of baroreceptor unloading and then fell back toward control but not below control for the remainder of the experiment.

View larger version (18K): [in this window] [in a new window]   Figure 1  Symbols indicate the daily averages (lines represent 1 S.E., n= 6) of mean arterial pressure (MAP; filled circles) and carotid sinus pressure (CSP, open circles) during a 5-day control period; a 7-day period of continuous baroreceptor unloading (BRU) and a 4-day recovery period. BRU was induced by ligating the common carotid below the innervated sinus and recovery began with removal of the ligature. *, Means that differ significantly (P < 0.05) from control measurements. (Adapted from Thrasher, 2002)

View larger version (19K): [in this window] [in a new window]   Figure 2  Symbols indicate the daily averages (lines represent 1 SE, n= 4) of mean arterial pressure (MAP; filled circles) and carotid sinus pressure (CSP, open circles) during a 5-day control period; a 7-day period of common carotid ligation (CCL) below a denervated sinus and a 4-day recovery period (carotid ligature removed). *, Means that differ significantly (P < 0.05) from control measurements. (Adapted from Thrasher, 2002)

Interest in baroreceptors as participants in the long term control of MAP virtually ceased in the 1970s. Based on the experiments and concepts as they were understood at the time, it is not hard to understand why many investigators arrived at that conclusion. However, recent studies described here, applying newer experimental approaches have produced results that are clearly not compatible with the current consensus of baroreceptor function. At the very least, there appears to be sufficient new information to reopen the discussion of the role of baroreceptors in the long term control of MAP.

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Acknowledgements

The work cited from the authors laboratory was supported by a grant from the National Institutes of Health, National Heart Lung and Blood Institute # HL 67329. The author acknowledges the invaluable technical assistance of Cassandra Smith and Sarah Muncie for work carried out in the author's laboratory.

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This Article Abstract Full Text (PDF) All Versions of this Article: 89/4/331    most recent expphysiol.2004.027441v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thrasher, T. N. Search for Related Content PubMed PubMed Citation Articles by Thrasher, T. N. Related Collections Exchange of Views Cardiovascular control Hot Topic Reviews