Where is the baroreceptor for the brain

The C1 area of the rostral ventrolateral medulla oblongata. A critical brainstem region for control of resting and reflex integration of arterial pressure.

Schreihofer, A. The kidneys stimulate vasopressin release during hemorrhage in rats with chronic NTS lesions. Chronic nucleus tractus solitarius lesions do not prevent hypovolemia-induced vasopressin secretion in rats.

Shafton, A. Neurons in the hypothalamic paraventricular nucleus send collaterals to the spinal cord and to the rostral ventrolateral medulla in the rat. Share, L. Blood pressure, blood volume and the release of vasopressin. In Greep, R. Endocrinology , Vol. Somogyi, P. Evidence for an excitatory amino acid pathway in the brainstem and for its involvement in cardiovascular control.

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Sun, M. Sved, A. PNMT-containing neurons of the C1 cell group express c-fos in response to changes in baroreceptor input. Swanson, L. Taniguchi, Y. The distribution of vasopressin-or oxytocin-neurons projecting to the posterior pituitary as revealed by a combination of retrograde transport of horseradish peroxidase and immunohistochemistry. Terui, N. Activity of barosensitive neurons in the caudal ventrolateral medulla that send axonal projections to the rostral ventrolateral medulla in rabbits.

Undesser, K. Baroreflex control of sympathetic nerve activity after elevations of pressure in conscious rabbits. Wallach, J. Projections of the aortic nerve to the nucleus tractus solitarius in the rabbit. Weinstock, M. Differentiation of cardiac baroreflex properties by cuff and drug methods in two rabbit strains. Download references. Roger A. Dampney, Jaimie W.

Polson, Patrick D. You can also search for this author in PubMed Google Scholar. Correspondence to Roger A. Reprints and Permissions. Cell Mol Neurobiol 23, — Download citation. Issue Date : October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search SpringerLink Search. Abstract 1. Google Scholar Hirooka, Y.

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PubMed Google Scholar Download references. However, the hindlimb dilatation changed to vasoconstriction in rabbits after sinoaortic denervation, suggesting that it was mainly due to a baroreflex response to the rise in blood pressure The profound increase in the sensitivity to central Ang II after sinoaortic denervation has been observed in rats with lateral ventricle administration In the conscious rabbit, chronic sinoaortic denervation augmented the sensitivity to Ang II given into the 4V by fold.

This effect was not observed in animals with depletion of spinal noradrenergic pathways, indicating that sensitization of the brainstem noradrenergic neurons to Ang may play a key role in this phenomenon This also suggests that pressor responses to central Ang II are normally suppressed by profound baroreflex inhibition. Furthermore, the Ang receptors that have been stimulated by 4V administration may be of greater physiological importance when the baroreflex is not functioning effectively as is the case in hypertension and heart failure 23, While much has been written about the effect of circulating Ang on cardiac and sympathetic baroreflexes, very few studies have examined the effect of intraventricular Ang on baroreflexes.

Thus, the upper plateau of the RSNA baroreflex curve was doubled and the curve shifted to the right due to the increase in blood pressure. Recently, we also infused Ang II into the lateral recess of the 4V in conscious rabbits Although in our study Ang infusion evoked pressor responses similar to those observed by Dorward and Rudd 25 , the magnitude of the RSNA increase after the baroreceptor unloading was lower Figure 2. This difference may indicate that access to the dorsal medulla and area postrema, which were much closer to the infusion site in the former study, may be critical in the excitatory action of intraventricular Ang II on the RSNA baroreflex in conscious rabbits.

Infusion of Ang II 2. Importantly, in both studies intravenous infusion of the same dose of Ang II had no effect on the baroreflex. More recently, we also found similar effects of infusion of a low dose of Ang II into the lateral recess of the 4V on cardiac baroreflex in rabbits Figure 3 It is interesting to note that the resetting appears to be complete.

However, since this occurs within 20 min, this is highly unlikely from what is known about the time course of baroreceptor resetting One possible explanation for the lack of acute bradycardia may be the fact that Ang II is also exciting cardiac sympathetic pathways in the brainstem. The advantage of such a combination of actions is that Ang can modulate the level of blood pressure rapidly while maintaining the very short-term regulation of heart rate within the high gain area of the reflex curve.

Studies concerning the cardiovascular role of central Ang II have predominantly involved acute administration of agonists and antagonists. However, perhaps even more important for the cardiovascular system is the impact of chronic activation or inhibition of central Ang II receptors. It has been known since the earlier 's that central infusion of Ang produces hypertension and central inhibition of the renin-angiotensin system attenuates hypertension Despite many such subsequent studies, relatively few have examined cardiovascular reflex mechanisms.

We recently examined the effect of chronic activation of central Ang II receptors on cardiac baroreflex function in conscious normotensive rabbits. Animals received a 4V infusion by osmotic minipump of Ang II for 2 weeks.

Assessment of the heart rate baroreflex was performed by a single slow ramp rise and fall in blood pressure by intravenous infusion of phenylephrine and by caval balloon inflation, respectively. The intriguing feature of this study was that the effect of Ang II took the full 2 weeks to develop. Within a week of stopping the infusion, cardiac baroreflex gain had returned to control levels Figure 3.

Ringer's solution or lower doses of Ang II did not modify the cardiac baroreflex function. Blood pressure and heart rate were not altered by any treatment nor was their variability affected as assessed by power spectral analysis Figure 3.

Dotted line - control, black line - Ang II. Error bars are average SEM. Figures adapted with permission from Refs.

There has been a great deal of interest in the cardiovascular role of the endogenous Ang system within the brain. The most effective method to determine the tonic activity of an endogenous Ang system has been to apply a specific receptor antagonist of converting enzyme inhibitor. Dorward and Rudd 25 examined the renal sympathetic and heart rate baroreflex effects of the specific, but non-subtype selective Ang II antagonist [Sar 1 ,Ile 8 ]-Ang II Sarile into the 4V of conscious rabbits.

The antagonist had no effect on renal sympathetic reflexes whilst an Ang-converting enzyme inhibitor, enalaprilat, slightly enhanced maximal baroreflex sympathetic responses. By contrast, in a similar conscious rabbit preparation, we found that the specific AT 1 receptor antagonist losartan increased resting RSNA and the upper plateau of the RSNA baroreflex, while blood pressure remained unaltered Figure 4 These results were somewhat surprising given that the receptor antagonist produced effects qualitatively similar to those of Ang itself and suggested that losartan is blocking a tonically active sympathoinhibitory action of endogenous Ang compare Figures 3 and 4.

However, the effects of trigeminal stimulation were not affected by losartan, suggesting that Ang normally modulates specific inputs to the presympathetic neurons, possibly by a presynaptic action.

The action of losartan was most likely a specific effect since in a later study we observed similar changes with the Ang-converting enzyme inhibitor, enalapril 32 , indicating a primary inhibitory role of hindbrain AT 1 receptors in conscious normotensive rabbits.

In all the above studies in intact rabbits, acute administration of various Ang II receptor antagonists neither changed resting blood pressure or heart rate, nor affected cardiac baroreflexes 17,25, However, rabbits with pacing-induced heart failure have inhibition of cardiac baroreflex function which can be restored by the AT 1 receptor antagonist L, By contrast, the cardiac baroreflex sensitivity in non-paced rabbits was not altered by AT 1 receptor blockade.

Thus, the participation of central Ang II in inhibiting cardiac baroreflexes does not appear to occur in the normal animal but requires a long-term perturbation of the cardiovascular system such as heart failure.

We recently examined the effect of chronic inhibition of central Ang II receptors on cardiac baroreflex function in conscious normotensive rabbits. Animals received a 4V infusion by osmotic minipump of losartan for 2 weeks. Similarly, chronic but not acute administration of the AT 1 receptor antagonist EXP has been shown to normalize cardiac baroreflex function in SHR These data indicate that there is a long-term modulation of cardiac baroreflexes by endogenous Ang II which is independent of the blood pressure level.

Possibly there is long-term regulation of the receptor or altered expression of AT 1 receptors. Another possibility may involve an interaction with nitric oxide. Zucker and colleagues 35 have elegantly shown an important interaction between nitric oxide and Ang in the modulation of baroreflexes in heart failure.

They suggest that the acute inhibitory effect of Ang on the baroreflex gain is opposed by the facilitatory effect of nitric oxide, but chronically, as is the case with heart failure, a reduction in nitric oxide synthase amplifies the effects of Ang II.

Figure 4. Dotted line - control, black line - losartan. Adapted with permission from Refs. Intraventricular administration has been a useful tool particularly in conscious animals to help unravel the role of the Ang peptides within the central nervous system but is limited by agents given in this way influencing large brain regions rather than specific nuclei.

In order to determine the distribution of neurons within the medulla activated by infusion of Ang II into the 4V of conscious rabbits, we used the expression of Fos, the protein product of the immediate early gene c- fos , as a marker of neuronal activation in baroreceptor intact and barodenervated animals We found that the distribution of Fos-positive neurons closely correlated with the location of Ang II receptor-binding sites as previously determined in the rabbit.

Of the regions that we examined using the Fos technique, it is clear that perhaps the most important is the RVLM where Ang peptides are likely to have their major sympathoexcitatory action 7.

The RVLM is a major source of excitatory drive to the pre-ganglionic sympathetic neurons in the spinal cord and contains high Ang II receptor binding in the rabbit 4 and other species including the cat and dog The existence of Ang II immunoreactive fibers in the ventrolateral medulla and extended neural processes of the RVLM neurons close to the ventral surface 38 suggest that Ang II may have ready access to the RVLM neurons both from neural pathways and from cerebrospinal fluid.

Allen and co-workers 39 demonstrated that direct microinjection of Ang II into the subretrofacial pressor region in the RVLM of the cat resulted in a pressor response. Andreatta and colleagues 40 suggested that the RVLM may contain a renin-angiotensin system since Ang I applied to the ventral surface of the brainstem of the cat produced an increase in blood pressure after conversion to Ang II.

Sasaki and Dampney 41 found that the sites which produced the greatest increase in blood pressure in the RVLM were also the sites containing the highest concentration of Ang receptors. We initially mapped various dorsal and ventral sites with microinjections of Ang II and found that marked pressor responses were observed only when Ang II was administered into a discrete region of the RVLM corresponding to the subretrofacial nucleus.

We found that injections as close as 1 mm from this region gave very much smaller pressor responses, suggesting that the Ang IIsensitive site is relatively small. Dose-response curves to Ang II in this region indicated that very low doses were required, with the half maximal dose being approximately 9 fmol. This was approximately fold less than that required by the 4V route and consistent with the earlier findings of Sasaki and Dampney 41 and others using cats 39, We also observed that local microinfusion of Ang II into the RVLM produced facilitation of the renal sympathetic baroreflex Figure 5 which was closely similar to that produced by 4V administration Figure 2 We found that glutamate infusions into the same region of the RVLM had effects similar to those of Ang, increasing blood pressure, resting RSNA and the upper sympathetic baroreflex plateau without affecting the lower plateau Figure 6 The similarity of Ang actions to those of glutamate suggests that it may directly excite sympathetic vasomotor cells in this region.

Microinjection techniques into the RVLM have been widely used to limit drug action to small brain regions, but until recently, have been confined in most cases to anesthetized preparations since this area is close to the flexion point of the cervical spinal cord and is subject to movement in the conscious animal.

However, the role of Ang peptides in the ventrolateral medulla may be very much influenced by the anesthetized animal preparations. Indeed, a high degree of surgical stress is typically associated with microinjection into the RVLM in the acute anesthetized preparation, and hormonal systems such as the renin-angiotensin system have been reported to become activated during anesthesia and surgery Due to their quiet nature, we have found that rabbits are suitable animals for microinjection into the RVLM while conscious and sitting in a standard rabbit box otherwise unrestrained.

We therefore developed a new cannula system which permitted us to make repeated bilateral microinjections into the RVLM of conscious rabbits During the infusion of Ang II baroreflexes were examined but no effects were observed Figure 6. At the same site glutamate produced increases in blood pressure and renal sympathetic activity and augmentation of the RSNA baroreflex in a similar fashion to what was seen in the anesthetized animal Figure 6 , compare right and left panels. Cardiovascular effects of blocking endogenous Ang II in the rostral ventrolateral medulla.

Administration of 10 pmol of the antagonist Sarile bilaterally into the subretrofacial region of anesthetized rabbits blocked the pressor response to locally applied Ang II and reduced the pressor responses to 4V Ang II by two thirds Figure 7. This is perhaps the strongest evidence to suggest that the RVLM is the major site of action for Ang II given into the cerebrospinal fluid surrounding the brainstem but the remaining response suggests that other sites make a small contribution.

There has been very much interest in whether there is a contribution to maintaining sympathetic tone by Ang II endogenously released in the RVLM. Andreatta and co-workers 40 provided the first evidence of tonically active Ang II in the RVLM of the anesthetized cat by showing that with the same topical application approach [Sar 1 ,Thr 8 ]-Ang II 13 nmol decreased blood pressure by 8 mmHg.

However, we did not observe any change in blood pressure or RSNA by giving an effective dose of Sarile 10 pmol to urethane-anesthetized rabbits. This contrasts the findings of other groups that found a marked reduction in blood pressure with this agent or with [Sar 1 ,Thr 8 ]-Ang II 41, A recent study suggests, however, that this effect is not related to the blockade of Ang II receptors Presumably this was an effect observed only at much higher doses used in these studies pmol since we observed no effect on basal blood pressure using 10 pmol, but still had a complete blockade of the pressor response when Ang II was administered into the RVLM.

Since we did not observe any attenuation of the glutamate response, the blockage by Sarile was likely to be specific. We also determined the effects of blocking Ang receptors in a conscious rabbit preparation The lack of an effect inhibiting Ang II receptors in the RVLM was unlikely to be due to leakage of the antagonist into the depressor region of the CVLM, since its bilateral microinjections into the intermediate ventrolateral medulla at or just rostral to the obex level also did not alter resting or baroreflex parameters.

The lack of effect inhibiting Ang II receptors in the RVLM is consistent with our previous findings in anesthetized animals but the lack of effect of Ang II itself is somewhat surprising.

One possibility is that the action of Ang II may depend very much on the state of excitatory inputs to the region. Fontes and colleagues 47 had also developed a method for administration of agents into the RVLM but in conscious rats.

They showed that Ang II and Ang increased blood pressure while the peptide antagonist Sarile produced a small decrease in blood pressure. The spectral analysis method to assess baroreceptor sensitivity, outputs the gain and phase of the transfer function. The gain corresponds to the effectiveness with which the baroreflex is able to maintain constant conditions. The phase is the time lag between the systolic blood pressure and RR interval. DSI offers several technologies to record ECG and blood pressure signals, including implantable telemetry, external telemetry or hardwired options.

Baroreflex data can be collected with the Ponemah Software Platform. Figure 1 Shows the data manipulation workflow to output BRS. Implantable Telemetry. DSI implants are designed for monitoring and collecting data from conscious, freely moving animals. Implants are offered in different sizes to support a variety of animal species including mice, rats, dogs and non-human primates. Several telemetry models are capable of monitoring ECG and blood pressure.

Hardwired Signals. Short durations of functional endpoints are collected non-invasively from chemically or physically restrained animals that are connected to external devices capable of monitoring surface ECG or blood pressure and recording directly into an acquisition and analysis computer system.

Jacketed External Telemetry. ECG and blood pressure signals are collected from conscious, freely moving animals wearing a jacket which contains and protects a small JET device capable of monitoring cardiovascular data and transmitting data to an acquisition and analysis computer system. Freeman, J. Chronic central ghrelin infusion reduces blood pressure and heart rate despite increasing appetite and promoting weight gain in normotensive and hypertensive rats.

Peptides , 42 ,