Central Cardiovascular Regulation Group
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Key findings.
Mapping the distribution of angiotensin receptors in the brain.
With Professor Mendelsohn, Director of the Howard Florey Institute, we mapped the distribution of receptors for angiotensin II throughout the central nervous system of a number of mammals, including humans (see Allen AM, Oldfield, BJ, Giles ME, Paxinos G, McKinley MJ, Mendelsohn FAO: Localization of angiotensin receptors in the nervous system, in Quirion R, Bjorklund A, Hokfelt T (eds): Peptide Receptors: An Update: The Handbook of Chemical Neuroanatomy. Elsevier Science B.V., Amsterdam, The Netherlands, 2000: 79-124). Our description of the distribution of angiotensin receptors in the human brainstem is a critical component of the knowledge regarding the anatomy and function of this part of the human brain (Allen AM, Chai SY, Clevers J, McKinley MJ, Paxinos G, Mendelsohn FAO: Localization and characterization of angiotensin II receptor binding and angiotensin converting enzyme in the human medulla oblongata. J Comp Neurol 1988;269:249-264).
| Figure 1. Angiotensin receptors in the human medulla oblongata. This pseudo-colour image shows the distribution of angiotensin AT1 receptors in a coronal section of the human medulla oblongata. The image was obtained using the method of quantitative in vitro autoradiography. Red indicates high concentrations of the receptor graded down to blue being background, or undetectable, receptor levels. The red/yellow area at the top of the section is the nucleus of the solitary tract, a sensory nucleus that receives information about visceral (heart, lungs, gut etc.) function and which is important for the regulation of blood pressure. The yellow/green dots moving towards the edge of the section are the ventrolateral medulla. This region is critical for the regulation of nervous activity to blood vessels and plays a key role in the regulation of cardiovascular function. |
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Understanding the role of angiotensin in the rostral ventrolateral medulla.
We discovered that the rostral ventrolateral medulla contains a high density of angiotensin AT1 receptors in all species studied, including humans. This region of the medulla is critical for the generation and regulation of sympathetic nervous activity supplying blood vessels and thus plays a pivotal role in the regulation of blood pressure. Subsequently we demonstrated that-
Angiotensin excites these neurons to increase blood pressure (Allen AM, Dampney RAL, Mendelsohn FAO: Angiotensin receptor binding and pressor effects in the cat subretrofacial nucleus. Am J Physiol 1988;255:H1011-H1017).
Stimulation of angiotensin receptors in the rostral ventrolateral medulla plays a role in the increased blood pressure observed in spontaneously hypertensive rats- a model of human essential hypertension (Allen AM: Blockade of angiotensin AT 1 receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats reduces blood pressure and sympathetic nerve discharge. J. Renin-Angiotensin-Aldosterone System 2001; 2: S120-S124).
Angiotensin and chemoreceptor function.
Whilst there was some information suggesting angiotensin might play a role in autonomic changes produced by hypoxia, a direct effect on the sensory organ, the carotid body, had not been examined. I demonstrated that the carotid body contains a very high density of angiotensin AT1 receptors and that these are localized on the principal chemoreceptor cells. In addition, I demonstrated that, independent of local blood flow changes, angiotensin excites these cells to increase chemoreceptor afferent activity (Allen, A.M: Angiotensin AT 1 receptor-mediated excitation of rat carotid body chemoreceptor afferent activity. J. Physiology 1998; 510: 773-782).
Hypothalamic modulation of basal sympathetic activity.
Based on transection studies performed in the mid 1900’s it was considered that the forebrain did not play a role in generating basal sympathetic activity. I showed that this is not the case. Particular regions in the hypothalamus exert significant influence over sympathetic vasomotor activity, and this influence is increased in the spontaneously hypertensive rat (Allen A.M: Inhibition of the hypothalamic paraventricular nucleus in spontaneously hypertensive rats dramatically reduces sympathetic vasomotor tone. Hypertension 2002; 39: 275-280). The functional significance of this in animal physiology is yet to be fully elucidated but the experiments change our understanding of the neural circuits involved in basal regulation of blood pressure.