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Commentary on Hot Topic Review |
Wolfson Institute, Queen Mary, Charterhouse Square, London, UK
(Received 16 February 2003;
accepted after revision 4 May 2004; first published online 6 May 2004)
The article by Terry Thrasher is a thoughtful and well-researched investigation of a field which may have a lot to tell us about the plasticity and what might be called the resilience of the central nervous system. As Thrasher says, it is difficult to incriminate baroreceptor malfunction as a cause of hypertension because:
Do these results apply equally well to other animals and to man? We can infer that they do, even when physiological measurements are lacking. People with established essential hypertension have the expected well-developed heart rate responses to changes in posture, or to the infusion of drugs raising or lowering blood pressure. Human arterial baroreceptors in virtually all situations appear to have been reset approximately to the centre of their working range. The so-called ‘baroreflex’ is commonly expressed as the ratio between a drug-, or posture-induced change in blood pressure and the consequent reflexly induced change in heart rate. ‘Baroreflex Sensitivity’ (BRS) was reported by Parmer et al. (1992) to be slightly reduced in human essential hypertension. It has also been reported by Minami et al. (1989) to be reduced in the spontaneously hypertensive rat. Most of these results have been confirmed many times by many others. The ‘BRS literature’ is enormous.
Thrasher makes the point that although carotid sinus baroreceptors reset their sensitivity rapidly, within a few days, unmyelinated baroreceptor fibre receptors do not appear to do so. They therefore need to be separately considered, in case they could play some part in long-term blood pressure control and even contribute to established hypertension. But Thrasher may have overlooked the work of Thoren et al. (1983) who examined the threshhold for pressure-activation of aortic C-fire receptors in SHR and Wistar/Kyoto (WKY) control rats at different ages. At 16 weeks of age they found that ‘... aortic C-fibres were not reset during the early established phase of hypertension in SHR.’. The pressure threshold was 139 mmHg in young SHR compared with 133 for WKY. However, at 36 weeks of age the threshold in SHR became substantially raised ‘... probably due to an increased collagen content of the aortic wall.’.
Yao & Thoren (1983) noted that aortic C-fibre baroreceptors in rabbits had thresholds some 30 mmHg higher than baroreceptors subserved by myelinated fibres. These authors suggested that perhaps the main function of unmyelinated C-fibre baroreceptors was to protect against sudden surges of blood pressure.
I think it unlikely that there are any peripheral arterial baroreceptor systems which will not eventually reset, given sufficient time. For example, Kaneko et al. (1968) reported that the threshold for renin release stimulated by a fall of effective renal perfusion pressure was shifted to a higher than normal level in human essential hypertension. If these – and doubtless other peripheral mechanisms – can be reset, we are thrown back on the fundamental question of whether there is any system which maintains long-term stability and which does not eventually reset to any prevailing blood pressure level.
I examined this question in my review in the Journal of Hypertension (Dickinson, 1998), quoting the results of a British Medical Research Council investigation of the effects of discontinuing long-term hypotensive treatment in man. This showed only short-term resetting of blood-pressure control systems. Despite holding down the blood pressure of large groups of hypertensive men for 4 years (using either a thiazide or a beta-blocker), the blood pressure went back to its previous level within a few weeks after stopping treatment. This spectacular result has been forgotten by most investigators. The new observations which Thrasher has reported should make us reconsider the central nervous system in the long term regulation of systemic arterial pressure. Measurement of so-called BRS is a popular clinical activity. Although it is far too complicated a measurement to tell us which part of the whole system might be causing hypertension (Dickinson, 2001), at least it directs attention to the brain rather than to the kidneys.
I cannot conclude without spurring my hobby horse to a gallop, reminding circulatory physiologists: (i) that Harris et al. (1989) reported that the unanaesthetized fetal lamb in utero has a well-developed independent central nervous system receptor which is responsible for an arterial pressor response to raised intracranial pressure; (ii) that Stephenson & Donald (1980) could not reduce arterial blood pressure in conscious dogs for longer than a few minutes by raising carotid sinus pressure; (iii) that Vatner et al. (1970) were not able to reduce arterial pressure for more than a few minutes in conscious dogs by electrical stimulation of the carotid sinus nerves.
I suggest that in all these experiments on unanaesthetized animals, the Cushing response is responsible for the observations. As McCubbin and I showed more than 40-years-ago (Dickinson & McCubbin, 1963) general anaesthesia almost eliminates the hypertensive response either to increased cerebrospinal fluid pressure or to reduction of cerebral arterial pressure. In each of the three situations I have mentioned above, it appears that some powerful blood pressure control and stabilizing system is operating. I have suggested (Dickinson, 1998, 1990) not only that the Cushing response may be responsible for observations such as these, but also that sustained hypertension could be caused by increased cerebrovascular resistance supplying a blood-pressure-raising stimulus. If increased cerebrovascular resistance was caused by arterial atheromatous stenosis or occlusion of brain arteries it could not be expected to disappear with time. Its putative hypertensive effect should be powerful and sustained enough to overcome the automatic resetting such as is seen in all peripheral baroreceptor systems.
This is why it is important to establish for sure whether or not C-fibre baroreceptors become reset to the prevailing level of systemic arterial pressure.
References
Dickinson CJ (1990). Reappraisal of the Cushing reflex: the most powerful neural blood pressure stabilizing system. Clin Sci 79, 543–550.[Medline]
Dickinson CJ (1998). The determinants of long-term blood pressure stability: control of trough blood pressure during sleep. J Hypertension 16, 907–912.[CrossRef][Medline]
Dickinson CJ (2001). The baroreflex bandwagon: time to get off?J Hypertension 197, 1857–1859.
Dickinson
CJ
&
McCubbin
JW (1963). Pressor effect of increased cerebrospinal fluid pressure and vertebral artery occlusion with and without anaesthesia. Circulat Res
12, 190–202.
Harris
AP, Koehler
RC, Gleason
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Traystman
RJ (1989). Cerebral and peripheral circulatory responses to intracranial hypertension in fetal sheep. Circulat Res
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H
&
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H (1968). Renin release in patients with benign essential hypertension. Circulation
38, 353–362.
Minami N, Imai Y, Munakata M, Susaki S, Sekino H, Abe K & Yoshinaga K (1989). Age-related changes in blood pressure, heart rate and baroreflex sensitivity in SHR. Clin Exp Pharmacol Physiol Suppl 15, 85–87.[Medline]
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RJ, Cervenka
JH
&
Stone
RA (1992). Baroreflex sensitivity and heredity in essential hypertension. Circulation
85, 497–503.
Stephenson
RB
&
Donald
DE (1980). Reflexes from isolated carotid sinuses of intact and vagotomised conscious dogs. Am J Physiol
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Thoren P, Andresen MC & Brown AM (1983). Resetting of aortic baroreceptors with non-myelinated afferent fibers in spontaneously hypertensive rats. Acta Physiol Scand 117, 91–97.[Medline]
Vatner SF, Franklin D, Van Citters RL & Braunwald E (1970). Effects of carotid sinus nerve stimulation on blood-flow distribution in conscious dogs at rest and during exercise. Circulat Res 79, 543–550.
Yao T & Thoren P (1983). Characteristics of brachiocephalic and carotid sinus baroreceptors with non-medullated afferents in rabbit. Acta Physiol Scand 117, 1–8.[Medline]
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