Elsevier

Neurochemistry International

Volume 35, Issue 3, September 1999, Pages 237-259
Neurochemistry International

Invited review
Nervous control of the cerebrovascular system: doubts and facts

https://doi.org/10.1016/S0197-0186(99)00067-4Get rights and content

Abstract

Increased function of the central neurons results in increased neuronal metabolism and, as a consequence, increased concentration of metabolic end-products (H+,K+, adenosin) results in an increased cerebral blood flow (CBF). There is a general agreement among investigators that products of cerebral tissue metabolism as well as chemical stimuli are key factors that determine the rate of blood flow in the brain. CBF, however, may increase out of proportion to metabolic demands, may increase without significant change in local metabolism, and may increase much faster than the accumulation of the metabolic end-products. Therefore, the 100-year-old metabolic hypothesis of Roy and Sherrington, cannot fully explain the increases of CBF during increased functional activity of the central neurons. The tight coupling of neuronal activity and blood flow in the brain is demonstrated by a large amount of data. Therefore, the likelihood exists that neurogenic stimuli via perivascular nerve endings may act as rapid initiators, to induce a moment-to-moment dynamic adjustment of CBF to the metabolic demands, and further maintenance of these adjusted parameters is ensured by the metabolic and chemical factors. Perivascular nerve endings were identified in the outer smooth muscle layer of the cerebral arteries, arterioles and veins. Their axonterminals contain a large variety of neurotransmitters, often co-localised in synaptic vesicles. Stimulation of the nerves results in a release of transmitters into the narrow neuromuscular synaptic clefts in the cerebrovascular smooth muscle, close to specific receptor sites in the vessel wall. In spite of these facts, however, and in spite of the large number of new experimental evidences, the role of the nervous control of the cerebrovascular system is underestimated both in medical textbooks and in the common medical knowledge since decades. In the last 20 years major advances have been made that make it necessary to revise this false view. The purpose of this review is to facilitate this process at the end of this century, when the importance of the nervous control of the cerebral circulation has been fully appreciated among investigators.

Introduction

The quantity of blood that passes a given point in the circulation in a given period of time (i.e. the rate of blood flow) is directly proportional to the fourth power of the radius of the supplying blood vessel of any special organ. Therefore, the diameter of the blood vessels supplying the brain plays by far the greatest role of all factors (perfusion pressure gradient, length of the vessels, blood viscosity) in determining the flow rate to this organ.

There always has been general agreement among investigators that products of cerebral tissue metabolism and chemical stimuli are among the key factors that affect the diameter of the cerebral vessels and, as a consequence, cerebrovascular conductance/resistance and blood flow of the brain. However, contribution of another group of regulatory components, neural stimuli to the control of the cerebral vessel calibre and brain blood supply has been controversial ever since the first description of perivascular nerve fibers in the walls of brain vessels.

In spite of the slow advancement in this topic, most of the factors and a substantial part of the questions causing the doubts were answered in the last 15 years. It is true, that clear-cut, detailed definition of the role of the cerebral perivascular nerves has still not been obtained (Edvinsson et al., 1993). However, extensive review of the literature that relates nervous control of cerebral blood flow (CBF) shows clearly that the basic question: importance of the nervous control of the cerebral circulation has been fully appreciated among the investigators of this field of research (Busija, 1996).

Textbooks of physiology, pathophysiology or neurology are much too slow and cautious to discuss important new data, to incorporate convincing new facts into the already existing body of evidences and to reflect the changed views on the role of nervous regulation of the cerebrovascular bed. Statements like ‘the role of these nerves remains a matter of debate’ or ‘the importance of neural regulation of the cerebral circulation is controversial’ are standard ‘fossils’ in the majority of the textbooks for graduate and postgraduate medical studies. As a result, students as well as experienced clinicians handle the role of the neural control as either a non-existing or, at best, a negligible component of CBF regulation. One may wonder how much time is needed until the numerous reliable, informative publications on this subject will finally gain the appropriate attention (some examples: Edvinsson and MacKenzie, 1976, Owman and Edvinsson, 1977, Kuschinsky and Wahl, 1978, Reis, 1979, Owman and Hardebo, 1986, MacKenzie and Scatton, 1987, McCalden, 1981, Heistad et al., 1981, Kontos, 1981, Edvinsson, 1982a, Heistad and Marcus, 1982, Edvinsson et al., 1993, Busija, 1996).

The purpose of this review is to facilitate this process and to provide a short, ‘state of the art’ review on the functional importance of the nervous regulation in the cerebrovascular bed.

Section snippets

Importance of the topic

One may wonder why nervous regulation of the cerebral circulatory system is an important question? The importance of this topic is supported by several facts and considerations. Here, because of space limitations, only two of these will be emphasized.

Firstly, what a neuroanatomist or neurochemist sees in the cerebral perivascular nerves is a wonderfully designed, highly complex network which contains all elements of an active neuroregulatory system. Perivascular nerve endings were identified in

Historical notes on the first evidences suggesting the possibility of nervous regulation of the cerebral circulation

Perivascular nerve fibers in the anterior and posterior human cerebral arteries were demonstrated already by Thomas Willis (1664). More than 200 years later Benedikt, 1874, Aronson, 1890, Hüber, 1899 independently from each other demonstrated the sympathetic origin of part of the perivascular nerves around all the major vessels at the base of the brain. At the beginning of this century, single myelinated and unmyelinated fibres, as well as nerve bundles were shown to reach the blood vesssels of

The origin of the controversy regarding nervous control of the cerebrovascular bed

The early enthusiasm, evoked by the anatomical and physiological observations however, was soon followed by disappointment because of several reasons.

One of the reasons is that α-adrenoceptor antagonists were unable to alter the pial arteriolar diameter in anesthetized cats, piglets and lambs (Kuschinsky and Wahl, 1975, Busija and Leffler, 1987b, Wagerle et al., 1990) and section of sympathetic nerves resulted either in minimal or no effect at all on the cerebral blood flow in different

The main causes of the controversy

The questions arise: what are the main causes of the doubts and the controversy? How it is possible that leading investigators in this field of research obtained so different data on the very same subject and reached often completely contradictory conclusions when the regulatory role of the cerebrovascular nerves was in the focus of their studies?

It was clear already at the beginning of the 1980 s, that much of this controversy has been due to the uncertainty regarding origins of nonsympathetic

Neuroanatomical considerations

Importance of the nervous control of the cerebrovascular system can not be verified without convincing experimental evidences to several questions: (1) What are the origins and the main pathways of the innervation of the intracranial vessels?; (2) Which types of vessels are innervated by the perivascular nerves?; (3) What is the location of the axon terminals within the cerebral vessel wall, how large is the neuromuscular synaptic cleft?; (4) Are there transmitter containing synaptic vesicles

Physiological–pathophysiological significance of the nervous control in the cerebral circulation

The data accumulated in the last two decades support the view that perivascular nerves in the central nervous system play a previously underestimated, important role in the regulation of the cerebral circulation. Reviewing the recent publications on the subject, one may conclude that this role (possibly because of its unusually complex nature) is either not discussed properly or, completely neglected in textbooks. The main conclusions of this review and those of other recent publications on the

Possibilities of nervous regulation by synaptic overflow of neurotransmitters in the vicinity of the cerebral vessels

One of the important new aspects of the nervous regulation of the cerebral circulation, as emphasized by Busija (1996), is that the likelihood exists that neurotransmitters, derived from non-perivascular nerves, can exert effect upon cerebral vessels both under baseline conditions and during pathophysiological conditions when these neurons are either physiologically or pathophysiologically activated. In peripheral circulations, neurotransmitters originating from perivascular nerves and blood

Acknowledgements

The author is grateful to Mrs Maria Harvich-Velkei for her excellent technical assistance and for typing the manuscript. He is indebted to his collaborators Dr Zoltan Benyo and Dr Katalin Komjáti, as well as to his students Benedek Erdös, Amrita Halmos, Zsombor Lacza, Balázs Lintner, Tamás Mersich, Tamás Nyári, Emese Szelke for the stimulating discussions on the subject. Original studies by the author’s research group that are mentioned in this review were supported by The Netherlands

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