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Adrenergic innervation of human middle cerebral artery ultrastructural observations
Surg Neural 1987;27:113-6
113
Adrenergic Innervation of Human Middle Cerebral Artery Ultrastructural Pedro
Cuevas,
Manuel
Observations M.D., Jose A. Gutierrez-Diaz,
Dujovny,
Departments Neurological
M.D.,
Fernando
G. Diaz, M.D., Ph.D.,
of Research (Histology) and Neurosurgery, Centro Surgery, Henry Ford Hospital, Detroit, Michigan
Cuevas P, Gutierrez-Diaz
JA, Reimers D, Dujovny M, Diaz FG, Ausman JI. Adrenergic innervation of human middle cerebral artery. Ultrastructural observations. Surg Neural 1987;27:113-6.
The innervation of the human middle cerebral artery is studied with transmission electron microscopy using the chromaffin reaction technique. Adrenergic nerve fibers and related terminals, with granular electrodense neurotransmitter vesicles, are confined to the tunica adventitia-tunica media transitional zone and the outer layers of the media. These findings may indicate the presence of an adrenergic vasoconstrictor system for circulation control in the human middle cerebral artery. KEY WORDS:
Middle
Adrenergic cerebral artery
Several
studies
have
innervation;
provided
Chromaffin
evidence
that
reaction;
cerebral
vessels have an adrenergic, cholinergic, and peptidergic innervation [4,5,10,11,13,20,22,25]. Although nerve fi-
bers in human intracranial arteries have been demonstrated by scanning and electron microscopy 1241, there is a lack of evidence indicating the nature of nerve terminals in the walls of these vessels. The present report documents our findings concerning the adrenergic innervation of the human middle cerebral artery using a specific chromaffin reaction technique.
Material
and Methods
For ultrastructural study of adrenergic nerves, segments of middle cerebral artery were removed from four patients during superficial temporal artery-middle cerebral artery anastomosis. The chromaffin reaction technique [26] was used, and fixation-immersion of vessel
AddtPss reprint reqtmrs to: Manuel Dujovny, M.D., Henry Ford Hospital, Department of Neurological Surgery, 2799 West Grand Boulevard, Detroit, Michigan 48202.
0
M.D., Diana Reimers,
1987 by Elsevier
Science Publishing
Co., Inc.
Especial
M-S.,
and James I. Ausman, Ramon
y Cajal, Madrid,
M.D., Ph.D.
Spain; Department
of
segments was performed in two consecutive steps. The primary fixative contained lY9 glutaraldehyde plus 0.4% formaldehyde in 0.1 M chromate/potassium dichromate buffer at pH 7.2. The second step in the reaction consisted of an incubation at O-4% in 0.2 M sodium chromate/potassium dichromate buffer at pH 6.0. After postfixation in 2% 0~0~ in 0.1 M sodium chromate/potassium dichromate at pH 7.2, the tissue was dehydrated in a graded series of alcohols and embedded in Epon 8 12. All blocks were oriented for transverse sections of the arteries. Ultrathin cross-sections of the arteries were obtained with an LKB ultratome (LKB Produkter AB, Bromma, Sweden) fitted with a diamond knife. Poststained (only with lead citrate) or unstained ultrathin sections were investigated with a Phillips 301 EM electron microscope (NV Phillips, Eindhoven, The Netherlands).
Results The sections of human middle cerebral artery contained two types of nerve terminals as judged by their neurotransmitter vesicles: the granular electron-dense vesicle fibers (Figure l), and the agranular electron-lucent vesicle fibers. Unmyelinated adrenergic nerve fibers were seen in the tunica adventitia, the confluent zone between tunica adventitia, and the tunica media external layer (Figure 1). Nerve fibers were principally found in the most internal part of the adventitia. The axons contained different populations of dense core vesicles (Figure l), typical of those that are known to contain catecholamines. The chromaffin electron-dense reaction product was found in both large and small vesicles (Figure 1 6). The dense core vesicles were surrounded by patent limiting membrane. An electron-lucent space exists between the neurotransmitter limiting membrane and the chromaffin reaction product (Figure 1). Some terminal nerves were found to contain large mitochondria (Figure 1 c). Frequently, the same preterminal nerve (nerve fiber surrounded by Schwann cell processes) contained both granular electron-dense and agranular electron-lucent
0090-3019/87/$3.50
114
Surg Neurol 1987;27:113-6
Cuevas et al
Figure 1. The cbromafjn reaction product in adrenergic nerve termhalf in the human middle cerebral artery. The electron-dense reaction product is shown in large and small uesicies. 3 mitochondria. x 58,000.
Adrenergic
Surg Neurol
Innervation
vesicles. The gap between the adrenergic terminal nerve and smooth muscle cells was variable (Figure 1); in some areas, the terminal nerve was intimately apposed to the smooth muscle cells (Figure 1 c).
Discussion A neural influence in the control of the cerebral vessels has been debated for over 100 years, but a clear-cut demonstration of the role of the sympathetic adrenergic nerve fibers has emerged only recently 181. Electron microscopic studies of the walls of cerebral arteries of various species {3,6,7] have demonstrated two classes of neurotransmitter vesicles: (a) electron-dense granular vesicles, indicating adrenergic nerves; and (6) electronlucent granular vesicles, suggestive of nonadrenergic (cholinergic) nerves. Adrenergic nerve terminals degenerate and disappear after surgical extirpation of the superior cervical ganglia, whereas cholinergic terminals remain. There is ample evidence suggesting that adrenergic sympathetic nerves are cerebral vasoconstrictor nerves 118,251. In contrast, the nerves of the cholinergic cerebral vessels have been claimed to be dilatory 112,251. Sympathetic nerve stimulation produced constriction of feline pial arteries and veins, with a more pronounced response in veins than in arteries [l], and marked attenuation by adrenoceptor antagonists (phentolamine, phenoxybenzamine, and yohimbine). Nagai et al [23] have reported their findings on the effects of vasoactive drugs on early and late arterial spasm, noting that phentolamine relaxed only early spasm. They also believed that serotonin may play an important role in the regulation of early spasm rather than late spasm in their experimental model. The proportion of cerebral dual adrenergic and cholinergic nerve terminals varies not only among different species, but in the same animal. For example, the percentages of adrenergic and cholinergic nerves in the walls of cat major cerebral arteries are as follows: basilar 36.7%:63.4%; middle cerebral artery 46.1%:53.9%; anterior cerebral artery: 39.8%:60.270 {17). The pial branches of the middle cerebral artery of the cat contain predominantly adrenergic nerves (88%) [ 171. These data suggest that: (a) dilator nerves (relative to constrictor nerves) decrease as the size of the cerebral blood vessels becomes smaller; and (b) neurogenic control of circulation in the brain of the cat varies with brain region (17). Both types of nerve terminals are separated from the smooth muscle cells by a distance of 80-90 nm, which is comparable with the terminal organization observed in peripheral blood vessels and fulfills accepted criteria for functional innervation f9]. It is known that cerebral arteries are more sensitive to depletion of extracellular calcium and to calcium
115
1987;27:113-6
blockers than are peripheral arteries 121). It has been demonstrated that early experimental vasospasm involving the large arteries at the base of the brain can be reversed by calcium blockers [15], and that this dilatation is associated with an increased cerebral blood flow [lb}. Likewise, it has been reported that human cerebrovascular smooth muscle depends on extracellular calcium for the maintenance not only of high potassiuminduced contraction (potential-sensitive channels), but also of amine-, prostaglandin-, and blood-induced contractions (receptor-operated channels) [2,28). These data indicate that: (a) only small calcium pools exist in cerebral arteries, with cerebral vessels extremely dependent on an adequate supply of extracellular calcium for their activation; and (6) these facts must be thoroughly considered in pharmacologic strategies for treatments of disorders in which intense constriction of cerebral vessels exists. Cerebral blood volume and intracranial pressure are enhanced after sympathectomy. Furthermore, sympathetic nerve stimulation reduces intracranial pressure and constricts cerebral vessels, indicating a role in the regulation of cerebral capacitance [ l]. The presence of sympathetic nerve terminals in the cerebral vasculature has been considered as a protective mechanism of the blood-brain barrier during hypertension 119,271. These data suggest that sympathetic perivascular nerves play an important role in cerebral circulation in health and disease. In conclusion, adrenergic innervation of the human middle cerebral artery provides a possible anatomical explanation for blood flow response after electrical stimulation of the human cervical sympathetic chain [ 141. The proportions of adrenergic and cholinergic nerve terminals in human cerebral arteries are important in obtaining a morphologic basis for comprehensive knowledge of regional distribution of vasoconstrictor and vasorelaxor cerebrovascular areas.
The authors express their appreciation to Chantal Boudier, Berman, and Elizabeth Kiselev for their editorial assistance, Peggy Wichmann for typing the manuscript.
S. Kim and to
References Auer L, Johansson BB, Lund S. Reaction of pial arteries and veins to sympathetic stimulation in the cat. Stroke 1981;12:528-31. Brandt L, Anderson KE, Edvinsson L, Ljunggren B. Effects of extracellular calcium and of calcium antagonists on the contractile responses of isolated human pial and mesenteric arteries. J Cereb Blood Flow Metab 1981;1:339-47. Brings L, Garcia JH, Conger KA, Pinto de Morales H, Geer JC, Hollander W. Innervation of brain intraparenchymal vessels in subhuman primates: ultrastructural observations. Stroke 1985;16:297-301.
116
Surg Neurol 1987;27:113-6
Cuevas
et al
of human
Hodge CP. The effects of calcium antagonist on the epicerebral circulation in early vasospasm. Stroke 1985; 1 J: 1017-20.
WG. Distribution of neuropeptide Y-im5. Cuevas P, Forssmann munoreactive nerves in dog cerebral blood vessels. Anat Embryo1 (in press).
17. Lee TJ-F. Ultrastructural distribution of vasodilator and constrictor nerves in cat cerebral arteries. Circ Res 1981;41:971-9.
4. Cuevas cerebral
P, Forssmann microvessels.
WG. Adrenergic innervation Anat Embryo1 (in press).
B. Cholinergic 6. Edvinsson L, Nielsen KC, Owman C, Sporrong mechanisms in pial vessels. Histochemistry, electron microscopy and pharmacology. 2 Zellforsch Mikrosk Anat 1972;134:31 l-25. R, Lindvall M, Owman C, Svensson KG. 7. Edvinsson L, Hakanson Ultrastructure and biochemical evidence for a sympathetic neural influence on the choroid plexus. Exp Neural 1975;48:241-51.
18. Lee TJ-F, Su C, Bevan JA. Neurogenic sympathetic vasoconstriction of the rabbit basilar artery. Circ Res 1976;39:120-6. AP, Graham DI, Fitch W, Edvinsson 19. MacKenzie ET, McGeorge L, Harper M. Effects of increasing arterial pressure on cerebral blood flow in baboon. Influence of the sympathetic nervous system. Pfliigers Arch 1979;378:189-95. 20.
8. Edvinsson L, Owman C. Sympathetic innervation and adrenergic receptors in intraparenchymal arterioles of baboon. Acta Neural Stand 1977;56 (Suppl 64):304. 9. Edvinsson Neurosci
L. Sympathetic 1982;5:425-8.
control
of cerebral
circulation.
Trends
peptides in the con10. Edvinsson L. Functional role of perivascular trol of cerebral circulation. Trends Neurosci 1985;8: 126-3 1. K, Kamei I, Naka Y, Nakai K, 11. Itakura T, Okuno T, Nakakita Imai H, Komai N, Kinura H, Maeda T. A light and electronhistochemical study of vasoactive intestinal polypeptide and substance P-containing nerve fibers along the cerebral blood vessels: a comparison with aminergic and cholinergic nerve fibers. J Cereb Blood Flow Metab 1984;4:407-14. 12. Iwayama T, Furness linergic innervation 1970;26:635-46.
JB, Burnstock of the cerebral
S, Tsukahara 13. Kobayashi cholinergic innervation 1981;70:129-38.
G. Dual adrenergic and choarteries of the cat. Circ Res
S, Sugita K, Nagata T. Adrenergic and of rat cerebral arteries. Histochemistry
nervous control of the cerebral 14. Krog J. Autonomic man. J Oslo City Hosp 1964;14:25-38.
blood flow in
15. Leblanc R, Feindel W, Yamamoto LY, Milton JG, Frojmovic Reversal of acute cerebral vasospasm by calcium antagonist verapamil. Can J Neurol Sci 1984;11:42-7.
MM. with
16. Leblanc R, Feindel W, Yamamoto
MM,
LY, Milton JG, Frojmovic
Matsuyama T, Shiosaka S, Matsumoto M, Yoneda S, Kimura K, Abe H, Hayakawa T, Inoue H, Tohyama M. Overall distribution of vasoactive intestinal polypeptide-containing nerves on the wall of cerebral arteries: an immunohistochemical study using wholemounts. Neuroscience 1983;10:89-96.
21. McCalden TA, Bevan JA. Sources of activator basilar artery. Am J Physiol 1981;241:H129-33.
calcium
22. McCulloch J. Perivascular nerve fibres and the cerebral tion. Trends Neurosci 1984;7: 135-8.
in rabbit circula-
23.
Nagai H, Noda S, Mabe H. Experimental cerebral vasospasm. 2. Effects of vasoactive drugs and sympathectomy on early and late spasm. J Neurosurg 1975;42:420-8.
24.
Nelson E, Takayangi T, Rennels ML, Kawamura J. The innervation of human intracranial arteries. A study by scanning and electron microscopy. J Neuropathol Exp Neural 1972;3 1:526-34.
25.
Owman C, Edvinsson L, Nielson KC. Autonomic neuroreceptor mechanisms in brain vessels. Blood Vessels 1974;11:2-31.
histochemistry of nervous tissue. In: 26. Richards JG. Ultrastructural Heyn CH, Forssman WG, eds. Techniques in neuroanatomical research. Berlin: Springer-Verlag, 1981:277-92. 27.
Sadoshima S, Busija D, Brody M, Heistad D. Sympathetic nerves protect against stroke in stroke-prone hypertensive rats. A preliminary report. Hypertension 1981;3 (Suppl I):I-124-7.
28.
Simeone FA, Vinall P. Mechanisms cerebral artery to externally-applied 1975;43:37-47.
of contractile fresh blood.
response of J Neurosurg
113
Adrenergic Innervation of Human Middle Cerebral Artery Ultrastructural Pedro
Cuevas,
Manuel
Observations M.D., Jose A. Gutierrez-Diaz,
Dujovny,
Departments Neurological
M.D.,
Fernando
G. Diaz, M.D., Ph.D.,
of Research (Histology) and Neurosurgery, Centro Surgery, Henry Ford Hospital, Detroit, Michigan
Cuevas P, Gutierrez-Diaz
JA, Reimers D, Dujovny M, Diaz FG, Ausman JI. Adrenergic innervation of human middle cerebral artery. Ultrastructural observations. Surg Neural 1987;27:113-6.
The innervation of the human middle cerebral artery is studied with transmission electron microscopy using the chromaffin reaction technique. Adrenergic nerve fibers and related terminals, with granular electrodense neurotransmitter vesicles, are confined to the tunica adventitia-tunica media transitional zone and the outer layers of the media. These findings may indicate the presence of an adrenergic vasoconstrictor system for circulation control in the human middle cerebral artery. KEY WORDS:
Middle
Adrenergic cerebral artery
Several
studies
have
innervation;
provided
Chromaffin
evidence
that
reaction;
cerebral
vessels have an adrenergic, cholinergic, and peptidergic innervation [4,5,10,11,13,20,22,25]. Although nerve fi-
bers in human intracranial arteries have been demonstrated by scanning and electron microscopy 1241, there is a lack of evidence indicating the nature of nerve terminals in the walls of these vessels. The present report documents our findings concerning the adrenergic innervation of the human middle cerebral artery using a specific chromaffin reaction technique.
Material
and Methods
For ultrastructural study of adrenergic nerves, segments of middle cerebral artery were removed from four patients during superficial temporal artery-middle cerebral artery anastomosis. The chromaffin reaction technique [26] was used, and fixation-immersion of vessel
AddtPss reprint reqtmrs to: Manuel Dujovny, M.D., Henry Ford Hospital, Department of Neurological Surgery, 2799 West Grand Boulevard, Detroit, Michigan 48202.
0
M.D., Diana Reimers,
1987 by Elsevier
Science Publishing
Co., Inc.
Especial
M-S.,
and James I. Ausman, Ramon
y Cajal, Madrid,
M.D., Ph.D.
Spain; Department
of
segments was performed in two consecutive steps. The primary fixative contained lY9 glutaraldehyde plus 0.4% formaldehyde in 0.1 M chromate/potassium dichromate buffer at pH 7.2. The second step in the reaction consisted of an incubation at O-4% in 0.2 M sodium chromate/potassium dichromate buffer at pH 6.0. After postfixation in 2% 0~0~ in 0.1 M sodium chromate/potassium dichromate at pH 7.2, the tissue was dehydrated in a graded series of alcohols and embedded in Epon 8 12. All blocks were oriented for transverse sections of the arteries. Ultrathin cross-sections of the arteries were obtained with an LKB ultratome (LKB Produkter AB, Bromma, Sweden) fitted with a diamond knife. Poststained (only with lead citrate) or unstained ultrathin sections were investigated with a Phillips 301 EM electron microscope (NV Phillips, Eindhoven, The Netherlands).
Results The sections of human middle cerebral artery contained two types of nerve terminals as judged by their neurotransmitter vesicles: the granular electron-dense vesicle fibers (Figure l), and the agranular electron-lucent vesicle fibers. Unmyelinated adrenergic nerve fibers were seen in the tunica adventitia, the confluent zone between tunica adventitia, and the tunica media external layer (Figure 1). Nerve fibers were principally found in the most internal part of the adventitia. The axons contained different populations of dense core vesicles (Figure l), typical of those that are known to contain catecholamines. The chromaffin electron-dense reaction product was found in both large and small vesicles (Figure 1 6). The dense core vesicles were surrounded by patent limiting membrane. An electron-lucent space exists between the neurotransmitter limiting membrane and the chromaffin reaction product (Figure 1). Some terminal nerves were found to contain large mitochondria (Figure 1 c). Frequently, the same preterminal nerve (nerve fiber surrounded by Schwann cell processes) contained both granular electron-dense and agranular electron-lucent
0090-3019/87/$3.50
114
Surg Neurol 1987;27:113-6
Cuevas et al
Figure 1. The cbromafjn reaction product in adrenergic nerve termhalf in the human middle cerebral artery. The electron-dense reaction product is shown in large and small uesicies. 3 mitochondria. x 58,000.
Adrenergic
Surg Neurol
Innervation
vesicles. The gap between the adrenergic terminal nerve and smooth muscle cells was variable (Figure 1); in some areas, the terminal nerve was intimately apposed to the smooth muscle cells (Figure 1 c).
Discussion A neural influence in the control of the cerebral vessels has been debated for over 100 years, but a clear-cut demonstration of the role of the sympathetic adrenergic nerve fibers has emerged only recently 181. Electron microscopic studies of the walls of cerebral arteries of various species {3,6,7] have demonstrated two classes of neurotransmitter vesicles: (a) electron-dense granular vesicles, indicating adrenergic nerves; and (6) electronlucent granular vesicles, suggestive of nonadrenergic (cholinergic) nerves. Adrenergic nerve terminals degenerate and disappear after surgical extirpation of the superior cervical ganglia, whereas cholinergic terminals remain. There is ample evidence suggesting that adrenergic sympathetic nerves are cerebral vasoconstrictor nerves 118,251. In contrast, the nerves of the cholinergic cerebral vessels have been claimed to be dilatory 112,251. Sympathetic nerve stimulation produced constriction of feline pial arteries and veins, with a more pronounced response in veins than in arteries [l], and marked attenuation by adrenoceptor antagonists (phentolamine, phenoxybenzamine, and yohimbine). Nagai et al [23] have reported their findings on the effects of vasoactive drugs on early and late arterial spasm, noting that phentolamine relaxed only early spasm. They also believed that serotonin may play an important role in the regulation of early spasm rather than late spasm in their experimental model. The proportion of cerebral dual adrenergic and cholinergic nerve terminals varies not only among different species, but in the same animal. For example, the percentages of adrenergic and cholinergic nerves in the walls of cat major cerebral arteries are as follows: basilar 36.7%:63.4%; middle cerebral artery 46.1%:53.9%; anterior cerebral artery: 39.8%:60.270 {17). The pial branches of the middle cerebral artery of the cat contain predominantly adrenergic nerves (88%) [ 171. These data suggest that: (a) dilator nerves (relative to constrictor nerves) decrease as the size of the cerebral blood vessels becomes smaller; and (b) neurogenic control of circulation in the brain of the cat varies with brain region (17). Both types of nerve terminals are separated from the smooth muscle cells by a distance of 80-90 nm, which is comparable with the terminal organization observed in peripheral blood vessels and fulfills accepted criteria for functional innervation f9]. It is known that cerebral arteries are more sensitive to depletion of extracellular calcium and to calcium
115
1987;27:113-6
blockers than are peripheral arteries 121). It has been demonstrated that early experimental vasospasm involving the large arteries at the base of the brain can be reversed by calcium blockers [15], and that this dilatation is associated with an increased cerebral blood flow [lb}. Likewise, it has been reported that human cerebrovascular smooth muscle depends on extracellular calcium for the maintenance not only of high potassiuminduced contraction (potential-sensitive channels), but also of amine-, prostaglandin-, and blood-induced contractions (receptor-operated channels) [2,28). These data indicate that: (a) only small calcium pools exist in cerebral arteries, with cerebral vessels extremely dependent on an adequate supply of extracellular calcium for their activation; and (6) these facts must be thoroughly considered in pharmacologic strategies for treatments of disorders in which intense constriction of cerebral vessels exists. Cerebral blood volume and intracranial pressure are enhanced after sympathectomy. Furthermore, sympathetic nerve stimulation reduces intracranial pressure and constricts cerebral vessels, indicating a role in the regulation of cerebral capacitance [ l]. The presence of sympathetic nerve terminals in the cerebral vasculature has been considered as a protective mechanism of the blood-brain barrier during hypertension 119,271. These data suggest that sympathetic perivascular nerves play an important role in cerebral circulation in health and disease. In conclusion, adrenergic innervation of the human middle cerebral artery provides a possible anatomical explanation for blood flow response after electrical stimulation of the human cervical sympathetic chain [ 141. The proportions of adrenergic and cholinergic nerve terminals in human cerebral arteries are important in obtaining a morphologic basis for comprehensive knowledge of regional distribution of vasoconstrictor and vasorelaxor cerebrovascular areas.
The authors express their appreciation to Chantal Boudier, Berman, and Elizabeth Kiselev for their editorial assistance, Peggy Wichmann for typing the manuscript.
S. Kim and to
References Auer L, Johansson BB, Lund S. Reaction of pial arteries and veins to sympathetic stimulation in the cat. Stroke 1981;12:528-31. Brandt L, Anderson KE, Edvinsson L, Ljunggren B. Effects of extracellular calcium and of calcium antagonists on the contractile responses of isolated human pial and mesenteric arteries. J Cereb Blood Flow Metab 1981;1:339-47. Brings L, Garcia JH, Conger KA, Pinto de Morales H, Geer JC, Hollander W. Innervation of brain intraparenchymal vessels in subhuman primates: ultrastructural observations. Stroke 1985;16:297-301.
116
Surg Neurol 1987;27:113-6
Cuevas
et al
of human
Hodge CP. The effects of calcium antagonist on the epicerebral circulation in early vasospasm. Stroke 1985; 1 J: 1017-20.
WG. Distribution of neuropeptide Y-im5. Cuevas P, Forssmann munoreactive nerves in dog cerebral blood vessels. Anat Embryo1 (in press).
17. Lee TJ-F. Ultrastructural distribution of vasodilator and constrictor nerves in cat cerebral arteries. Circ Res 1981;41:971-9.
4. Cuevas cerebral
P, Forssmann microvessels.
WG. Adrenergic innervation Anat Embryo1 (in press).
B. Cholinergic 6. Edvinsson L, Nielsen KC, Owman C, Sporrong mechanisms in pial vessels. Histochemistry, electron microscopy and pharmacology. 2 Zellforsch Mikrosk Anat 1972;134:31 l-25. R, Lindvall M, Owman C, Svensson KG. 7. Edvinsson L, Hakanson Ultrastructure and biochemical evidence for a sympathetic neural influence on the choroid plexus. Exp Neural 1975;48:241-51.
18. Lee TJ-F, Su C, Bevan JA. Neurogenic sympathetic vasoconstriction of the rabbit basilar artery. Circ Res 1976;39:120-6. AP, Graham DI, Fitch W, Edvinsson 19. MacKenzie ET, McGeorge L, Harper M. Effects of increasing arterial pressure on cerebral blood flow in baboon. Influence of the sympathetic nervous system. Pfliigers Arch 1979;378:189-95. 20.
8. Edvinsson L, Owman C. Sympathetic innervation and adrenergic receptors in intraparenchymal arterioles of baboon. Acta Neural Stand 1977;56 (Suppl 64):304. 9. Edvinsson Neurosci
L. Sympathetic 1982;5:425-8.
control
of cerebral
circulation.
Trends
peptides in the con10. Edvinsson L. Functional role of perivascular trol of cerebral circulation. Trends Neurosci 1985;8: 126-3 1. K, Kamei I, Naka Y, Nakai K, 11. Itakura T, Okuno T, Nakakita Imai H, Komai N, Kinura H, Maeda T. A light and electronhistochemical study of vasoactive intestinal polypeptide and substance P-containing nerve fibers along the cerebral blood vessels: a comparison with aminergic and cholinergic nerve fibers. J Cereb Blood Flow Metab 1984;4:407-14. 12. Iwayama T, Furness linergic innervation 1970;26:635-46.
JB, Burnstock of the cerebral
S, Tsukahara 13. Kobayashi cholinergic innervation 1981;70:129-38.
G. Dual adrenergic and choarteries of the cat. Circ Res
S, Sugita K, Nagata T. Adrenergic and of rat cerebral arteries. Histochemistry
nervous control of the cerebral 14. Krog J. Autonomic man. J Oslo City Hosp 1964;14:25-38.
blood flow in
15. Leblanc R, Feindel W, Yamamoto LY, Milton JG, Frojmovic Reversal of acute cerebral vasospasm by calcium antagonist verapamil. Can J Neurol Sci 1984;11:42-7.
MM. with
16. Leblanc R, Feindel W, Yamamoto
MM,
LY, Milton JG, Frojmovic
Matsuyama T, Shiosaka S, Matsumoto M, Yoneda S, Kimura K, Abe H, Hayakawa T, Inoue H, Tohyama M. Overall distribution of vasoactive intestinal polypeptide-containing nerves on the wall of cerebral arteries: an immunohistochemical study using wholemounts. Neuroscience 1983;10:89-96.
21. McCalden TA, Bevan JA. Sources of activator basilar artery. Am J Physiol 1981;241:H129-33.
calcium
22. McCulloch J. Perivascular nerve fibres and the cerebral tion. Trends Neurosci 1984;7: 135-8.
in rabbit circula-
23.
Nagai H, Noda S, Mabe H. Experimental cerebral vasospasm. 2. Effects of vasoactive drugs and sympathectomy on early and late spasm. J Neurosurg 1975;42:420-8.
24.
Nelson E, Takayangi T, Rennels ML, Kawamura J. The innervation of human intracranial arteries. A study by scanning and electron microscopy. J Neuropathol Exp Neural 1972;3 1:526-34.
25.
Owman C, Edvinsson L, Nielson KC. Autonomic neuroreceptor mechanisms in brain vessels. Blood Vessels 1974;11:2-31.
histochemistry of nervous tissue. In: 26. Richards JG. Ultrastructural Heyn CH, Forssman WG, eds. Techniques in neuroanatomical research. Berlin: Springer-Verlag, 1981:277-92. 27.
Sadoshima S, Busija D, Brody M, Heistad D. Sympathetic nerves protect against stroke in stroke-prone hypertensive rats. A preliminary report. Hypertension 1981;3 (Suppl I):I-124-7.
28.
Simeone FA, Vinall P. Mechanisms cerebral artery to externally-applied 1975;43:37-47.
of contractile fresh blood.
response of J Neurosurg