C E R E B R A L VASOSPASM
ANTONIO A. F. DE SALLES *
T h e r e a r e essentially two principal end points in c e r e b r o s v a s c u l a r r e g u l a t i o n : m a i n t e n a n c e of an a d e q u a t e supply of blood and energy-yielding s u b s t r a t e s to the brain, despite the imposition of physiological or pathological s t r e s s e s such a s hypoxemia or reduced perfusion p r e s s u r e , and precise and rapid coupling of regional cerebral bload flow ( C B F ) to c h a n g e s in n e u r o n a l r e q u i r e m e n t s3 2
. T h e s e t w o features of the cerebral circulation a r e met under a complex control of the cerebral v a s c u l a t u r e by a still unknown mechanism of a u t o r e g u l a t i o n T h i s a u t o r e g u l a t i o n d e p e n d s on direct action of metabolites a n d / o r p r e s s u r e stimuli in the smooth muscle vessel w a l l2 6 , 2 8 , 3 2
. In several pathological conditions t h e c e r e b r o v a s c u l a r a u t o r e g u l a t i o n can be impaired, not in t o t o , but in variable d e g r e e s3 2
. Cerebral vessels no longer obey the physiological stimuli, but assume a s t e a d y s t a t e t o n u s not coupled w i t h the brain metabolism of their a r e a of s u p p l y3 9
. T h e y can remain dilated or contracted. In the last case, the phe-nomenon is k n o w n a s cerebral v a s o s p a s m . V a s o s p a s m can be due either to an a b n o r m a l responsiveness of the v a s c u l a r smooth muscle cells or to abnormally high levels of e n d o g e n o u s v a s o c o n s t r i c t o r s u b s t a n c e s5 1
. It r e m a i n s unclear as to w h e t h e r v a s o s p a s m is a normal or a b n o r m a l contraction or failure relaxation of arterial smooth muscle cells or w h e t h e r it r e p r e s e n t s a cytoarchitectural thickening in the vessel w a l l2 3
. Cerebral v a s o s p a s m occurs in pathological cir-c u m s t a n cir-c e s sucir-ch a s migraine, s u b a r a cir-c h n o i d h e m o r r h a g e ( S A H ) , head trauma, post-cerebral ischemia a n d / o r h y p o x i a1 3 , 2 3 , 2 4 , 5 1
. Cerebral v a s o s p a s m is parti-cularly i m p o r t a n t in SAH. While the surgical morbidity and mortality of uncom-plicated cerebral a n e u r y s m a p p r o a c h e s t h a t of a c h o l e c y s t e c t o m y2 4
, it h a s been d e m o n s t r a t e d t h a t the leading cause of d e a th and disability in p a t i e n t s with a n e u r y s m a l SAH is cerebral v a s o s p a s m2 3
. T h e cerebral v a s o s p a s m t h a t follows SAH is a biphasis phenomenon. It consist of a relatively s h o r t early phase ( m i n u t e s )2
, reversible by a n t a g o n i s t s of smooth muscle contraction and a late and long-lasting p h a s e of s p a s m ( w e e k s ) , refractory to every muscle r e l a x a n t2 3 , 4 5
. Each p h a s e h a s a different p h y s i o p a t h o l o g y2 3
, with similarities to other causes of cerebral v a s o s p a s m . T h u s , SAH is a good model for the study of cerebral v a s o s p a s m . Much a s been learned a b o u t the cerebral v a s o s p a s m t h a t follows SAH since it w a s first described 30 y e a r s a g o1 3
. T h i s accumulated knowlege can ben applied to other diseases w h e r e cerebral v a s o s p a s m is present. It can also provide further u n d e r s t a n d i n g of the physiological control of cerebrovascular smooth m u s c l e2 3 , 3 2 , 5 1 .
V a s o s p a s m following SAH will be e l a b o r a t e d in this review. Hemodynamic repercussions, lesions in the vessel w a l l s a n d biochemical a s p e c t s of cerebral v a s o s p a s m wil be discussed. T h e applicability of the concepts obtained in the SAH r e s e a r c h to other causes of cerebral v a s o s p a s m will be mentioned en passage.
H E M O D Y A M I C R E P E R C U S S I O N S O F C E R E B R A L . V A S O S P A S M
T h e flow of blood in a r t e r i e s is caused by a g r a d i e n t of p r e s s u r e a n d is r e t a r d e d by the forces of friction. T h i s s t a t e m e n t embodies N e w t o n ' s law of motion and the concept of viscosity 15. T h e mechanism a n d extent to which flow d e p e n d s on p r e s s u r e and forces of friction is shown in Poiseuille equation. A laminar flow within the vessels is directly p r o p o r t i o n a l to the fourth p o w e r of the r a d i u s of the vessels a n d inversely p r o p o r t i o n a l to the viscosity of the fluid a n d the length of the vascular bed 18,32. it is i m p o r t a n t here to emphasize the effect t h a t a c h a n g e in vascular caliber w o u l d have on flow. T h u s , decreasing the r a d i u s of a vessel by 5 0 % should decrease the flow by a factor of 1 6 1 8 Cerebral vessels a r e not rigid but a r e both distensible and capable of con-traction, particularly in the precapillary segment. Cerebral v a s o s p a s m seen in SAH is not a generalized phenomenon, but is concentrated in arteries of large caliber in the b a s e of the b r a i n 20,23,45^ while the a u t o r e g u l a t i o n of the micro vessels d o w n s t r e a m r e m a i n s intact. Since the cerebral perfusion p r e s s u r e ( C P P ) is decreased by the v a s o s p a s m u p s t r e a m , the microvessels present a profound vasodilation causing a n increase in cerebral blood volume ( C B V ) 20. At the venous end of the vascular bed, the vessels a r e collapsible. T h e craniospinal system in enclosed within a rigid container which h a s only limited external venting. T h u s , the increase in CBV, associated with b r a i n edema due to dis-ruption of the blood b r a i n b a r r i e r p r e s e n t in v a s o s p a s m 6,23,40, causes a n increase in the i n t r a c r a n i a l c o m p a r t m e n t p r e s s u r e . T h i s high p r e s s u r e in the extravascular space becomes an i m p o r t a n t factor a n d m a y impair blood flow to the b r a i n 32.
Vessel stenosis also leads to flow instabilités, turbulence, a n d increased shear s t r e s s on the endothelium n.18. T h i s increased s h e a r s t r e s s associated with an a b r u p t constriction h a s been shown to be directly injurious to the endothe-lium 16,18,41. An acute increase in s h e a r s t r e s s m a y injure a n d erode the endothelial lining of n a r r o w e d arteries. S u b s e q u e n t platelet a g g r e g a t i o n a n d t h r o m b o -sis, with their obvious pontential for embolization, s u g g e s t s a mechanism for ischemia and infarction associated with cerebral v a s o s p a s m 18. Morphological c h a n g e s in the vessel wall a r e an i m p o r t a n t component g e n e r a t o r of t h e second p h a s e of t h e SAH-induced v a s o s p a s m . T h e y will be discussed in the next section.
S P A S M A N D L E S I O N O F T H E V E S S E L , W A L L
t h a t is associated with morbidity in p a t i e n t s with SAH 2,13,23,45. T h e biochemical aspects of the SAH-induced cerebral v a s o s p a s m will be the subject of the next section.
After SAH the cerebral basal arterial walls show some or all of the follow-ing u l t r a s t r u c t u r a l c h a n g e s : intimal a p p e a r a n c e of vacuoles and dense bodies in endothelial cells, detachment of endothelial cells and intimal thickening. T h e s e c h a n g e s a p p e a r 2 h o u r s after SAH, culminate at 3 to 7 d a y s after SAH, and persist up to 1 month after SAH 44. T h e media of these arterial walls show the m o t h - e a t e n contour of muscle cells, a p p e a r a n c e of intracytoplasmic vacuoles and dense bodies, a p p e a r a n c e of cell debris, e n l a r g e m e n t of the interstitial space,
and the a p p e a r a n c e therein of dense p a r t i c l e s 4
6 . In addition, there is
intralu-minar platelet adhesion and a g g r e g a t i o n with white cell adhesion and t h r o m b u s formation, increased endothelial pinocytosis activity or channel formation, intimal swelling, proliferation, d e g e n e r a t i o n , a n d d e s q u a m a t i o n , opening of interendo-thelial junctions, subendointerendo-thelial fibrosis, a n d proliferation of smooth muscle cells, medial infiltration of lymphocytes, p l a s m a cells and m a c r o p h a g e s , and the deposition of IgG and complement, necrosis of smooth muscle cells, c o r r u g -ation of the internal elastic lamina, d e g r a n u l a t i o n of perivascular nerve terminals a n d d e g e n e r a t i o n of perivascular nerves 23,44. Indeed, a severe injury occurs in the wall of the cerebral vessel.
T h e healing vessel after SAH morphologically resembles the healing ather-oma, in which myofibroblats and collagen also a p p e a r . T h e interstitial deposition of collagen within the vessel w a s is believed to occur in lock step with the m i g r a t i o n a n d proliferation of myoblasts. T h u s , the lumen of the vessel may be held in a contracted p h a s e for weeks to s t r e n g t h e n the injured arterial wall
d u r i n g the healing period 4 4
. A similar contraction p h a s e occurs in skin w o u n d s , semingly related to the a p p e a r a n c e of myofibroblasts. As w o u n d e d g e s a p p r o -ximate, collagen deposition m a i n t a i n s the tissue in this constricted p h a s e for further repair 44. it is possible t h a t myofibroblast migration and proliferation
could be inhibited by modification of g r o w t h factor release i -4 4
. Also, it is possible t h a t swollen vessel w a l l s m a y n a r r o w the a r t e r i e s ' lumen 23.
T h e vessel injury described is likely to be caused d u r i n g the acute phase
of v a s o c o n s t r i c t i o n2
. It is due to s h e a r endothelial s t r e s s of the arterial e n d o -thelial cells t h a t d e g e n e r a t e with opening of the interendo-thelial tight junctions. It results in m a r k e d d i s t u r b a n c e in the blood arterial wall b a r r i e r or direct action of catecholamines in the smooth muscle cells, or both 2,18,23. Evidence of endothelial cell erosion a n d platelet adhesion can be seen a s early a s 15 minutes after the onset of focal v a s o s p a s m !8. On the other hand, 3 and 5 d a y s following SAH with reserpinized d o g ' s blood, u l t r a s t r u c t u r a l findings of the intima and media of b a s a l truncal arterial wall were entirely normal 46. While this evidence a r e suggestive t h a t a s h e a r s t r e s s a n d / o r direct action of catecholamines in the vessel w a l l s a r e the causal factor of the vessel wall lesions, they do not exclude the possibility t h a t the a r t e r i a l hypertension p r e s e n t d u r i n g the episode of
SAH is the cause of lesions in the endothelium 2 3
»2 6
B I O C H E M I C A L A S P E C T S O F C E R E B R A L , V A S O S P A S M
T h e principles underlying the entire circulatory system hold good for the cerebral circulation a s well. T h u s , most investigators interested in a r t e r i a l smooth muscle have chosen to study arteries from a r e a s outside the brain and have reasoned t h a t a r t e r i a l smooth muscle cells have the s a m e general biochemical p r o c e s s e s involving contraction and relaxation, r e g a r d l e s s of the anatomical site of the a r t e r y 55. T h e present in vitro techniques, using small volume c h a m b e r s and m e a s u r i n g isometric contractions of a r t e r i e s segments, allows testing of any biochemical c o m p o u n d s a n d the comparison of the physiological r e s p o n s e s to
these compounds by vessels of different anatomical sites 3
<>. T h i s section will review intracellular m e s s e n g e r s a n d related s u b s t a n c e s possibly involved in the genesis a n d control of the cerebral v a s o s p a s m .
Calcium — Until now, various a g e n t s have been identified which constrict cerebral vessels; these include catecholamine, serotonin a n d its metabolites,
prost-aglandins, t h r o m b o x a n e A2, whole blood, hemoglobin, erythrocyte b r e a k d o w n
products, fibrinogen d e g r a d a t i o n p r o d u c t s a n d m a n y others. All these known vasoconstrictive a g e n t s m a y act by m a n y different mechanisms, but they all induce contraction of the smooth muscle of the cerebral vessel by increasing the free intracellular concentration of calcium 3,20,25,51. T h u s , cerebral v a s o s p a s m , the sustained c o n t r a c t u r e of vascular smooth muscle, m a y be caused by an in-crease of m e m b r a n e permeability to Ca++, inin-creased Ca++ mobilization from
intracellular stores, decreased Ca++ sarcoplasmic reticulum uptake 47 0r
theoretically, by a n inhibition of Ca++ p u m p i n g 31. Ca++ u p t a k e by the s a r c o -plasmic reticulum a p p e a r s to be the main p r o c e s s responsible for relaxation since the r a t e of a r t e r i a l smooth muscle relaxation after a high K+ exposure is much faster t h a n the r a t e of net loss of Ca++ from the cells 50. T h e intracellular calcium activity a p p e a r s to be r e g u l a t e d by the adenylate a n d g u a n y l a t e cyclase systems 7,22 Adenylate cyclase a n d g u a n y l a t e cyclase catalyze the h y d r o
-p s e s of A T P and G T P to cyclic adenosine m o n o -p h o s -p h a t e ( c A M P ) and cyclic
guanosine m o n o p h o s p h a t e ( c G M P ) , respectively T h e myoplasmic increase
of both cAMP and c G M P induces vessel relaxation 22,36. T h e relaxing action of
cAMP is due to a decrease in the level of myoplasmic free calcium by bringing about a suppression of extracellular calcium influx and by p r o m o t i n g its active u p t a k e by intracellular s t o r a g e s t r u c t u r e s . Also, for contraction the presence of the complex C o + + - c a l m o d u l i n - m y o s i n light-chain k i n a s e is necessary. cAMP
also a p p e a r s to decrease the affinity of myosin-light chain to c a l m o d u l i n1 2
. T h e mechanism by which c G M P causes relaxation is still not clear. T h e relax-ation induced by n i t r a t e s (nitroprusside, glyceryl t r i n i t r a t e ) , and endothelium dependent relaxing factor, a p p e a r to be caused by an increase in intracellular
levels of c G M P 2 2
- 3 6 . Although there is a n association of high myoplasmic cGMP
with low myoplasmic Ca++, further investigation are required to clarify w h e t h e r there are different pools of Ca++ which can regulate different cellular processes such a s p h o s p h o r y l a s e a formation and myosin lightchain phosphorylation. A differential effect of c G M P on one or more pools of Ca++ would explain the
effects of c G M P on the various Ca++ regulated p r o c e s s e s2 2
Calcium antagonists — According to t h e classical definition, calcium anta-gonist d r u g s or calcium entry blockers inhibit t h e calcium influx t h r o u g h the excited m e m b r a n e of smooth muscle. Verapamil a n d D-600 a r e t h o u g h t t o act in this w a y 3. T h e s e a g e n t s do n o t have specificity to t h e cerebral vessels smooth muscle a n d tend t o cause systemic vasodilation. Obviously, a systemic vasodil-ation is n o t desired w h e n t h e goal is to increase perfusion in the brain. Ni-modipine is a new calcium a n t a g o n i s t with special affinity for the
receptor-operated calcium channels in cerebral vessels 2 0 , 2 5 . ]n d o g s Nimodipine increases
the cerebral blood flow ( a s m e a s u r e d b y1 3 3
X e - c l e a r a n c e ) much more effectively t h a n t h e femoral a r t e r y blood flow ( m e a s u r e d by a n electromagnetic flow m e t e r ) 25. T h i s increase in cerebral blood flow is n o t related to t h e increase in
brain metabolism caused by this calcium a n t a g o n i s t3 3
-3 4
. Nimodipine is expected
to improve cerebral perfusion w h e n it is impaired by spasmogenic a g e n t s 25,27.
A recent s t u d y h a s shown a beneficial effect of prophylatic oral administration
of N i m o d i p i n e4
. However, it w a s n o t effective w h e n injected directly in the carotid a r t e r y of p a t i e n t s with established SAH cerebral v a s o s p a s m ^ Cons-triction of vessels, which is believed to be produced by mobilization of intracel-lular calcium stores, is refratory to the action of calcium channel blokers in some vessels 25. T h u s , it is necessary to have a g e n t s t h a t a c t i n t r a c e l l u l a r ^ by blocking calcium mobilization. Recently, it h a s been shown t h a t calmodulin ant-a g o n i s t s decreant-ase t h e intensity of bant-asilant-ar ant-a r t e r y s p ant-a s m in experimentant-al SAH 8 P s y c h o t r o p i c d r u g s , such as phenothiazine a n d derivatives, have shown a ligh-affinity, C a + + - s p e c i f i c binding to calmodulin, forming a calmodulin-calcium-psychotropic complex t h a t cannot activate t h e calmodulin-sensitive form of en-zyme 37.
Biogenic amines — A d r e n e r g i c fibers originating from t h e locus ceruleus a r e considered t o r e g u l a t e intracerebral microcirculation. T h e large a r t e r i e s at the base of the b r a i n t h a t a r e involved in t h e cerebral v a s o s p a s m and the superficial arteries of t h e cortex derive their a d r e n e r g i c innervation mainly from
the superior cervical ganglion 3 2
T h e biphasic cerebral v a s o s p a s m seen in SAH is followed by a biphasic catecholamine concentration in t h e vessel walls and locus ceruleus. It consists of a reduction d u r i n g t h e first 24 h o u r s followed by a m a r k e d increase a t 3 d a y s 35. T h e loss of catecholamine-induced fluorescence of t h e a d r e n e r g i c fibers innervating t h e cerebral vessels h a s been well document-ed 2,40,53. SAH experimental studies s h o w i n g immdocument-ediate d i s a p p e a r a n c e of t h t catecholamines from t h e nerve e n d i n g s of cerebral a r t e r i e s , a n d prevention ol acute early vascular s p a s m by a — adrenergic blocking a g e n t s have implicated the sympathetic nervous system in t h e etiology of cerebral v a s o s p a s m 2.49,54. T h e massive release of catecholamines from a d r e n e r g i c fibers after SAH h a s also been implicated a s t h e cause of myonecrosis 19. T h i s myonecrosis can be prevented by prior catecholamine depletion. T h e elevation of catecholamine con-centration within arterial walls d u r i n g t h e p h a s e of delayed cerebral v a s o s p a s m may a g g r a v a t e the vascular wall contraction during the healing process t h a t
follows t h e vascular myonecrosis 2
3 , 4 4 , 4 6 . Also, it h a s been d e m o n s t r a t e d that there is an increased reactivity of t h e cerebral vessel smooth muscle to biogenic
amines following s u b a r a c h n o i d h e m o r r h a g e 2
the increased sensitivity to biogenic amines would be a denervation-supersen-sitivity type of response 40. Serotonin ( 5 - H T ) is k n o w n to cause severe and
acute vasoconstriction 14
, proliferation of fibroblasts a n d the contraction of myofibroblasts. Platelets, which a r e k n o w n to a g g r e g a t e upon the intima surface of vessels following either endothelium injury, vessel r u p t u r e or induced spasm, contain virtually all of the 5 - H T in blood 54, Release of vasoactive s u b s t a n c e s from platelets h a s been p r o p o s e d a s a possible mechanism of v a s o s p a s m
gener-ation in SAH a n d m i g r a i n e a s well 9>5i. Also, cerebral a r t e r y contraction induced
by the Hemoglobin-containing test solution a n d serum is a t t e n u a t e d or s u p p r e s s e d by the 5 - H T a n t a g o n i s t s cinaserin a n d methysergide 48. Biogenic amines a p p e a r to cause not only the initial a n d brief vasocontriction p h a s e , b u t a r e also involved in the g e n e r a t i o n of vessel wall lesions p r e s e n t in SAH cerebral vasospasm.
Prostaglandins — It h a s recently been hypothesized t h a t the endothelial d a m a g e resulting from SAH is r e l a t e d to the s u b s e q u e n t arterial n a r r o w i n g .
Current thinking holds t h a t prostacyclin (PGl2) synthesis is compromised in
the d e m a g e d endothelium 43. W i t h o u t this vasodilator prostaglandin, the potent
vasoconstrictor t h r o m b o x a n e A2 (TXA2) remains unopposed. T h e imbalance
between p r o s t a c y c l i n - t h r o m b o x a n e A2 m a y be directly implicated in the genesis
of chronic cerebral v a s o s p a s m a n d ischemic complications following aneurysmal SAH 2 3 . 4 5 . Lesions in the endothelium also give rise to a recent hypothesis ol
a predominance of contractile activity of p r o s t a g l a n d i n s such a s PGF2a a n d othei
contractile a g e n t s *0, due to lack of a still unknown endothelial dependent
relax-ing factor 1 7 , 2 3 , 5 2 . T h e n a t u r e a n d number of potentially vasoactive compounds
in blood m a y be greatly underestimated a n d the genesis of v a s o s p a s m following s u b a r a c h n o i d h e m o r r h a g e m a y indeed involve multiple factors 8.42.
C O N C L U S I O N
S U M M A R Y
Cerebral v a s o s p a s m is an i m p o r t a n t component of pathological entities such a s migraine, s u b a r a c h n o i d h e m o r r h a g e ( S A H ) , h e a d t r a u m a , post cerebral ischemia a n d / o r hypoxia. T h e mechanisms underlying cerebral v a s o s p a s m in these diseases are not completely u n d e r s t o o d . Neurochemical and morphological factors involved in the cerebral circulation control are reviewed in this article. T h e circulatory c h a n g e s observed after s u b a r a c h n o i d h e m o r r h a g e are taken a s a model. It is concluded t h a t multiple biochemical, physiological and mor-phological factors are involved in the cerebral vascular responses after SAH. Possible t r e a t m e n t alternatives for cerebral v a s o s p a s m based on its etiology are discussed.
R E S U M O
Vasoespasmo cerebral.
V a s o e s p a s m o cerebral ocorre em p a t o l o g i a s como enxaqueca, h e m o r r a g i a s u b a r a c n ó i d e a , t r a u m a de crânio, após isquemia e / o u hipoxia. A fisiopatologia do v a s o e s p a s m o cerebral n e s t a s p a t o l o g i a s n ã o está completamente desvendada. Neste a r t i g o s ã o a n a l i s a d o s os fatores neuroquímicos e morfológicos r e s p o n s á -veis pelo controle circulatório cerebral. As alterações circulatórias que seguem a h e m o r r a g i a s u b a r a c n ó i d e a s ã o utilizadas como exemplo. Conclui-se que fatores bioquímicos, fisiológicos e morfológicos s ã o responsáveis pelas manifestações vasculares que ocorrem a p ó s a h e m o r r a g i a s u b a r a c n ó i d e a . Alternativas de t r a t a -mento do v a s o e s p a s m o cerebral s ã o discutidas.
R E F E R E N C E S
1. A L E X A N D E R I I I , E . ; B L A C K , P . M . C . L . ; L I S Z C Z A K , T . M . ; Z E R V A S , N . T . — D e l a y e d C S F l a v a g e f o r a r t é r i o g r a p h i e a n d m o r p h o l o g i c a l v a s o s p a s m a f t e r e x p e -r i m e n t a l S A H . J . N e u -r o s u -r g 6 3 : 9 4 9 , 1985.
2. A L K S N E , J . F . ; G R E E N H O O T , J . H . — E x p e r i m e n t a l c a t e c h o l a m i n e - i n d u c e d c e r e b r a l v a s o s p a s m : m y o n e c r o s i s i n v e s s e l w a l l . J . N e u r o s u r 4 1 : 4 4 0 , 1974.
3. A L L E N , G . S . — C e r e b r a l a r t e r i a l s p a s m : a d i s c u s s i o n o f p r e s e n t a n d f u t u r e r e s e a r c h . N e u r o s u r g e r y 1 : 1 4 2 , 1977.
4. A L L E N , G . S . ; A H N , H . S . ; P R E Z I O S I , T . J . e t a l . — C e r e b r a l a r t e r i a l s p a s m — a c o n t r o l l e d t r i a l of n i m o d i p i n e i n p a t i e n t s w i t h s u b a r a c h n o i d h e m o r r h a g e . N . E n g l . J . M e d . 3 0 8 : 6 1 9 , 1983.
5. B A U M B A C H , G . L . ; H E I S T A D , D . D . — E f f e c t of s y m p a t h e t i c s t i m u l a t i o n a n d c h a n g e s i n a r t e r i a l p r e s s u r e o n s e g m e n t a l r e s i s t a n c e o f c e r e b r a l v e s s e l s i n r a b b i t s a n d c a t s . C i r . R e s . 5 2 : 5 2 7 , 1983.
6. B E K S , J . W . F . — C e r e b r a l v a s o s p a s m a n d i n c r e a s e d i n t r a c r a n i a l p r e s s u r e . I n R . H . W i l k i n s ( e d . ) : C e r e b r a l A r t e r i a l S p a s m . B a l t i m o r e , W i l l i a m & W i l k i n s , 1980, p . 412. 7. B E R R I D G E , M . J . — C e l l u l a r c o n t r o l t h r o u g h i n t e r a c t i o n b e t w e e n n u c l e o t i d e s a n d
c a l c i u m . A d v a n c e s i n C y c l i c N u c l e o t i d e a n d P r o t e i n P h o s p h o r y l a t i o n R e s . 1 7 : 3 2 9 , 1984.
8. B L A U M A N I S , O . R . ; G R A D Y , P . A . — E x p e r i m e n t a l c e r e b r a l v a s o s p a s m : r e s o l u t i o n b y c h l o r o p r o m a z i n e . S u r g . N e u r o l . 1 7 : 2 6 3 , 1982.
i n M i g r a i n e R e s e a r c h 1. L o n d o n , P i t m a n P r e s s , 1981. p. 17.
10. B U S I J A D . W . — R o l e of p r o s t a g l a n d i n s i n m o d u l a t i n g s y n m p a t h e t i c v a s o c o n s -t r i c -t i o n i n -t h e c e r e b r a l c i r c u l a -t i o n i n a n e s -t h e -t i z e d r a b b i -t s . J C B F M 1 7 : 2 4 , 1985. 11. C L A R K , C. — T u r b u l e n t v e l o c i t y m e a s u r e m e n t s i n a m o d e l of a o r t i c s t e n o s i s .
J . B i o m e c h . 9 : 6 7 7 , 1976.
12. C O N T I , M . A . ; A D E L S T E I N , R . S . — P h o s p h o r y l a t i o n b y c y c l i c a d e n o s i n e 3' : 5 - m o ¬ n o p h o s p h a t e - d e p e n d e n t p r o t e i n k i n a s e r e g u l a t e s m y o s i n l i g h t c h a i n k i n a s e . F e d . P r o c . 3 9 : 1 5 6 9 , 1980.
13. E C K E R , A . ; R I E M E N S C H N E I D E R , P . A . — A r t e r i o g r a p h i c d e m o n s t r a t i o n of s p a s m of t h e i n t r a c r a n i a l a r t e r i e s : w i t h s p e c i a l r e f e r e n c e t o s a c c u l a r a r t e r i a l a n e u r y s m s . J . N e u r o s u r g . 8 : 6 6 0 , 1951.
14. E D V I N S S O N , L . ; H A R D E B O , J . E . ; O W M A N , C . H . — P h a r m a c o l o g i c a l a n a l y s i s o f 5 - H T r e c e p t o r s i n i s o l a t e d i n t r a c r a n i a l a n d e x t r a c r a n i a l v e s s e l s of r a t a n d m a n . C i r . R e s . 4 2 : 1 4 3 , 1978.
15. F O R R E S T E R , J . H . ; Y O U N G , D . F . — F l o w t h r o u g h a c o n v e r g i n g - d i v e r g i n g t u b e a n d i t s i m p l i c a t i o n i n o c c l u s i v e v a s c u l a r d i s e a s e : 1. T h e o r e c t i c a l d e v e l o p m e n t . J . B i e m e c h . 3 : 2 9 7 , 1970.
16. F R Y , D . L . — C e r t a i n h i s t o l o g i c a l a n d c h e m i c a l r e s p o n s e s o f t h e v a s c u l a r i n t e r f a c e t o a c u t e l y i n d u c e d m e c h a n i c a l s t r e s s i n t h e a o r t a o f t h e d o g . C i r . R e s . 2 4 : 9 3 , 1969. 17. F U R C H G O T T , R . F . — R o l e o f e n d o t h e l i u m i n r e s p o n s e s o f v a s c u l a r s m o o t h m u s c l e .
C i r . R e s . 5 3 : 5 5 7 , 1983.
18. G R A D Y , P . A . ; B L U A M A N I S , O . R . ; N E L S O N E . R . — M o r p h o l o g y a n d f l o w d y n a m i c s of f o c a l a r t e r i a l c o n s t r i c t i o n . I n R . H . W i l k i n s ( e d . ) : C e r e b r a l A r t e r i a l S p a s m . B a l t i m o r e , W i l l i a m & W i l k i n s , 1980, p . 107.
19. G R E E N H O O T , J . H . ; R E I C H E N B A C H , D . D . — C a r d i a c i n j u r y a n d s u b a r a c h n o i d h e m o r r h a g e , a c l i n i c a l p a t h o l o g i c a l , p h y s i o l o g i c a l c o r r e l a t i o n . J . N e u r o s u r 3 0 : 5 2 1 , 1969.
20. G R O T E N H U I S , H . A . ; B E T T A G , W . ; F I E B A C H , B . J . O . ; D A B I R , K . — I n t r a c a r o t i d s l o w b o l u s i n j e c t i o n o f n i m o d i p i n e d u r i n g a n g i o g r a p h y f o r t r e a t m e n t o f c e r e b r a l v a s o s p a s m a f t e r S A H . J . N e u r o s u r 6 1 : 2 3 1 , 1984.
21. G R U B B , R . L . ; R A I C H L E , M . E . ; E I C H L I N S J . O . ; G A D O , M . H . — E f f e c t s of s u b a r a c h n o i d h e m o r r h a g e o n c e r e b r a l b l o o d v o l u m e , b l o o d f l o w , a n d o x y g e n u t i -l i z a t i o n i n h u m a n s . J . N e u r o s u r g 4 6 : 4 4 6 , 1977.
22. J O H N S O N , R . M . ; L I N C O L N , T . M . — E f f e c t s of n i t r o p r u s s i d e , g l y c e r y l t r i n i t r a t e , a n d 8 - b r o m o c y c l i c G M P o n p h o s p h o r y l a s e a f o r m a t i o n a n d m y o s i n l i g h t c h a i n p h o s p h o r y l a t i o n i n r a t a o r t a . M o l . P h a r m a c o l . 2 7 : 3 3 3 , 1985.
23. K A S S E L L , N . F . ; S A S A K I , T . ; C O L O H A N , A . R . T . ; N A Z A R , G. — C e r e b r a l v a -s o -s p a -s m f o l l o w i n g a n e u r y -s m a l -s u b a r a c h n o i d h e m o r r h a g e . S t r o k e 1 6 : 5 6 2 , 1985. 24. K A S S E L , N . F . ; P E E R L E S S , S . J . ; D R A K E , C.G. — A c u t e p r o l i f e r a t i v e v a s c u l o p t h y ?
I. H y p o t h e s i s . I n R . H . W i l k i n s ( e d . ) : C e r e b r a l A r t e r i a l S p a s m . B a l t i m o r e , W i l l i a m & W i l k i n s , 1980, p . 85.
25. K A Z D A , S . ; T O W A R T , R . — N i m o d i p i n e : a n e w c a l c i u m a n t a g o n i s t d r u g w i t h a p r e f e r e n t i a l c e r e b r o v a s c u l a r a c t i o n . A c t a . N e u r o c h i r . 6 3 : 2 5 9 , 1982.
26. K O N T O S , H . A . ; W E I , E . P . ; D I E T R I C H , D . ; N A V A R Y , R . M . ; P O V L I S H O C K , J . T . ; G H A T A K , N . R . ; E L L I S , E . F . : P A T T E R S O N , J . L . J r . — M e c h a n i s m o f c e r e b r a l a r t e r i o l a r a b n o r m a l i t i e s a f t e r a c u t e h y p e r t e n s i o n . A m . . J . . P h y s i o l . 240 ( H e a r t . C i r c . P h y s i o l . 9 ) : H 5 1 1 , 1981.
27. K R U E G E R , C . ; W E I R , B . ; N O S K O , M . ; C O O K , D . ; N O R R I S , S. — N i m o d i p i n e a n d c h r o n i c v a s o s p a s m i n m o n k e y s : 2 — P h a r m a c o l o g i c a l s t u d i e s o f v e s s e l s i n s p a s m . N e u r o s u r g e r y 1 6 : 1 3 7 , 1985.
28. L A S S E N , N . A . — B r a i n . I n P . C . J o h n s o n ( e d . ) : P e r i p h e r a l C i r c u l a t i o n . N e w Y o r k , J o h n W i l e y & S o n s , 1978, p . 337.
29. L O B A T O , R . D . ; M A N N , J . ; S A L A I C E S , M . ; R I V I L L A , F . ; B U R G O S , J . — C e r e b r o v a s c u l a r r e a c t i v i t y t o n o r a d r e n a l i n e a n d s e r o t o n i n f o l l o w i n g e x p e r i m e n t a l s u b a r a c h n o i d h e m o r r h a g e . J . N e u r o s u r g . 5 3 : 4 8 0 , 1980.
3 1 . M I L L E R , C A . — B i o c h e m i s t r y of v a s c u l a r s m o o t h m u s c l e : C o n t r a c t i l e m e c h a n i s m of h u m a n b a s i l a r a r t e r y . I n R . H . W i l k i n s ( e d . ) : C e r e b r a l A r t e r i a l S p a s m . B a l t i -m o r e , W i l l i a -m &a-mp; W i l k i n s , 1980, p . 68.
32. M I L L E R , J . D . — C o n t r o l o f t h e c e r e b r a l c i r c u l a t i o n . I n R . H . W i l k i n s ( e d . ) : C e -r e b -r a l A -r t e -r i a l S p a s m . B a l t i m o -r e , W i l l i a m & W i l k i n s , 1980, p . 76.
33. M O H A M E D , A . A . ; M E N D E L O W , A . D . : T E A S D A L E , G . M . ; H A R P E R , A . M . ; M c C U L L O C H , J . — E f f e c t o f t h e c a l c i u m a n t a g o n i s t n i m o d i p i n e o n l o c a l c e r e b r a l b l o o d f l o w a n d m e t a b o l i c c o u p l i n g . J C B F M 5 : 2 6 , 1985.
34. M O H A M E D , A . A . ; M c C U L L O C H , J . ; M E N D E L O W , A . D . ; T E A S D A L E , G . M . ; H A R P E R , A . M . — E f f e c t of t h e c a l c i u m a n t a g o n i s t n i m o d i p i n e o n l o c a l c e r e b r a l b l o o d f l o w : r e l a t i o n s h i p t o a r t e r i a l b l o o d p r e s s u r e . J C B F M 4 : 2 0 6 , 1984.
35. M O R O O K A , H . — C e r e b r a l a r t e r i p ' s p a s m : I . A d r e n e r g i c m e c h a n i s m i n e x p e r i m e n t a l c e r e b r a l v a s o s p a s m . A c t a . M e d . O k a y a m a 3 2 : 2 3 , 1978.
36. P E A C H , M . J . ; L O E B , A . L . ; S I N G E R , H . A . ; S A Y E , J . — E n d o t h e l i u m - d e r i v e d v a s c u l a r r e l a x i n g f a c t o r . H y p e r t e n s i o n 7 ( s u p p l . 1 ) : 1, 1985.
37. N A K A N O , M . ; T A N I , E . ; F U K U M O R I , T . ; Y O K O T A , M . — E f f e c t s o f c h l o r p r o ¬ m a z i n e o n e x p e r i m e n t a l d e l a y e d c e r e b r a l v a s o s p a s m . J . N e u r o s u r g . 6 1 : 8 5 7 , 1984. 38. N O R W O O D , C . W . — A r e v i e w o f r e c e n t a d v a n c e s i n v a s c u l a r s m o o t h m u s c l e p h a r m a c o l o g y . I n R . H . W i l k i n s ( e d . ) . C e r e b r a l A r t e r i a l S p a s m . B a l t i m o r e , W i l l i a m & W i l k i n s , 1980, p . 57.
39. O L E S E N , J . ; L A U R I T Z E N , J . — T h e r o l e o f v a s o c o n s t r i c t i o n i n t h e p a t h o g e n e s i s of m i g r a i n e . I n W . D . A m e r y , J . M . V . N u e t e n & A . W a u q u i e r ( c d s . ) : P h a r m a c o l o g i c a l B a s i s o f M i g r a i n T h e r a p y . L o n d o n . P i t m a n P r e s s , 1984, p . 7.
40. P I C K A R D , J . D . ; P E R R Y , S. — S p e c t r u m o f a l t e r e d r e a c t i v i t y o f i s o l a t e d c e r e b r a l a r t e r i e s f o l l o w i n g s u b a r a c h n o i d h e m o r r h a g e : r e s p o n s e t o p o t a s s i u m , p H , n o r a d r e -n a l i -n e , 5 - h y d r o x y t r y p t a m i -n e , a -n d s o d i u m l o a d i -n g . J C B F M 4 : 5 9 9 , 1984.
4 1 . R A Y , G . ; D A V I D S , N . — S h e a r s t r e s s a n a l y s i s o f b l o o d - e n d o t h e l i a l s u r f a c e i n i n l e t s e c t i o n o f a r t e r y w i t h p l u g g i n g . J . B i o m e c h a n i c s 3 : 9 9 , 1970.
4 2 . S A S A K I , T . ; A S A N O , T . ; T A K A K U R A , K . ; S A N O , K . ; K A S S E L L , N . F . — N a t u r e o f t h e v a s o a c t i v e s u b s t a n c e i n C S F f r o m p a t i e n t s w i t h s u b a r a c h n o i d h e m o r r h a g e . J . N e u r o s u r g . 6 0 : 1 1 8 6 , 1984.
43. S H O H A M I , E . ; S I D I , A . — A c c u m u l a t i o n o f p r o s t a c y c l i n i n r a t b r a i n d u r i n g h e m o r r h a g i c h y p o t e n s i o n — P o s s i b l e r o l e o f P G 12 i n a u t o r e g u l a t i o n . J C B F M
4 : 1 0 7 , 1984.
44. S M I T H , R . R . ; C L O W E R , B . R . ; G R O T E N D O R S T , G . M . ; Y A B Y N O , N . ; C R U S E , J . M . — A r t e r i a l w a l l c h a n g e s i n e a r l y h u m a n v a s o s p a s m . N e u r o s u r g e r y 1 6 : 1 7 1 , 1985.
45. S P A L L O N E , A . — C e r e b r a l v a o s o p a s m a s a c o m p l i c a t i o n o f a n e u r y s m a l s u b a -r a c h n o i d h e m o -r -r h a g e : b -r i e f -r e v i e w . I t a l . J . N e u -r o l . S e i . 6 : 1 9 , 1985.
46. T A N A B E , Y . ; S A K A T A , K . ; Y A M A D A , H . ; I T O , T . ; T A K A D A , M . — C e r e b r a l v a s o s p a s m a n d u l t r a s t r u c t u r a l c h a n g e s i n c e r e b r a l a r t e r i a l w a l l a n e x p e r i m e n t a l s t u d y . J . N e u r o s u r g . 4 9 : 2 2 9 , 1978.
47. T A N I , E . ; Y A M A G A T A , S . ; M A E D A , Y . ; I T O , Y . — C y t o c h e m i c a l d e m o n s t r a t i o n o f a d e n y l a t e a n d g u a n y l a t e c y c l a s e s i n v a s c u l a r s m o o t h m u s c l e o f c i r c l e o f W i l l i s . J . N e u r o s u r . 4 9 : 2 3 9 , 1978.
48. T O D A , N . ; S H I M I Z Y , K . ; O H T A , T . — M e c h a n i s m o f c e r e b r a l a r t e r i a l c o n t r a c t i o n i n d u c e d b y b l o o d c o n s t i t u e n t s . J . N e u r o s u r g . 5 3 : 3 1 2 , 1980.
49. T S U K A H A R A , T . ; T A N I G Y C H I , T . ; F U J I W A R A , M . ; H A N D A , J . ; N I C H I K A M A , M . — A l t e r a t i o n s i n a l p h a a d r e n e r g i c r e c e p t o r s i n h u m a n c e r e b r a l a r t e r y a f t e r s u b a r a c h n o i d h e m o r r h a g e . S t r o k e 1 6 : 5 3 , 1985.
50. V A N B R E E M E N , C . ; S I E G E L , B . ; K A L I N O S K I , L . ; A E R A , P . ; H W A N G , O. — T h e C a - f - f c y c l e o f a r t e r i a l s m o o t h m u s c l e . C e r e b r a l A r t e r i a l S p a s m . B a l t i m o r e , W i l l i a m a n d W i l k i n s , 1980, p . 6 1 .
52. W E I , E . P . ; K O N T O S , H . A . ; C H R I S T M A N , C . W . ; D e W I T T , D S ; P O V L . I S H O C K , J . T . — S u p e r o x i d e g e n e r a t i o n a n d r e v e r s a l o f a c e t y c h o l i n e i n d u c e d c e r e b r a l a r t e -r i o l a -r d i l a t i o n a f t e -r a c u t e h y p e -r t e n s i o n . C i -r . R e s . ( I n p -r e s s ) .
5 3 . W E L L . T J M , G . R . ; P E T E R S O N , J . W . ; Z E R V A S , N . T . — T h e r e l e v a n c e o f i n v i t r o s m o o t h m u s c l e e x p e r i m e n t s o f c e r e b r a l v a s o s p a s m . S t r o k e 6 : 5 7 3 , 1985.
54. Y O S H I O K A , J . ; C L O W E R , B . R . ; S M I T H , R . R . — T h e a n g i o p a t h y o f s u b a r a c h n o i d h e m o r r h a g e . I . R o l e o f v e s s e l w a l l c a t e c h o l a m i n e s . S t r o k e 1 5 : 2 8 8 , 1984.
55. E I J L S T R A , W . G . — P h y s i o l o g y o f t h e c e r e b r a l c i r c u l a t i o n . I n J . M . M i n d e r h o u d ( e d . ) : C e r e b r a l B l o o d F l o w , B a s i c K n o w l e d g e a n d C l i n i c a l I m p l i c a t i o n s . E x e r p t a M e d i c a , A m s t e r d a m , 1981.
