:Acta . . Nduro&lrurglca

ActaNeurochir (Wien) (1992) 119:139 i45

9 Springer-Verlag 1992 Printed in Austria

Cerebrovascular Effects of Substance P After Experimental Subarachnoid Haemorrhage A. Pasqualin, T. Tsukahara, K. Hongo, O. Van Beek, N. F. Kassell, and J. C. Torner Department of Neurological Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia, U.S.A.

Summary The vasoactive effects of substance P (SP), as well as the content of cyclic guanine monophosphate (cGMP), were determined in the rabbit basilar artery after subarachnoid haemorrhage (SAH). Out of 47 rabbits, 24 were subjected to a SAH, induced by injecting 5 ml of autologous arterial blood into the cisterna magna; 23 were used as controls. In 20 animals (10 SAH and 10 controls), isometric tension recording of isolated rings of the basilar artery - dissected 2 days after SAH - was employed to assess the dosedependent vasodilatation to SP (10 10 to 10-6M) after precontraction with serotonin (10 .8 to 10-SM). In 15 animals (8 SAH and 7 controls), the basal cGMP content was measured in the basilar artery 2 days after SAH. In the other 12 animals (6 SAH and 6 controls), the increase in cGMP content was measured in the basilar artery after a 10-minute incubation with SP (10 6M). SP caused significantly less dilatation in animals subjected to SAH than in controls, especially for concentrations between 10 .9 and 10-6M (p < 0.001). The cGMP content in the arteries 2 days after SAH was significantly lower than in control arteries (31.5 4- 7.3 against 57.3 :t_ 4.3 pmoles/g tissue). In the preparations incubated with SP, the increase of cGMP was 440 • 115% in the control arteries, and only 97 • 30% in the arteries after SAH. It is concluded that the vasodilator activity of SP is significantly impaired after SAH. Moreover, the changes in cGMP content after SAH suggest a link between impaired vasoactive response to SP and decreased production of cGMP after SAH.

Keywords: Substance P; vasospasm; snbarachnoid haemorrhage; isometric tension recording; cyclic GMP; rabbit.

Introduction T h e p a t h o g e n e s i s o f c e r e b r a l v a s o s p a s m after suba r a c h n o i d h a e m o r r h a g e ( S A H ) is n o t fully u n d e r s t o o d , a l t h o u g h it is likely due to a n i m b a l a n c e b e t w e e n vas o d i l a t o r y a n d v a s o c o n s t r i c t o r y influences, with increased v a s o c o n s t r i c t o r responses to amines (norepin e p h r i n e a n d m a i n l y serotonin)23, 38 a n d with i m p a i r e d v a s o d i l a t o r responses to acetylcholine, A T P , a n d / o r o t h e r agents19' 20, 2s. T h e effect o f m o s t v a s o d i l a t o r

agents has been s h o w n of endothelium-derived 2g. E D R F release m a y S A H , due to e n d o t h e l i a l

to be m e d i a t e d b y the release relaxing f a c t o r (EDRF)10' 11, be m a r k e d l y decreased after d a m a g e 2' 16,21,36; alternatively,

a n i m p a i r e d r e s p o n s e to E D R F has been suggested to occur after S A H 19,20, p r o b a b l y due to interference with p r o d u c t i o n o f cellular c G M P b y o x y h e m o g l o b i n 25' 31 a n d / o r h e m o l y s a t e 41. T h e prevalence o f v a s o c o n s t r i c t i v e influences m a y also be d e t e r m i n e d b y the a d d e d effects o f o t h e r vasoactive agents such as p l a s m i n 47 a n d p r o s t a g l a n dins12, 34, p r o d u c e d directly or indirectly by the presence o f the s u b a r a c h n o i d clot. Recently, a new g r o u p o f vasoactive agents has been d i s c o v e r e d - the so-called n e u r o p e p t i d e s s, 9, 32. V a r i o u s studies have suggested their possible role as n e u r o transmitters, w i t h synergistic o r alternative actions w h e n c o m p a r e d to c o n v e n t i o n a l n e u r o t r a n s m i t t e r s such as n o r a d r e n a l i n e a n d acetylcholine 5' 9, 32. Significant concentrations of various neuropeptidesespecially C a l c i t o n i n G e n e - R e l a t e d P e p t i d e ( C G R P ) , V a s o a c t i v e I n t e s t i n a l P e p t i d e (VIP), substance P (SP) - have been r e c o g n i z e d in the p e r i v a s c u l a r nerves o f h u m a n c e r e b r a l arteries l, 5. T h e role o f these neur o p e p t i d e s in the genesis o f v a s o s p a s m has been very recently discussed 3' 13, 43, 45, 4a T h e c e r e b r o v a s c u l a r effects o f S P - a p e p t i d e localized in m a n y regions o f the central n e r v o u s system 5' 7, s, 13, 14, 22, 29, 4s, 46 a n d exhibiting a m a r k e d v a s o d i l a t o r effectS-7, 9, 27, 44, m o s t likely m e d i a t e d t h r o u g h release o f E D R F 6' 10, 26, 27, 3< 41, 42 a n d p o s s i b l y p r o s t a g l a n dins 3 ~ have n o t yet been e v a l u a t e d in a n i m a l m o d e l s o f S A H a n d v a s o s p a s m . C o n s e q u e n t l y , this p a p e r presents o u r experience with SP in the r a b b i t m o d e l o f

140

SAH, to assess the possible implication of this substance in the phenomenon of cerebral vasospasm, as suggested by other authors 3' 13, 45, 48. In particular, SPinduced vasodilatation has been evaluated, as well as the effect of SAH on this vasoactive response. Further, since SP has been reported to exert its vasodilatory effect via an increase in the c G M P level in smooth muscle cells 10, 37, 41, 42, the content of c G M P has been measured as an indicator of the intracellular mechanism and of the released E D R F stimulated by SP.

Materials and Methods Animal Preparation Forty-seven male New Zealand white rabbits, weighing from 3.3 to 3.7 kg, constituted the material of this study. Twenty-four rabbits were subjected to SAH according to the model previously established in our laboratory 28 and described below. Twenty-three rabbits were used as controls. All animals in the SAH group were initially anaesthetized with an i.m. injection of ketamine (30 mg/kg) and xylazine (6 mg/kg). The animals were intubated, and muscular paralysis was induced with intravenous pancuronium bromide (0.03 mg/kg), Ventilation was maintained with a Harvard dual-phase control respirator (Model 683, Harvard Apparatus, South Natick, Massachusetts). The left ear artery of each animal was cannulated for monitoring blood pressure and withdrawing arterial blood. Arterial blood gases were checked, and arterial pH, PCO2, and PO2 were maintained within the physiological range. The arterial line was connected to a pressure transducer, and arterial blood pressure was continuously monitored and recorded on a chart recorder (Model 78172A, Hewlett-Packard, Palo Alto, California). A 23-gauge butterfly needle was inserted percutaneously into the cisterna magna and 5 ml of autologous non-heparinized arterial blood was injected over 10 seconds. The animals were then tilted with the head down to facilitate gravitational settling of the blood in the basal cisterns. The cisternal injection of blood transiently elevated the mean arterial pressure by 10-20 mmHg. Following this procedure, the animals were disconnected from the respirator and allowed to breathe by themselves, and were then extubated when fully awake. Tissue Preparation On day 2, i.e., 48 hours after SAH, the animals were re-anaesthetized with an i.m. injection of ketamine (60 mg/kg) and xylazine (6 mg/kg) and arterial pressure was recorded. The animals without previous SAH were similarly prepared and sacrified. The brain was carefully removed immediately after death and was placed in a chamber with modified Krebs' solution (millimolar composition; NaC1 120; KC1 4.5; MgSO4 1.0; NaHCO 3 27.0; KH2PO 4 1.0; CaC12 2.5; dextrose I0.0). The basilar artery was dissected free under magnification, taking care in the animals subjected to SAH to remove the thick subarachnoid clots (almost always encasing the artery) without damage or strain on the artery itself. Tension Measurement Three mm long rings of the basilar artery were prepared, and each was suspended between two L-shaped stainless steel rods in a

A. Pasqualin et al.: Cerebrovascular Effects of Substance P chamber filled with 10ml of modified Krebs' solution, which was aerated with 95% 02 and 5% CO2. The pH of the solution ranged between 7.4 and 7.5. The resting tension was adjusted to 400rag, according to the previously reported experience from our laboratory TM indicating that the best relaxation is obtained at this tension. The preparation was allowed to equilibrate at 37 ~ before use. Isometric tension was recorded using a Grass FT.03 force-displacement transducer (Grass Instrument Co., Quincy, Massachusetts) and was displayed on a Soltec 3418 chart recorder (Soltec, San Fernando, California), using a Grass Model 79D polygraph. Initially, 40 mM KC1 was applied to the chamber in order to verify a consistent contractile response to the drug. The preparation was then washed at least three times with Krebs' solution, and allowed to re-equilibrate for 45 minutes before applying serotonin (5HT). Only those specimens that showed an adequate response to KC1 (i.e., a contraction of at least 0.3 gm of tension, followed by a stable plateau) were used for tension recording. Serotonin was applied at progressively increasing molar concentrations (from 10 -8 to 10 -5 M), When the contraction reached a plateau after application of 10- 5 M 5-HT, SP was added to the bath in progressively increasing molar concentrations (from 10 -1~ to 10- 6 M). When the dilatation reached a plateau, 10- 5 M papaverine was added to the bath, producing in all cases immediate and complete relaxation. Measurement of cGMP Content The isolated basilar arteries of normal rabbits (n = 7) and SAH rabbits (n = 8) were quickly weighed and placed in a tube containing 2ml of Krebs' solution oxygenated with 95% Oz and 5% CO2 at 37 ~ At the end of 60 minutes equilibration, the arteries were quickly removed from the tube and immediately immersed in liquid nitrogen for at least 30 seconds to ensure complete freezing. For the measurement of the change in cGMP content induced by SP, another set of isolated basilar arteries (normal n = 6, SAH n = 6) were cut into two pieces and weighed separately; each piece was then placed in a tube with aerated Krebs' solution. After 60 minutes of equilibration, SP was added at a final concentration of 10-6M. The other piece of the artery was used as a control. Ten minutes after the addition of SP, the arteries were quickly removed from the tube and immersed in liquid nitrogen. They were then crushed, dissolved, and homogenized by a Polytron (Brinkman Inst., Westbury, New York) in 1 ml of ice-cold acid-ethanol (1 ml 1 N HC1/ 100ml ethanol) containing 2 m M EGTA. After centrifugation at 2,000 g for 30 seconds, 0.8 ml of the supernatant was transferred to a small assay tube and the ethanol was evaporated with a stream of air. Cyclic GMP was measured using a 3H-cGMP radioimmunoassay kit (Amersham, Arlington Heights, Illinois). The cGMP concentration extracted into the incubation medium was analyzed directly with a standard radioimmunoassay curve made up in an identical medium. The amount of eGMP content in the basilar artery was expressed as pmoles/g wet weight. The increase of cGMP content was calculated from the cGMP content in the arterial segments with and without incubation in 10 -6 M SP. Drugs Substance P (in powder and with acid buffer) was obtained from Sigma Chemical Co. (St. Louis, Missouri). The drug was dissolved in distilled water to produce a concentration of 10-3 M. The drug was divided into 0.3 ml aliquots and stored in ampules in the freezer.

A. Pasqualin et al. : Cerebrovascular Effects of Substance P

141

Each ampule was taken out of the freezer the day of the experiment and kept in the refrigerator until used. For the other drugs applied in vitro, stock solutions ofpapaverine (I 0 - 3 M) were made by dissolving the drug in distilled water. Serotonin was dissolved in 0 . 1 N HC1 with 0.1% ascorbic acid, and hemoglobin solutions were prepared according to the method of Tanishima 4~ Atl o f the drugs used for tension recording were diIuted further in Krebs' solution before use, such that volumes of less than 0.1 ml were added to the organ bath.

Statistical Analysis The data is expressed as m e a n :t: standard error of the m e a n (SEM). Statistical comparison between two groups was done by Student's t-test for unpaired observations. Values were considered to be significantly different if the probability level was less than 0.05.

Results Tension Measurement As shown in Table 1, 40 m M KCl-induced contraction was 1.10 + 0.13 gm in control animals (19 obserTable 1. Contractile Response of the Rabbit Basilar Artery After

Application of KC1 and 5-HT: Control Versus S A H Animals Group

No.

Control SAH

19 19

Signif.:

g m of Tension 4 0 m M KC1

1 0 - S M 5-HT

1.10 + 0.13 0.55 + 0.06

1.28 • 0.14 1.10 • 0.09

p < 0.001

N.S.

Data expressed as m e a n + SEM.

eGMP Content in the Rabbit Basilar Artery The basal c G M P content was assessed in a group of 15 rabbits. The c G M P content in normal basilar arteries was 57.3 + 4.3pmoles/g tissue (n = 7). The c G M P content in the arteries 2 days after SAH was significantly lower (31.5 • 7.3 pmoles/g tissue) (n = 8) than in normal arteries (Table 2). In another group of 12 animals (6 control and 6 SAH), the effect of SP on the c G M P content was examined by comparing the c G M P content in the 10 minute SP-incubated artery with the c G M P content in

100.0%,

250%-

-x-CTR --e-SAH

200%. zO b-0< 150%

.." ...... I~ ............... ~**

CTR

BO.O%, z 0 I-- 60.0%. < I-< d 40.0% c3

z tO0% o

50%

0%J

vations out of 10 animals), and 0.55 + 0.06 gin in animals submitted to SAH (19 observations out of 10 animals). The difference was highly significant (p = 0.0006). Serotonin-induced contraction was expressed in absolute values (Table 1) and as a percent of the contraction elicited by a standard dose of 40 m M KC1. As shown in Fig. 1 (19 observations in each group), 5-HT (10 -8 to 10 -5 M) caused significantly more contraction in animals subjected to SAH than in controls. The difference was highly significant (p < 0.00t) for concentrations between 10- 8 and 10 - 5 M. The dose-response curves of the basilar artery to SP are shown in Fig. 2. The data are expressed as a percentage of the contraction elicited by 1 0 - S M 5-ttT. SP ( 1 0 - 1 ~ to 1 0 - 6 M ) caused significantly less dilation in animals subjected to SAH than in controls. The difference was highly significant (p < 0.001) for concentrations between 10 - 8 and 10 - 6 M.

.r ~ ( ~ (

20.0%

-B

-7

-6

-5

LOG MOLARCONCENTRATIONOF 5-HT

Fig. 1. Dose-response curve of rabbit basilar arteries to serotonin (5-HT) in control and SAH animals. D a t a are mean values expressed as a percentage of the contraction to the standard dose o f 40 m M KC1. Vertical bars indicate two standard errors, * p < 0,05, ** p < 0.01

t~ ~ ~

..... { ............. { ........

i

O.OI

-B

-7

-6

-5

-4

LOG MOLAR CONCENTRATIONOF SP Fig. 2. Effect of substance P (SP) on serotonin-induced contraction in control and S A H animals. D a t a are expressed as a percentage of the contraction induced by 1 0 - 5 M 5-HT. Vertical bars indicate two standard errors. * p < 0.05, ** p < 0.01

A. Pasqualin etal. : Cerebrovascular Effects of Substance P

142 Table 2. Basal cGMP Content in the Rabbit Basilar Artery. Control

Versus SAH Animals Group

No.

pmol/g Tissue

Control SAH

7 8

57.3 + 4.3 31.5 -4- 7.3

Signif.:

p = 0.01

Data expressed as mean + SEM.

600.

rO

500. 400.

(.9 O -6 a00. [/1 o m 200O ill

t00.

O.. 0

CTR n=6

SAH n=6

Fig. 3. Increase in cGMP content of the rabbit basilar artery after incubation with 1 0 - 6 M substance P (SP); the increase rate is expressed as a relative value of basal cGMP content in the basilar artery of SAH animals as compared to controls. * p = 0.01

tion of the vessels. In 1983, Edvinsson et al. 8 also noted that, in the brain of various species (guinea pig, cat, rabbit, and man), the highest concentration of SP was around cerebral vessels. In the same year, Liu-Chen etal. 22 established the presence of a "trigemino-vascular SP-containing pathway" to large pial vessels of the anterior circulation in various animal species (rat, dog, cat, calf). In an excellent review on the argument, Owman et al. 32 in 1984 described the ultrastructural features of the so-called p-type nerve terminals (the terminals containing SP, VIP, and probably other neuropeptides). They appeared as large electron-dense granular vesicles (100-200 nm), in contrast to the small vesicles of adrenergic and cholinergic nerve terminals (50 nm)32. In the last few years, the cerebrovascular effects of SP have been documented by other investigators 5' 6, 9, 26, 27, 30, 31, 41, 42, 44 in various animal species as well as man. However, it has also been demonstrated that SP coexists with C G R P in the trigeminal ganglion and in the nerve fibers around cerebral vessels of various animal species 44' 46 and that SP-induced vasodilatation is less pronounced than CGRP-induced vasodilatation 5' 6, 26, 44. Thus, although the presence of SP innervation around cerebral vessels is soundly established, the role of SP as a physiological neurotransmitter mediating vasodilatation is still questionable. Vasoactive Responses to S P After S A H

the control portion. Figure 3 shows the increase in c G M P content in the normal and SAH basilar arteries when the arteries were incubated with SP (10-6M). The increase induced by SP was significantly lower in arteries 2 days after SAH than in normal basilar arteries: 440 4- 115% (SEM) in controls (n = 6), and 97 4- 30% (SEM) in SAH animals (n = 6). Discussion

Substance P and Cerebral Arteries

The discovery of neuropeptides with a cerebral vasoditatory effect is a recent one. In particular, the first report to deal specifically with the cerebrovascular effects of SP was published in 1981 by Edvinsson etal. 7. The authors, studying pial arteries of cats, documented a rich SP-immunoreactivity at the adventitia and adventitia/media border, and detected a relaxation response of SP either in vitro (through isometric tension recording) or in vivo (through direct surgical exposure) after prostaglandin Fza (PGF2~)-induced precontrac-

As mentioned above, the in vitro application of SP (10-8 M to 10-6 M ) t o cerebral arteries of various species after precontraction with physiological vasoconstrictors results in a dose-dependent vasodilatation 5-7' 9, 26, 27, 30, 31, 41-43 Vasodilatation has been reported to amount to 55% of PGFz~-indueed contraction 5 and 36% of K+-induced contraction 26 in human cerebral arteries, and to 33% and 44% of K+-induced contraction in pig and cat cerebral arteries, respectively 26. Our findings in rabbit cerebral arteries are similar (with dilatation amounting to almost 60% of the contractile response to 5-HT). The maximum dilatation has been observed after application of a 10-6M SP in feline, porcine, and human cerebral arteries 7' 26, and also in rabbit basilar artery according to our experience. Some authors 6' 26, 27, 30, 41, 42 consider the dilatory response of cerebral arteries to SP to be endotheliumdependent, as well as the SP-induced vasodilatation of systemic vessels 10,37. This constitutes a significant difference from CGRP-induced vasodilatation, which is considered to be endothelium-independent in human, pig, cat, and rabbit cerebral arteries 6' 17. 26

A. Pasqualin et al. : Cerebrovascular Effects of Substance P It is well k n o w n that endothelial d a m a g e often occurs after SAH. In ultrastructural studies, various abnormalities have been d o c u m e n t e d in the endothelial cells 2,21,36, with probable impairment o f the endothelial functions after SAH. I n particular, this could disrupt the secretion o f E D R F , a substance ultimately mediating vasodilatation to various agents (such as acetylcholine, A T P , SP, bradykinin, etc. 10, 11, 26, 30, 41, 42) and recently identified with nitric oxide (NO) 24' 25, 33 O u r results show that after S A H the vasodilatory response to SP is m a r k e d l y impaired, and endothelial d a m a g e m a y well be the underlying cause o f this phen o m e n o n . Alternatively, as suggested by K i m et al. 19, 20 an impaired response to E D R F could occur after S A H ; to this regard, it has been recently postulated that o x y h e m o g l o b i n a n d / o r hemolysate can cause an interference in the p r o d u c t i o n o f c G M P , ultimately mediating the vasodilatation to E D R F 25' 31, 41. Other authors have also reported that endothelium-dependent vasodilatation is impaired after experimental S A H 28. This impairment o f e n d o t h e l i u m - d e p e n d e n t vasodilatation m a y be a m a j o r determining factor in the genesis o f cerebral vasospasm. The decreased response to SP observed in rabbit basilar artery after S A H m a y also be consistent with the decrease in the concentration o f the S P - i m m u n o reactive perivascular fibers observed after S A H in dogs 45 as well as in m o n k e y s 13. c G M P Release After S A H It has been previously d e m o n s t r a t e d that a powerful vasodilator such as V I P elevates c A M P levels in n o r m a l basilar arteries and that c A M P content increases significantly in spastic basilar arteries after S A H 39, 43. Substance P, c o n t r a r y to V I P but similar to acetylcholine and A T P 10, seems to act t h r o u g h E D R F release. According to various authors, E D R F causes relaxation t h r o u g h the p r o d u c t i o n o f c G M P in the s m o o t h muscle cells 4, 10, 15, 18, 24, 25, 30, 31, 35, 37, 41, 42. Thus, SP-induced vasodilatation is ultimately associated with a rise in the c G M P content o f the s m o o t h muscle cell, as confirmed by recent studies 31' 41, 42 According to our data, the c G M P content decreases significantly in rabbit basilar artery after SAH, as opposed to c A M P content 43. After incubation o f the artery with SP, the c G M P content increases in control as well as in S A H animals, suggesting a close relationship between SP and c G M P ; however, after S A H the increase o f c G M P content is significantly lower than in controls. Thus, it is reasonable to speculate that some

143 inhibition o f the n o r m a l response to SP occurs after SAH, p r o b a b l y due to endothelial d a m a g e a n d / o r to selective blockade o f the second messenger c G M P by o x y h e m o g l o b i n a n d / o r hemolysate 31'41 In conclusion, the inhibition o f the n o r m a l vasodilatory response to SP after S A H is associated with a decreased p r o d u c t i o n o f c G M P and with an impaired increase o f c G M P after SAH, following incubation with SP. All of these p h e n o m e n a m a y have an implication in the genesis and maintenance o f cerebral vasospasm, although it is still unclear whether SP and other vasoactive peptides (such as V I P and C G R P ) exert a p r i m a r y or supplementary role in the physiological process o f cerebral vasodilatation.

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29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41. 42.

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Cerebrovascular effects of substance P after experimental subarachnoid haemorrhage.

The vasoactive effects of substance P (SP), as well as the content of cyclic guanine monophosphate (cGMP), were determined in the rabbit basilar arter...
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