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Effect of nimodipine on the autoregulation of cerebral blood flow studied by laser-Doppler flowmetry
Brain Research, 625 (1993) 301-306
301
© 1993 Elsevier Science Publishers B.V. All rights reserved 0006-8993/93/$06.00 BRES 19316
Effect of nimodipine on the autoregulation of cerebral blood flow studied by laser-Doppler flowmetry Genevieve
Florence
a, G i l l e s B o n v e n t o
b, P a s c a l
and Jacques
Seylaz
Roucher
b Robert
Charbonne
b
b
a Centre d'Etudes et de Recherches de M~decine A~rospatiale, Section de Physiologie Compar~e, Br~tigny sur Orge (France) and b Laboratoire de Recherches C~r~brovasculaires, CNRS, UA 641, Universit~ Paris VII, Facult~ de M[decine Villemin, Paris (France)
(Accepted 26 May 1993)
Key words: Cerebral blood flow; Autoregulation; Laser Doppler flowmetry; Calcium antagonist; Rabbit
The present work examines whether nimodipine impairs autoregulation of CBF during hypotension. The CBF of 16 anesthetized rabbits was measured with a laser-Doppler flowmetry probe placed on the external surface of a plexiglas window, chronically inserted in the skull. Autoregulation was triggered by aortic bleeding. First, the effects of three doses of nimodipine (1, 3 and 10/xg/kg) and the solvent were studied in 10 rabbits in which MABP was maintained at 50 mmHg for one minute. Second, 10 ~g/kg i.v. nimodipine was administered to 6 rabbits in which MABP was kept at 30 mmHg for one minute. Before bleeding, the 10/~g/kg dose significantly decreased MABP (from 96d: 11 mmHg to 81 + 11 mmHg, P < 0.01) and increased CBF (from 1045:20% to 147_+25%, P < 0.01) as compared to the solvent. In the first set of experiments, only the 10 p.g/kg dose suppressed the autoregulatory vasodilation, but CBF was not different from control (84 5:17% versus 87 5:12%), probably because of the previous induced vasodilation. In the second set of experiments, active vasodilation occurred and the CBF during hypotension was not different from control (72+26% versus 65+11%). We conclude that under nimodipine the triggering of the active autoregulatory vasodilation is dependent on both the severity of hypotension and the previous nimodipine-induced vasodilation.
INTRODUCTION T h e a u t o r e g u l a t i o n o f c e r e b r a l b l o o d flow ( C B F ) , which e n s u r e s a c o n s t a n t b l o o d flow to t h e b r a i n d e spite c h a n g e s in p e r f u s i o n p r e s s u r e , results f r o m vasodilation when cerebral perfusion pressure decreases and vasoconstriction when cerebral perfusion pressure increases. T h e m e c h a n i s m s r e s p o n s i b l e for a u t o r e g u l a tion a r e still u n k n o w n , b u t m y o g e n i c , m e t a b o l i c , n e u r o genic a n d e n d o t h e l i u m - r e l a t e d t h e o r i e s have b e e n p r o posedl0,11,16. P h a r m a c o l o g i c a l a b o l i t i o n o f a u t o r e g u l a t i o n has b e e n a t t e m p t e d in vivo in o r d e r to investigate t h e mechanisms underlying the phenomenon. The calcium c h a n n e l a n t a g o n i s t o f t h e 1 , 4 - d i h y d r o p y r i d i n e class, n i m o d i p i n e , has b e e n u s e d in t h e p a s t a n d m o s t aut h o r s have c o n c l u d e d t h a t it a b o l i s h e d C B F a u t o r e g u lation 6'8'22'23. Since c a l c i u m a n t a g o n i s t s inhibit calcium e n t r y n e c e s s a r y for t h e c o n t r a c t i o n b u t n o t t h e relax-
a t i o n o f t h e v a s c u l a r s m o o t h m u s c l e cells 19, a u t o r e g u l a tory v a s o d i l a t i o n s h o u l d p e r s i s t w h e n p e r f u s i o n pressure d e c r e a s e s . T h e r e f o r e , t h e s u p p r e s s i o n of a u t o r e g u l a t i o n o b t a i n e d with c a l c i u m a n t a g o n i s t s d u r i n g a c u t e d e c r e a s e s in m e a n a r t e r i a l b l o o d p r e s s u r e ( M A B P ) is unexpected. A s n i m o d i p i n e is widely u s e d u n d e r p a t h o l o g i c a l c o n d i t i o n s in m a n to p r e v e n t a n d t r e a t t h e d e l a y e d v a s o s p a s m d u e to s u b a r a c h n o i d h e m o r r h a g e , m i g r a i n e a t t a c k s o r ischemic s t r o k e 13'17, it is i m p o r t a n t to d e t e r m i n e w h e t h e r this d r u g i m p a i r s the a u t o r e g u l a t i o n of C B F d u r i n g a c u t e h y p o t e n s i o n . In t h e p r e s e n t study, a u t o r e g u l a t i o n was t r i g g e r e d by r a p i d b l e e d i n g , a n d C B F was m e a s u r e d by l a s e r - D o p p l e r f l o w m e t r y ( L D F ) . M e a s u r e m e n t s o f c h a n g e s in C B F m a d e by L D F a r e well c o r r e l a t e d with m e a s u r e m e n t s m a d e by e s t a b lished t e c h n i q u e s 3'18. L D F also allows c o n t i n u o u s m o n itoring o f c h a n g e s in flow a n d is non-invasive. T h e C B F p r o b e is n o t i m p l a n t e d in t h e c e r e b r a l tissue, unlike
Correspondence: G. Florence, CERMA - Section de Physiologie Compar6e, BP 73, 91223 Br&igny sur Orge Cedex, France. Fax: (33) (1)
6084-0448.
302
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PlAL UNDER PL \
Fig. 1. Dorsal view of the rabbit head.
the probe for thermal clearance, the only other available continuous method. MATERIALS AND METHODS Experiments were carried out on 16 'Fauve de Bourgogne' male rabbits weighing 2.5-3.2 kg. Surgery was performed in two sessions, as described previously s. First operation: each rabbit was premedicated with acepromazine (Vetranquil, Clin Midy, 7.5 m g / k g i.v.) and anesthetized with sodium pentobarbital (Clin Midy, 30-40 m g / k g i.v.). Anesthesia was maintained by hourly injections of pentobarbital (2-3 m g / k g i.v.). A parietal trepanation was performed and a bone area (6 m m in diameter) was removed without damaging the dura-mater. The bone was replaced by a 3 m m thick plexiglas window secured with dental cement. The cement was spread over the whole exposed surface of the skull in order to anchor the window. A 10 m m long screw was glued onto the frontal bone, perpendicular to the window surface, and used during the second operation (see Fig. 1). The animal was then returned to its cage. Second operation: 7-13 days later a catheter was inserted in a marginal ear vein of the rabbit and used for i.v. injections. The rabbit was anesthetized with urethane (Sigma, 500 m g / k g i.v.) and chloralose (Sigma, 70 m g / k g i.v.) and placed in a supine position for tracheal cannulation. It was paralyzed with gallamine triethiodide (Flaxedil, May & Baker, 10 m g / k g i.v.) and mechanically ventilated with 70% N~ and 30% O 2. The right brachial artery was cannulated with a polyethylene catheter (Biotrol, internal diameter: 0.57 mm). This catheter was used for: (i) M A B P recording (Statham transducer); (ii) arterial blood sampling for measuring PaO2, PaCO2 and arterial pH (Corning 178). The respiratory p u m p (tidal volume and ventilation rate) was adjusted to maintain arterial partial pressures (PaO2, PaCO2,) and arterial pH within physiological ranges. Abdominal temperature was maintained at 38_+ 0.5°C throughout the experiment using a thermostatically controlled blanket and additional radiant heat. Additional gallamine (5 m g / k g i.v.), urethan (125 m g / k g i.v.) and chloralose (15 m g / k g i.v.) were given hourly to ensure paralysis and anesthesia. CBF was measured using a Laserflo monitor (BPM 403, Vasamedics Inc., St Paul, MN). A needle probe (P433-1) was placed on the external surface of the window and secured by a stereotaxic system fixed to the skull via the chronically implanted screw. Since
the laser-Doppler flowmetry readings represent the flow in the superficial cortex, in the dura-mater and the pial vasculature, care was taken not to place the laser-Doppler flowmetry probe above large pial vessels. The averaging time of the m e a s u r e m e n t was set at 0.5 s. The probe and window were protected from direct light. A teflon catheter (internal diameter: 1.6 mm, Biotrol) was placed in the abdominal aorta after a medial laparotomy. This second catheter was used to decrease M A B P by bleeding. Heparine was then given intravenously (Heparine Leo, Leo, 1,000 I U / k g ) and subsequently at hourly intervals (1,000 I U / k g ) to ensure patency of the two catheters. The aortic catheter was connected to a syringe so that the operator could maintain M A B P constant at 50 m m H g or 30 mmHg. The blood volume withdrawn to induce hypotension was 20 to 40 ml. Blood was returned to the animal at the end of the hypotension. The rabbit was allowed to rest for about one hour after surgery to stabilize the CBF and systemic variables. The preparation was checked by stimulating vasoreactivity by hypercapnia. All the animals underwent a control bleeding. Autoregulatory vasodilation was triggered in 10 rabbits by withdrawing blood to decrease M A B P from the control value to 50 mmHg. In seven of these rabbits i.v. injections of the vehicle and three doses of nimodipine (Nimotop, Bayer; 1 /~g/kg, 3 p~g/kg and 10 /xg/kg) were made. The maximum total volume given to one rabbit was 0.6 ml. The effects on autoregulation were assessed 3 min after the end of each injection. The sequence of injections in a given rabbit was randomized. Thirty minutes separated each injection. Three other rabbits were injected i.v. with 1 0 / z g / k g nimodipine and given a single i.v. injection of 2.5 m g / k g papaverine during the bleeding and after CBF had reached a steady-state. Six other rabbits were used to study the effect of 10 ~ g / k g nimodipine on the cerebrovascular adaptation when the M A B P was maintained at 30 m m H g for one minute. The total duration of the experiment did not exceed 4 hours. The rabbits were sacrificed by injecting barbiturates at the end of the experiment. The plexiglas window was removed and the underlying brain was examined under a lens and checked for the absence of lesions. Results are expressed as means+_ S.D. P < 0.05 was considered as statistically significant. The effects of the solvent and the doses of nimodipine were compared to the control by an analysis of variance and D u n n e t t ' s test a. The effects of 1 0 / z g / k g of nimodipine on CBF autoregulation while M A B P was maintained at 30 m m H g were studied by Student's paired t-test. The index of autoregulation was compared to zero by Student's t-test.
RESULTS
As laser-Doppler accurately measures changes in CBF rather than CBF 3, all changes in CBF are expressed as percentages of CBFo, which is the mean CBF at the beginning of the experiment, before the first bleeding and before the first injection. Mean values of the physiological variables (16 rabbits) before injections, were: MABP = 96 _+ 11 mmHg; p H = 7.40 + 0.03; P a O 2 = 112.0 _+ 14.4 m m H g and PaCO2 = 32.5 + 4.2 mmHg. CBF followed the steep decrease in MABP, during the first seconds of rapid bleeding, decreasing from its control value (CBFo) to a minimal value (CBFmin). CBF then increased and tended towards a plateau (CBFp) at the end of the one-minute period of hypotension. The difference between CBFp and CBFmin was calculated (ACBF) for each animal and was used
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Fig. 2. Time-courses of CBF and M A B P after single bolus injections (t = 0 min) of solvent (A) and nimodipine (1 Ixg/kg (B); 3 Ixg/kg (C); 10 / z g / k g (D). Values are m e a n s + S . D . Only one S.D. bar is shown to avoid overlap and clutter. Numbers in brackets indicate the number of rabbits. Significantly different from the mean value measured before injection (t = 0 min): * P < 0.05; * * P < 0.01.
as an index of the active autoregulatory vasodilation. CBF markedly increased when blood was restored and it subsequently tended towards the control level. When MABP was maintained at 50 mmHg for one minute during the control test, CBF decreased to a minimum of 47 + 6% of CBFo and then increased to a plateau of 87 + 12% of CBFo. ACBF (40 + 12% of CBFo) was statistically different from zero ( P < 0 . 0 0 1 ) . When MABP was lowered to 30 mmHg before nimodipine administration, the minimal flow was: 34 + 9% of CBFo and the flow at the end of the hypotensive period was: 6 5 + 1 1 % of CBFo. ACBF ( 3 2 + 8 % of CBFo) was statistically different from zero (P < 0.001). Three minutes after injection of the solvent and the 3 / ~ g / k g and 1 0 / z g / k g doses of nimodipine, CBF was statistically greater than CBF just before injection (see
Fig. 2). However, only the highest dose of nimodipine significantly increased CBF (from 104 + 20% to 147 + 25%, P < 0.01) when compared to the solvent. This dose also induced a statistically significant decrease in MABP (from 96 + 11 mmHg to 81 + 11 mmHg, P < 0.01) when compared to MABP just before injection. Regardless of the material injected, CBF and MABP thirty minutes after injection were not statistically different from CBF and MABP before injection. The effects of injections on the autoregulatory vasodilation when MABP was maintained at 50 mmHg are summarized in Table I and Fig. 3. The solvent and the lowest two doses of the calcium antagonist did not affect the time-course of the vascular events when compared to control. The 10 /~g/kg dose prevented any active increase in CBF during hypotension; how-
TABLE I Effects of single bolus injections of solvent and nimodipine (1, 3 and 10 txg / kg) on autoregulation when MABP was maintained at 50 mmHg for one minute CBFo is the mean CBF at the beginning of the experiment, before the first bleeding and before the first injection. Values are m e a n + S . D . Numbers in brackets present the number of rabbits.
Treatment Control Solvent Nimodipine (1 Ixg/kg) Nimodipine (3 Ixg/kg) Nimodipine (10 Ixg/kg)
CBFmin
CBFp
(% CBFo)
(% CBFo)
ACBF (% CBFo)
47+ 6 (10) 5 0 5 : 8 (7) 465:15 (5) 5 4 5 : 9 (6) 855:25 (10) **##
87+ 12 (10) 99+13 (6) 905:21 (7) 875:10 (7) 84+ 17 (9)
405:12 495:13 445:18 335:12 -45:19
Significantly different from the control: ** P < 0.01. Significantly different from the solvent: ## P < 0.01.
(10) (6) (5) (6) (9) ** ##
304 ---
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MABP
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Fig. 3. Schematic CBF changes occurring when M A B P was lowered to 50 m m H g for one minute, before and after injection of 10 p . g / k g nimodipine. CBFo = mean CBF at the beginning of the experiment, before the first bleeding and before the first injection; CBFmin = CBF minimal value during the first seconds of bleeding; CBFp = CBF at the end of the one-minute hypotension.
ever ACBF was not statistically different from zero. The flow changes paralleled the MABP changes. The minimal flow was not statistically different from CBFo. Interestingly, the flow at the end of the hypotension was not different from the control. Papaverine injected during the 50 mmHg period increased the plateau of flow in all three rabbits; from 70% of CBFo to 158% of CBFo in rabbit 1, from 116% of CBFo to 335% of CBFo in rabbit 2 and from 99% of CBFo to 255% of CBFo in rabbit 3. The effects of 10 ~ g / k g nimodipine on autoregulation when MABP was decreased to 30 mmHg are described in Table II and Fig. 4. The CBFmin after injection was 50 _+ 15% of CBFo which was significantly smaller than CBFo ( P < 0.001). Autoregulatory vasodilation occurred and ACBF was statistically different from zero ( P < 0.05). The flow reached at the end of the hypotension was not different from control. Examination of the brain after sacrifice animals showed no inflammation or infection of the underlying cortex.
Fig. 4. Schematic CBF changes occuring when M A B P was lowered to 30 m m H g for one minute, before and after injection of 10 / x g / k g nimodipine. Same abbreviations as in Fig. 3.
DISCUSSION
The main finding of this study is that CBF was still regulated after nimodipine injection in the rabbit. The discussion examines three points: (i) the protocol that was used, (ii) the effects of the solvent and nimodipine per se on MABP and CBF prior to hypotension, (iii) the results on CBF autoregulation. Care was taken to measure CBF under close-to-normal conditions, since no probe was implanted in the cerebral tissue itself. CBF was measured with the skull closed, giving a preparation closer to the normal situation than when the LDF probe is placed directly on the dura. MABP was decreased by bleeding to produce rapid, controlled and reversible hypotension. Drugs were not used to induce hypotension because they can have direct effects on cerebral vessels 2°. The lower limit of autoregulation was found to be 40 mmHg in a previous study using the same preparation 5. In the present study, CBF was measured while MABP was maintained at two values: 50 mmHg and 30 mmHg. Single injections of nimodipine were used rather than continuous infusions because this type of delivery al-
T A B L E II
Effects of a single bolus injection of nimodipine (10 ~ g / kg) on autoregulation when MABP was maintained at 30 mmHg for one minute CBFo is the mean CBF at the beginning of the experiment, before the first bleeding and before the first injection. Values are m e a n + S . D . N u m b e r s in brackets present the n u m b e r of rabbits.
Treatment
CBFmin (% CBFo)
CBFp (% CBFo)
ACBF (% CBFo)
Control Nimodipine ( 1 0 / ~ g / k g )
34 + 9 (6) 50 + 15 (6) * *
65 + 11 (6) 72 5:26 (6)
32 + 8 (6) 22 + 14 (6)
Significantly different from the control: ** P < 0.01.
305 lowed us to check the reversibility of the effects, since the tl/2 of nimodipine is approximately 10 min 8'13. This choice also allowed us to study several doses in the same animal. The solvent, which contained ethanol and propylene glycol, increased CBF without affecting MABP. A previous study 2 showed that topical application of the ethanol-containing vehicle induced an 8% increase in the diameter of the pial arteries whereas MABP remained unchanged. This result corresponds to a theoretical increase in CBF greater than the increase seen in our study. This difference may be due to the administration route. Previous in vivo experiments showed that intravenous nimodipine produces a dose-dependent reduction in MABP, dilation of the pial arteries 2m'12 and an increase in C B F 1'12'7'9. Single i.v. doses of nimodipine have been used previously. 1 / z g / kg produced a maximal increase in pial vessel diameter of 5.6% and a decrease of 17.3 mmHg in MABP in cats 2. A dose of 10/~g/kg induced a 44.1 mmHg drop in MABP and a 14.3% increase in the diameter of pial vessels. In a second study on dogs ~, it was found that 1 ~ g / k g nimodipine lowered MABP ( - 8 % ) and increased CBF (+ 19%) and 10/zg/kg accentuated these effects: - 2 4 % in MABP and + 50% in CBF. In a third study, in baboons 12, 3 and 10 /zg/kg nimodipine decreased MABP but did not change CBF. However, flow increased markedly when the drug was infused into the carotid artery following disruption of the blood-brain barrier. Our results are close to those obtained in the first and second studies, and the differences may be due to the animal species used. The absence of effects of intravenous nimodipine in the baboon may be due to poor passage of nimodipine across the blood-brain barrier of non-human primates. The influence of nimodipine on CBF autoregulation when MABP is decreased has been studied previously in the rat, in the baboon and in the cat, but the results have been contradictory (see Table III). We used rab-
bits because this species tolerates repeated bleeding better than rats. Globally, the previous studies suggest that nimodipine impairs autoregulation, but CBF was always measured by discontinuous methods. The present work using laser-Doppler flowmetry allowed us to follow rapid changes in flow. We were therefore able to calculate the difference between the flow at the end of the one-minute hypotension and the minimal flow reached in the early phase of hypotension. Since CBF passively follows changes in MABP during the initial fall in pressure, and since autoregulatory mechanisms persist for at lest one minute of hypotension5, the difference between the flow at the end of hypotension and the minimal flow is a better criterion of the autoregulatory capacity than the steady-state flow reached at the end of a one-minute hypotension. The absence of active vasodilation at 50 mmHg following 10/xg/kg i.v. nimodipine was not correlated with a maximal dilatory state of the cerebral vessels, since papaverine was still able to increase CBF. The triggering of the active vasodilation seems to depend on the minimal flow reached during the first seconds of bleeding. The closer the minimal flow is to the initial reference flow CBFo, measured before bleeding and nimodipine injection, the smaller the dilatory response. The minimal flow after at 50 mmHg following 1 0 / z g / k g i.v. was not different from the reference flow because of the nimodipine-induced vasodilation, and active vasodilation did not occur. Active regulation was observed when the MABP was more reduced, down to 30 mmHg, in which case the minimal flow was lower than the reference flow. Thus, CBF was still regulated after 10 /xg/kg nimodipine and the apparent passiveness of the CBF changes during hypotension seems not to be due to a specific effect of nimodipine, such as the blockade of the voltage-sensitive calcium channels 15. In conclusion, the present investigation shows that nimodipine does not abolish CBF autoregulatory capacity. Normoperfusion is preserved either by the ni-
TABLE III
Previous studies done on the effects of nimodipine on CBF autoregulation References
Species
CBF after nimodipine and prior to changes in MABP
MABP tested (mmHg)
Results on autoregulation
8 22
baboon rat
unchanged above control
25-125 ?
rat
above control
70-120
14
baboon
modestincrease
84
23
cat
unchanged
75
impaired: pressure-flow curve linear poorly maintained: normoperfusion preserved during hypotension impaired: no plateau of flow but normoperfusion preserved preserved: cerebrovascular resistance similar to control impaired: CBF reduced after nimodipine and during hypotension
6
306 modipine-induced vasodilation prior to bleeding or by an active dilation during pronounced hypotension.The results suggest, therefore, that nimodipine-treated patients may safely undergo controlled hypotensions of limited severity. Acknowledgements. The authors thank Mme. Taillardat (Bayer Pharma) and M. Eric Priol for their technical assistance. This work was supported by CNRS, Universit6 Paris VII and a grant from the D61~gation G6n~rale pour I'Armement (Direction des Recherches et Etudes, contrat n ° 91/1011J). REFERENCES 1 Auer, L.M., Pial arterial vasodilation by intravenous nimodipine in cats, Drug Res., 31 (1981) 1423-1425. 2 Auer, L.M. and Mockry, M., Effect of topical nimodipine versus its ethanol-containing vehicle on cat pial arteries, Stroke, 17 (1986) 225-228. 3 Dirnagl, U., Kaplan, B., Jacewicz, M. and Pulsinelli, W., Continuous measurement of cerebral cortical blood flow by laser-Doppler flowmetry in a rat stroke model, J. Cereb. Blood Flow Metab., 9 (1989) 589-596. 4 Dunnett, C.W., New tables for multiple comparisons with a control, Biometrics, 20 (1964) 482-491. 5 Florence, G. and Seylaz, J., Rapid autoregulation of cerebral blood flow: a laser-Doppler flowmetry study, J. Cereb. Blood Flow Metab., 12 (1992) 674-680. 6 Gaab, M.R., Hollerhage, H.G., Zumkeller, M. and Trost, H.A., The effect of the Ca-antagonist nimodipine on cerebral blood flow autoregulation, J. Cereb. Blood Flow Metab., 7 (1987) S170. 7 Harper, A.M., Craigen, L. and Kazda, S., Effect of the calcium antagonist, nimodipine, on cerebral blood flow and metabolism in the primate, J. Cereb. Blood Flow Metab., 1 (1981) 349-356. 8 Harris, R.J., Branston, N.M., Symon, L., Bayhan, M. and Watson, A., The effects of a calcium antagonist, nimodipine, upon physiological responses of the cerebral vasculature and its possible influence upon focal cerebral ischemia, Stroke, 13 (1982) 759-766. 9 Haws, C.W., Gourley, J.K. and Heistad, D.D., Effects of nimodipine on cerebral blood flow, J. Pharmacol. Exp. Ther., 225 (1983) 24-28.
10 Heistad, D.D. and Kontos, H.A., Cerebral circulation. In J.T. Shephard and F.N. Abboud (Eds.), Handbook of Physiology. The Cardiovascular System, Vol. 3, American Physiological Society Publishers, Bethesda, 1983, pp. 137-182. 11 Johnson, P.C., Autoregulation of blood flow, Circ. Res., 59 (1986) 483 -495. 12 Kazda, S., Garthoff, B., Krause, H.P. and Schlossmann, K., Cerebrovascular effects of the calcium antagonistic dihydropyridine derivative nimodipine in animal experiments, Drug Res., 32 (1982) 331-338. 13 Langley, M.S. and Sorkin, E.M., Nimodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cerebrovascular disease, Drugs, 37 (1989) 669-699. 14 McCalden, T.A. and Nath, R.G., Cerebrovascular autoregulation is resistant to calcium channel blockade with nimodipine, Experentia, 45 (1989) 305-306. 15 Nowycky, M.C., Fox, A.P. and Tsien, R.W., Three types of neuronal calcium channel with different calcium agonist sensitivity, Nature, 316 (1985) 440-443. 16 Paulson, O.B., Strandgaard, S. and Edvinsson, L., Cerebral autoregulation, Cerebrovasc. Brain Metab. Rev. , 2 (1990) 161-192. 17 Scriabine, A., Schurman, T. and Traber, J., Pharmacological basis for the use of nimodipine in central nervous system disorders, FASEB J., 3 (1989) 1799-1806. 18 Skarphedinsson, J.O., Harding, H. and Thoren P., Repeated measurements of cerebral blood flow in rats. Comparisons between the hydrogen clearance method and laser Doppler flowmetry, Acta Physiol. Scand., 134 (1988) 133-142. 19 Spedding, M., Calcium antagonist subgroups, Trends Pharmacol. Sci., 6 (1985) 109-114. 20 Strandgaard, S. and Paulson, O.B., Cerebral autoregulation, Stroke, 15 (1984) 413-416. 21 Tanaka, K., Gotoh, F., Muramatsu, F., Fukuuchi, Y., Amano, T., Okayasu, H. and Suzuki, N., Effects of nimodipine (Bay e 9736) on cerebral circulation in cats, Drug Res., 30 (1980) 1,494-1,497. 22 Van den Kerckhoff, W. and Kazda, S., The autoregulation of cerebral blood flow is influenced by calcium antagonists, J. Cereb. Blood Flow Metab., 7 (1987) S169. 23 Von Kummer, R., Vogt, M., Stingele, R. and Back, T., Effect of nimodipine on local cerebral blood flow and autoregulatory capacity in non ischemic cats, J. Cereb. Blood Flow Metab., 11 (1991) $276.
301
© 1993 Elsevier Science Publishers B.V. All rights reserved 0006-8993/93/$06.00 BRES 19316
Effect of nimodipine on the autoregulation of cerebral blood flow studied by laser-Doppler flowmetry Genevieve
Florence
a, G i l l e s B o n v e n t o
b, P a s c a l
and Jacques
Seylaz
Roucher
b Robert
Charbonne
b
b
a Centre d'Etudes et de Recherches de M~decine A~rospatiale, Section de Physiologie Compar~e, Br~tigny sur Orge (France) and b Laboratoire de Recherches C~r~brovasculaires, CNRS, UA 641, Universit~ Paris VII, Facult~ de M[decine Villemin, Paris (France)
(Accepted 26 May 1993)
Key words: Cerebral blood flow; Autoregulation; Laser Doppler flowmetry; Calcium antagonist; Rabbit
The present work examines whether nimodipine impairs autoregulation of CBF during hypotension. The CBF of 16 anesthetized rabbits was measured with a laser-Doppler flowmetry probe placed on the external surface of a plexiglas window, chronically inserted in the skull. Autoregulation was triggered by aortic bleeding. First, the effects of three doses of nimodipine (1, 3 and 10/xg/kg) and the solvent were studied in 10 rabbits in which MABP was maintained at 50 mmHg for one minute. Second, 10 ~g/kg i.v. nimodipine was administered to 6 rabbits in which MABP was kept at 30 mmHg for one minute. Before bleeding, the 10/~g/kg dose significantly decreased MABP (from 96d: 11 mmHg to 81 + 11 mmHg, P < 0.01) and increased CBF (from 1045:20% to 147_+25%, P < 0.01) as compared to the solvent. In the first set of experiments, only the 10 p.g/kg dose suppressed the autoregulatory vasodilation, but CBF was not different from control (84 5:17% versus 87 5:12%), probably because of the previous induced vasodilation. In the second set of experiments, active vasodilation occurred and the CBF during hypotension was not different from control (72+26% versus 65+11%). We conclude that under nimodipine the triggering of the active autoregulatory vasodilation is dependent on both the severity of hypotension and the previous nimodipine-induced vasodilation.
INTRODUCTION T h e a u t o r e g u l a t i o n o f c e r e b r a l b l o o d flow ( C B F ) , which e n s u r e s a c o n s t a n t b l o o d flow to t h e b r a i n d e spite c h a n g e s in p e r f u s i o n p r e s s u r e , results f r o m vasodilation when cerebral perfusion pressure decreases and vasoconstriction when cerebral perfusion pressure increases. T h e m e c h a n i s m s r e s p o n s i b l e for a u t o r e g u l a tion a r e still u n k n o w n , b u t m y o g e n i c , m e t a b o l i c , n e u r o genic a n d e n d o t h e l i u m - r e l a t e d t h e o r i e s have b e e n p r o posedl0,11,16. P h a r m a c o l o g i c a l a b o l i t i o n o f a u t o r e g u l a t i o n has b e e n a t t e m p t e d in vivo in o r d e r to investigate t h e mechanisms underlying the phenomenon. The calcium c h a n n e l a n t a g o n i s t o f t h e 1 , 4 - d i h y d r o p y r i d i n e class, n i m o d i p i n e , has b e e n u s e d in t h e p a s t a n d m o s t aut h o r s have c o n c l u d e d t h a t it a b o l i s h e d C B F a u t o r e g u lation 6'8'22'23. Since c a l c i u m a n t a g o n i s t s inhibit calcium e n t r y n e c e s s a r y for t h e c o n t r a c t i o n b u t n o t t h e relax-
a t i o n o f t h e v a s c u l a r s m o o t h m u s c l e cells 19, a u t o r e g u l a tory v a s o d i l a t i o n s h o u l d p e r s i s t w h e n p e r f u s i o n pressure d e c r e a s e s . T h e r e f o r e , t h e s u p p r e s s i o n of a u t o r e g u l a t i o n o b t a i n e d with c a l c i u m a n t a g o n i s t s d u r i n g a c u t e d e c r e a s e s in m e a n a r t e r i a l b l o o d p r e s s u r e ( M A B P ) is unexpected. A s n i m o d i p i n e is widely u s e d u n d e r p a t h o l o g i c a l c o n d i t i o n s in m a n to p r e v e n t a n d t r e a t t h e d e l a y e d v a s o s p a s m d u e to s u b a r a c h n o i d h e m o r r h a g e , m i g r a i n e a t t a c k s o r ischemic s t r o k e 13'17, it is i m p o r t a n t to d e t e r m i n e w h e t h e r this d r u g i m p a i r s the a u t o r e g u l a t i o n of C B F d u r i n g a c u t e h y p o t e n s i o n . In t h e p r e s e n t study, a u t o r e g u l a t i o n was t r i g g e r e d by r a p i d b l e e d i n g , a n d C B F was m e a s u r e d by l a s e r - D o p p l e r f l o w m e t r y ( L D F ) . M e a s u r e m e n t s o f c h a n g e s in C B F m a d e by L D F a r e well c o r r e l a t e d with m e a s u r e m e n t s m a d e by e s t a b lished t e c h n i q u e s 3'18. L D F also allows c o n t i n u o u s m o n itoring o f c h a n g e s in flow a n d is non-invasive. T h e C B F p r o b e is n o t i m p l a n t e d in t h e c e r e b r a l tissue, unlike
Correspondence: G. Florence, CERMA - Section de Physiologie Compar6e, BP 73, 91223 Br&igny sur Orge Cedex, France. Fax: (33) (1)
6084-0448.
302
LUED ONTO THE RONTAL BONE
PlAL UNDER PL \
Fig. 1. Dorsal view of the rabbit head.
the probe for thermal clearance, the only other available continuous method. MATERIALS AND METHODS Experiments were carried out on 16 'Fauve de Bourgogne' male rabbits weighing 2.5-3.2 kg. Surgery was performed in two sessions, as described previously s. First operation: each rabbit was premedicated with acepromazine (Vetranquil, Clin Midy, 7.5 m g / k g i.v.) and anesthetized with sodium pentobarbital (Clin Midy, 30-40 m g / k g i.v.). Anesthesia was maintained by hourly injections of pentobarbital (2-3 m g / k g i.v.). A parietal trepanation was performed and a bone area (6 m m in diameter) was removed without damaging the dura-mater. The bone was replaced by a 3 m m thick plexiglas window secured with dental cement. The cement was spread over the whole exposed surface of the skull in order to anchor the window. A 10 m m long screw was glued onto the frontal bone, perpendicular to the window surface, and used during the second operation (see Fig. 1). The animal was then returned to its cage. Second operation: 7-13 days later a catheter was inserted in a marginal ear vein of the rabbit and used for i.v. injections. The rabbit was anesthetized with urethane (Sigma, 500 m g / k g i.v.) and chloralose (Sigma, 70 m g / k g i.v.) and placed in a supine position for tracheal cannulation. It was paralyzed with gallamine triethiodide (Flaxedil, May & Baker, 10 m g / k g i.v.) and mechanically ventilated with 70% N~ and 30% O 2. The right brachial artery was cannulated with a polyethylene catheter (Biotrol, internal diameter: 0.57 mm). This catheter was used for: (i) M A B P recording (Statham transducer); (ii) arterial blood sampling for measuring PaO2, PaCO2 and arterial pH (Corning 178). The respiratory p u m p (tidal volume and ventilation rate) was adjusted to maintain arterial partial pressures (PaO2, PaCO2,) and arterial pH within physiological ranges. Abdominal temperature was maintained at 38_+ 0.5°C throughout the experiment using a thermostatically controlled blanket and additional radiant heat. Additional gallamine (5 m g / k g i.v.), urethan (125 m g / k g i.v.) and chloralose (15 m g / k g i.v.) were given hourly to ensure paralysis and anesthesia. CBF was measured using a Laserflo monitor (BPM 403, Vasamedics Inc., St Paul, MN). A needle probe (P433-1) was placed on the external surface of the window and secured by a stereotaxic system fixed to the skull via the chronically implanted screw. Since
the laser-Doppler flowmetry readings represent the flow in the superficial cortex, in the dura-mater and the pial vasculature, care was taken not to place the laser-Doppler flowmetry probe above large pial vessels. The averaging time of the m e a s u r e m e n t was set at 0.5 s. The probe and window were protected from direct light. A teflon catheter (internal diameter: 1.6 mm, Biotrol) was placed in the abdominal aorta after a medial laparotomy. This second catheter was used to decrease M A B P by bleeding. Heparine was then given intravenously (Heparine Leo, Leo, 1,000 I U / k g ) and subsequently at hourly intervals (1,000 I U / k g ) to ensure patency of the two catheters. The aortic catheter was connected to a syringe so that the operator could maintain M A B P constant at 50 m m H g or 30 mmHg. The blood volume withdrawn to induce hypotension was 20 to 40 ml. Blood was returned to the animal at the end of the hypotension. The rabbit was allowed to rest for about one hour after surgery to stabilize the CBF and systemic variables. The preparation was checked by stimulating vasoreactivity by hypercapnia. All the animals underwent a control bleeding. Autoregulatory vasodilation was triggered in 10 rabbits by withdrawing blood to decrease M A B P from the control value to 50 mmHg. In seven of these rabbits i.v. injections of the vehicle and three doses of nimodipine (Nimotop, Bayer; 1 /~g/kg, 3 p~g/kg and 10 /xg/kg) were made. The maximum total volume given to one rabbit was 0.6 ml. The effects on autoregulation were assessed 3 min after the end of each injection. The sequence of injections in a given rabbit was randomized. Thirty minutes separated each injection. Three other rabbits were injected i.v. with 1 0 / z g / k g nimodipine and given a single i.v. injection of 2.5 m g / k g papaverine during the bleeding and after CBF had reached a steady-state. Six other rabbits were used to study the effect of 10 ~ g / k g nimodipine on the cerebrovascular adaptation when the M A B P was maintained at 30 m m H g for one minute. The total duration of the experiment did not exceed 4 hours. The rabbits were sacrificed by injecting barbiturates at the end of the experiment. The plexiglas window was removed and the underlying brain was examined under a lens and checked for the absence of lesions. Results are expressed as means+_ S.D. P < 0.05 was considered as statistically significant. The effects of the solvent and the doses of nimodipine were compared to the control by an analysis of variance and D u n n e t t ' s test a. The effects of 1 0 / z g / k g of nimodipine on CBF autoregulation while M A B P was maintained at 30 m m H g were studied by Student's paired t-test. The index of autoregulation was compared to zero by Student's t-test.
RESULTS
As laser-Doppler accurately measures changes in CBF rather than CBF 3, all changes in CBF are expressed as percentages of CBFo, which is the mean CBF at the beginning of the experiment, before the first bleeding and before the first injection. Mean values of the physiological variables (16 rabbits) before injections, were: MABP = 96 _+ 11 mmHg; p H = 7.40 + 0.03; P a O 2 = 112.0 _+ 14.4 m m H g and PaCO2 = 32.5 + 4.2 mmHg. CBF followed the steep decrease in MABP, during the first seconds of rapid bleeding, decreasing from its control value (CBFo) to a minimal value (CBFmin). CBF then increased and tended towards a plateau (CBFp) at the end of the one-minute period of hypotension. The difference between CBFp and CBFmin was calculated (ACBF) for each animal and was used
303 200
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< T
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o
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< T
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<
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20 30 (mln)
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,
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Time
Fig. 2. Time-courses of CBF and M A B P after single bolus injections (t = 0 min) of solvent (A) and nimodipine (1 Ixg/kg (B); 3 Ixg/kg (C); 10 / z g / k g (D). Values are m e a n s + S . D . Only one S.D. bar is shown to avoid overlap and clutter. Numbers in brackets indicate the number of rabbits. Significantly different from the mean value measured before injection (t = 0 min): * P < 0.05; * * P < 0.01.
as an index of the active autoregulatory vasodilation. CBF markedly increased when blood was restored and it subsequently tended towards the control level. When MABP was maintained at 50 mmHg for one minute during the control test, CBF decreased to a minimum of 47 + 6% of CBFo and then increased to a plateau of 87 + 12% of CBFo. ACBF (40 + 12% of CBFo) was statistically different from zero ( P < 0 . 0 0 1 ) . When MABP was lowered to 30 mmHg before nimodipine administration, the minimal flow was: 34 + 9% of CBFo and the flow at the end of the hypotensive period was: 6 5 + 1 1 % of CBFo. ACBF ( 3 2 + 8 % of CBFo) was statistically different from zero (P < 0.001). Three minutes after injection of the solvent and the 3 / ~ g / k g and 1 0 / z g / k g doses of nimodipine, CBF was statistically greater than CBF just before injection (see
Fig. 2). However, only the highest dose of nimodipine significantly increased CBF (from 104 + 20% to 147 + 25%, P < 0.01) when compared to the solvent. This dose also induced a statistically significant decrease in MABP (from 96 + 11 mmHg to 81 + 11 mmHg, P < 0.01) when compared to MABP just before injection. Regardless of the material injected, CBF and MABP thirty minutes after injection were not statistically different from CBF and MABP before injection. The effects of injections on the autoregulatory vasodilation when MABP was maintained at 50 mmHg are summarized in Table I and Fig. 3. The solvent and the lowest two doses of the calcium antagonist did not affect the time-course of the vascular events when compared to control. The 10 /~g/kg dose prevented any active increase in CBF during hypotension; how-
TABLE I Effects of single bolus injections of solvent and nimodipine (1, 3 and 10 txg / kg) on autoregulation when MABP was maintained at 50 mmHg for one minute CBFo is the mean CBF at the beginning of the experiment, before the first bleeding and before the first injection. Values are m e a n + S . D . Numbers in brackets present the number of rabbits.
Treatment Control Solvent Nimodipine (1 Ixg/kg) Nimodipine (3 Ixg/kg) Nimodipine (10 Ixg/kg)
CBFmin
CBFp
(% CBFo)
(% CBFo)
ACBF (% CBFo)
47+ 6 (10) 5 0 5 : 8 (7) 465:15 (5) 5 4 5 : 9 (6) 855:25 (10) **##
87+ 12 (10) 99+13 (6) 905:21 (7) 875:10 (7) 84+ 17 (9)
405:12 495:13 445:18 335:12 -45:19
Significantly different from the control: ** P < 0.01. Significantly different from the solvent: ## P < 0.01.
(10) (6) (5) (6) (9) ** ##
304 ---
Before n l m o d l p l n e I n J e c t i o n - A f t e r I 0 lag/kg nlmodlplne I n j e c t i o n
-Before nlmodlplne Injection - - - A f t e r I 0 t~g/kg nlmodlplne I n j e c t i o n
MABP
MABP
t
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'-200 • of CBfo
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Fig. 3. Schematic CBF changes occurring when M A B P was lowered to 50 m m H g for one minute, before and after injection of 10 p . g / k g nimodipine. CBFo = mean CBF at the beginning of the experiment, before the first bleeding and before the first injection; CBFmin = CBF minimal value during the first seconds of bleeding; CBFp = CBF at the end of the one-minute hypotension.
ever ACBF was not statistically different from zero. The flow changes paralleled the MABP changes. The minimal flow was not statistically different from CBFo. Interestingly, the flow at the end of the hypotension was not different from the control. Papaverine injected during the 50 mmHg period increased the plateau of flow in all three rabbits; from 70% of CBFo to 158% of CBFo in rabbit 1, from 116% of CBFo to 335% of CBFo in rabbit 2 and from 99% of CBFo to 255% of CBFo in rabbit 3. The effects of 10 ~ g / k g nimodipine on autoregulation when MABP was decreased to 30 mmHg are described in Table II and Fig. 4. The CBFmin after injection was 50 _+ 15% of CBFo which was significantly smaller than CBFo ( P < 0.001). Autoregulatory vasodilation occurred and ACBF was statistically different from zero ( P < 0.05). The flow reached at the end of the hypotension was not different from control. Examination of the brain after sacrifice animals showed no inflammation or infection of the underlying cortex.
Fig. 4. Schematic CBF changes occuring when M A B P was lowered to 30 m m H g for one minute, before and after injection of 10 / x g / k g nimodipine. Same abbreviations as in Fig. 3.
DISCUSSION
The main finding of this study is that CBF was still regulated after nimodipine injection in the rabbit. The discussion examines three points: (i) the protocol that was used, (ii) the effects of the solvent and nimodipine per se on MABP and CBF prior to hypotension, (iii) the results on CBF autoregulation. Care was taken to measure CBF under close-to-normal conditions, since no probe was implanted in the cerebral tissue itself. CBF was measured with the skull closed, giving a preparation closer to the normal situation than when the LDF probe is placed directly on the dura. MABP was decreased by bleeding to produce rapid, controlled and reversible hypotension. Drugs were not used to induce hypotension because they can have direct effects on cerebral vessels 2°. The lower limit of autoregulation was found to be 40 mmHg in a previous study using the same preparation 5. In the present study, CBF was measured while MABP was maintained at two values: 50 mmHg and 30 mmHg. Single injections of nimodipine were used rather than continuous infusions because this type of delivery al-
T A B L E II
Effects of a single bolus injection of nimodipine (10 ~ g / kg) on autoregulation when MABP was maintained at 30 mmHg for one minute CBFo is the mean CBF at the beginning of the experiment, before the first bleeding and before the first injection. Values are m e a n + S . D . N u m b e r s in brackets present the n u m b e r of rabbits.
Treatment
CBFmin (% CBFo)
CBFp (% CBFo)
ACBF (% CBFo)
Control Nimodipine ( 1 0 / ~ g / k g )
34 + 9 (6) 50 + 15 (6) * *
65 + 11 (6) 72 5:26 (6)
32 + 8 (6) 22 + 14 (6)
Significantly different from the control: ** P < 0.01.
305 lowed us to check the reversibility of the effects, since the tl/2 of nimodipine is approximately 10 min 8'13. This choice also allowed us to study several doses in the same animal. The solvent, which contained ethanol and propylene glycol, increased CBF without affecting MABP. A previous study 2 showed that topical application of the ethanol-containing vehicle induced an 8% increase in the diameter of the pial arteries whereas MABP remained unchanged. This result corresponds to a theoretical increase in CBF greater than the increase seen in our study. This difference may be due to the administration route. Previous in vivo experiments showed that intravenous nimodipine produces a dose-dependent reduction in MABP, dilation of the pial arteries 2m'12 and an increase in C B F 1'12'7'9. Single i.v. doses of nimodipine have been used previously. 1 / z g / kg produced a maximal increase in pial vessel diameter of 5.6% and a decrease of 17.3 mmHg in MABP in cats 2. A dose of 10/~g/kg induced a 44.1 mmHg drop in MABP and a 14.3% increase in the diameter of pial vessels. In a second study on dogs ~, it was found that 1 ~ g / k g nimodipine lowered MABP ( - 8 % ) and increased CBF (+ 19%) and 10/zg/kg accentuated these effects: - 2 4 % in MABP and + 50% in CBF. In a third study, in baboons 12, 3 and 10 /zg/kg nimodipine decreased MABP but did not change CBF. However, flow increased markedly when the drug was infused into the carotid artery following disruption of the blood-brain barrier. Our results are close to those obtained in the first and second studies, and the differences may be due to the animal species used. The absence of effects of intravenous nimodipine in the baboon may be due to poor passage of nimodipine across the blood-brain barrier of non-human primates. The influence of nimodipine on CBF autoregulation when MABP is decreased has been studied previously in the rat, in the baboon and in the cat, but the results have been contradictory (see Table III). We used rab-
bits because this species tolerates repeated bleeding better than rats. Globally, the previous studies suggest that nimodipine impairs autoregulation, but CBF was always measured by discontinuous methods. The present work using laser-Doppler flowmetry allowed us to follow rapid changes in flow. We were therefore able to calculate the difference between the flow at the end of the one-minute hypotension and the minimal flow reached in the early phase of hypotension. Since CBF passively follows changes in MABP during the initial fall in pressure, and since autoregulatory mechanisms persist for at lest one minute of hypotension5, the difference between the flow at the end of hypotension and the minimal flow is a better criterion of the autoregulatory capacity than the steady-state flow reached at the end of a one-minute hypotension. The absence of active vasodilation at 50 mmHg following 10/xg/kg i.v. nimodipine was not correlated with a maximal dilatory state of the cerebral vessels, since papaverine was still able to increase CBF. The triggering of the active vasodilation seems to depend on the minimal flow reached during the first seconds of bleeding. The closer the minimal flow is to the initial reference flow CBFo, measured before bleeding and nimodipine injection, the smaller the dilatory response. The minimal flow after at 50 mmHg following 1 0 / z g / k g i.v. was not different from the reference flow because of the nimodipine-induced vasodilation, and active vasodilation did not occur. Active regulation was observed when the MABP was more reduced, down to 30 mmHg, in which case the minimal flow was lower than the reference flow. Thus, CBF was still regulated after 10 /xg/kg nimodipine and the apparent passiveness of the CBF changes during hypotension seems not to be due to a specific effect of nimodipine, such as the blockade of the voltage-sensitive calcium channels 15. In conclusion, the present investigation shows that nimodipine does not abolish CBF autoregulatory capacity. Normoperfusion is preserved either by the ni-
TABLE III
Previous studies done on the effects of nimodipine on CBF autoregulation References
Species
CBF after nimodipine and prior to changes in MABP
MABP tested (mmHg)
Results on autoregulation
8 22
baboon rat
unchanged above control
25-125 ?
rat
above control
70-120
14
baboon
modestincrease
84
23
cat
unchanged
75
impaired: pressure-flow curve linear poorly maintained: normoperfusion preserved during hypotension impaired: no plateau of flow but normoperfusion preserved preserved: cerebrovascular resistance similar to control impaired: CBF reduced after nimodipine and during hypotension
6
306 modipine-induced vasodilation prior to bleeding or by an active dilation during pronounced hypotension.The results suggest, therefore, that nimodipine-treated patients may safely undergo controlled hypotensions of limited severity. Acknowledgements. The authors thank Mme. Taillardat (Bayer Pharma) and M. Eric Priol for their technical assistance. This work was supported by CNRS, Universit6 Paris VII and a grant from the D61~gation G6n~rale pour I'Armement (Direction des Recherches et Etudes, contrat n ° 91/1011J). REFERENCES 1 Auer, L.M., Pial arterial vasodilation by intravenous nimodipine in cats, Drug Res., 31 (1981) 1423-1425. 2 Auer, L.M. and Mockry, M., Effect of topical nimodipine versus its ethanol-containing vehicle on cat pial arteries, Stroke, 17 (1986) 225-228. 3 Dirnagl, U., Kaplan, B., Jacewicz, M. and Pulsinelli, W., Continuous measurement of cerebral cortical blood flow by laser-Doppler flowmetry in a rat stroke model, J. Cereb. Blood Flow Metab., 9 (1989) 589-596. 4 Dunnett, C.W., New tables for multiple comparisons with a control, Biometrics, 20 (1964) 482-491. 5 Florence, G. and Seylaz, J., Rapid autoregulation of cerebral blood flow: a laser-Doppler flowmetry study, J. Cereb. Blood Flow Metab., 12 (1992) 674-680. 6 Gaab, M.R., Hollerhage, H.G., Zumkeller, M. and Trost, H.A., The effect of the Ca-antagonist nimodipine on cerebral blood flow autoregulation, J. Cereb. Blood Flow Metab., 7 (1987) S170. 7 Harper, A.M., Craigen, L. and Kazda, S., Effect of the calcium antagonist, nimodipine, on cerebral blood flow and metabolism in the primate, J. Cereb. Blood Flow Metab., 1 (1981) 349-356. 8 Harris, R.J., Branston, N.M., Symon, L., Bayhan, M. and Watson, A., The effects of a calcium antagonist, nimodipine, upon physiological responses of the cerebral vasculature and its possible influence upon focal cerebral ischemia, Stroke, 13 (1982) 759-766. 9 Haws, C.W., Gourley, J.K. and Heistad, D.D., Effects of nimodipine on cerebral blood flow, J. Pharmacol. Exp. Ther., 225 (1983) 24-28.
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