ACTA NEUROCHIRURGICA
Acta Neurochirurgica 43, 297--306 (1978)
9 by Springer-Verlag 1978
University Clinic of Neurosurgery, Graz, Austria (Head: Univ.-Prof. Dr. F. Heppner)
T h e A c t i o n of S o d i u m N i t r o p r u s s i d e on the Pial V e s s e l s By
L. Auer With 3 Figures
Summary This study in cats investigates the action of sodium nitroprusside on the pial vessels by systemic and local administration, with an intravital microscopic window technique and a photometric technique for graphic documentation of vessel diameter changes. Intravenous infusion caused vasodilatation parallel with decreasing blood pressure. Pial arterioles dilated more than venules, smaller vessels more than larger ones. Local administration caused maximal dilatation within 5-10 seconds. With blood pressure returning to normal after i.v. therapy, piaI vessels remained wider than they were before hypotension at the same pressure level. From these data it is concluded that the substance acts longer on the brain vessels than on vessels elsewhere in the body, and that cerebrovascular autoregulation to blood pressure changes is disturbed during this period.
Introduction Sodium nitroprusside, also refered to as sodium nitroferricyanide, sodium nitrosylpentacyanoferrate, or sodium nitroprussiate, was first described by Playfair in 1849 5. In 1886, Hermann ~ was the first to observe the haemodynamic actions of this substance. First information on its therapeutic possibilities were given by Page e t al. .2 in 1950. Since that time, the substance has been increasingly for the management of hypertensive emergencies 7, a, ~ and for surgery under controlled hypotension 1-2, 17. Since the hypotensive and antihypertensive action of this drug is of great interest to the neurosurgeon, its effect on the brain vessels appeared to be a challenging problem. 20
Acta Neurochirurgica, Vo[. 48, Fasc. 3--4
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Sodium nitroprusside has been assumed to act directiy on the vascular smooth muscle cells, resulting in peripheral dilatation 10. Descriptions of the influence of sodium nitroprusside on cerebral blood flow (CBF) are somewhat controversial up to now 6, t6. The observation of CBF decrease parallel with blood pressure lowering 6 and the assumption that autoregulation might become disturbed by administration of the drug were important considerations. Material and M e t h o d s The investigations were performed in 20 cats of both sexes with body weights of 1.5-3 kg. They were anaesthetized with 30 mg/kg Nembutal i.m., intubated endotracheally, and respirated with a 4 : 1 mixture of N20 : O~. The left femoral vein and artery were cannulated for continuous blood pressure monitoring, blood sampling for frequent arterial pC| pO.2 and pH measurement (AVL-gascheck), and for administration of drugs. After the head had been placed in a stereotaxic head holder, a cranial window was made in the right parietal region by a technique like that of Forbes 7. The dura was opened by using microsurgical techniques to avoid touching pial structures. The cranial window was closed with a microscopical cover glass, and sealed with acrylic. Detailed description of the technique has been given elsewhere 1.2. Piai vessels were observed with a Leitz Intravitalmikroskop and photographed with an Orthomat camera. Arterial vessel diameter changes were measured from magnified slides. Magnifications were determined with a Leitz micrometer scale, photographed, and reproduced through the same optical systems as slides from pial vessels. At the beginning of each experiment and at the end of three experiments, the CO2-reactivity of pial vessels was tested by hyper- and hypocapnia induced by 5-20% CQ-inhalation and hyperventilation, respectively. In twelve animals, controlled hypotension was induced by intravenous infusion of 4ttg/kg/min sodium nitroprusside (Nipride | * In 4 of the 12 animals with a closed cranial window, ai~terial vessel diameter changes during intravenous Nipride administration were monitored continuously with a photometric measurement device a, 4 in the place of the photocamera. The method allows an exact study of the time course of vascular reactions to Nipride | administration and blood pressure changes (Fig. 3). The measurement unit consists of a Knott photomultiplier with high stability power supply. It measures the red extinction by means of a Leitz S-585 filter, which makes the red vessels appear black. Thus, extinction increases with vasodilatation and decreases with vasoconstriction. These changes are transmitted to a two channel writer showing blood pressure or. the lower and vessel diameter changes on the upper curve (Fig. 3). Six animals served as controls, treated in the same way, without hypotension. In two additional animals the effect of locally applied Nipride was tested. Here, the cranial window technique was performed without using a cover glass. The pial surface was irrigated with synthetic CSF at 37 ~ kept in a thermostatically heated water bath. Pial surface temperature was permanently controlled with a YSI-telethermometer. Nipride | was added to the irrigation fluid for 15 seconds with the above mentioned dosage rate. * Roche.
The Action of Sodium Nitroprusside on the Pial Vessels
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Results The CO2-reactivity test on pial vessels before and also after Nipride | administration--systemic and local--was normal in all animals, i.e. there was vasodilatation during hypercapnia and constriction during hypocapnia. Detailed descriptions of normal CO2reactivity are given in another paper 5. Repeated diameter measure250
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jorn Fig. 1. Resting arterial diameters plotted against percentual diameter increase during Nipride| Intravenous: 0 local administration; 0~ = resting diameter value
ments over five minutes in control animals gave mean diameter changes of about _+ l~ MABP was lowered within 1 to 3.5 minutes (mean 2.78 minutes) from 80-150 mm Hg (mean 133 mm Hg) to 20-60 mm Hg (mein 4 4 m m H g ) . After finishing the intravenous administration of Nipride | blood pressure returned constantly to original values within 1,5 to 7 minutes (mean 3.9 minutes). Arterial pCO 2 was 2(}*
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29-41 mm Fig (mean 35 mm Fig) at the beginning and 27-44 mm Hg (mean 34 mm Hg) at the end of treatment. P a| on an average, was 144 mm Hg before and 146 mm Hg after treatment, at pH's 7.35 and 7.37 respectively. The observed arterial vessel resting diameters varied bevween 10 and 135 pro. The total number of diameter measurements was 854. Visible vasoditatation occurred only when blood pressure was lowered. Thus, in one animal blood pressure remained unchanged during Nipride | infusion, pial vessels
Fig. 2a
rema{ning unchanged also. Maximal dila:ation during Nipride | administration was + 82O/o in vessels up to 30 ~tm resting diameter and 42O/o in vessels above 30 pm, on an average. Mean values of single experiments are given in Table 1. They show that smaller vessels react more than larger ones. This observation is still further clarified by Fig. 1, where resting diameters are plotted against percentual diameter increase. Fig. 2 gives an example of typical pial vessel reaction to intravenous Nipride | infusion. Besides marked arteriolar and capillary dilatation during controlled hypotension, it shows that pial venous vessels react much less than do arterial vessels. In one animal (F 66 A), controlled hypotension was induced following a phase of spontaneous hypertension with MABP 150 m m H g and break-through conditions with vasodilatation. During hypotension, induced by Nipride | vessels above 30 btm were even smaller at MABP 50 mm Hg than they were
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Fig. 2. a Normal pial vessels before controlled hypotension with Nipride | M A B P = 1 2 0 m m Hg, PACOe=41, PAO~= 183mm Hg, p H = 7 . 3 2 . - + = arteriole, black line = 183 ~tm. b Same picture six minutes later during hypotension, M A B P = 4 5 m m H g , P A C O 2 = 3 4 m m H g , PAO2= 178mmHg, p H = 7.38. c Together with blood pressure returning to normal (MABP = 105 mm Hg), arterial vessels constrict and return to their resting values 20**
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at MABP 110 mm H g immediately before and after acute hypertension. Smaller vessels, however, were dilated, as they were in the other animals during Nipride | administration. Repeated locally applied Nipride | lead to extreme vasodilatation in both animals within 5-10 seconds, the blood pressure remaining constant. The extent of dilatation was somewhat higher than in animals with systemic administration of the substance. Vessels up to 30 ~tm original diameter dilated up to + 108~ larger vessels up to 540/0 on average. Normalization of diameters occurred within 5-10 minutes after local administration.
Fig. 3. Lower curve: Blood pressure in mmHg; upper curve: Vessel red colour extinction changing with vasodilatation (D) and constriction (C). In the normal situation, a five per minute rhythm is visible, which increases during mild hypotension induced by Nipride (N). Further lowering of blood pressure is accompanied by a change of rhythmic diameter changes from four per minute to two per minute during increasing vasodilatatiol~ The two per minute wave is abolished at a certain level of vasodilatation Photometric investigations in four ariimals gzve the following results: In one artima[, blood pressure did not change, vessel diameters remaining unchanged also. The other three showed pial vasodilatation parallel with blood pressure decrease without any free interval (see Fig. 3). When blood pressure reached its lower peak, vasodilatation continued for one to five minutes until maximum diameter values were observed. When blood pressure returned to
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normal, vessels began to constrict, but did not reach their original sizes before 6.5-11.5 minutes after blood pressure normalization. The normal vessel diameter curve shows a five per minute rhythm that increases in amplitude at the beginning of hypotension. It becomes a two per minute wave until it is abolished at a certain pressure level (Fig. 3). Discussion
The results indicate that the substance must evidently act directly on the smooth muscle cells of pial vessels as indicated by the quick reaction within less than 10 seconds after local administration. As for the mode of action, a metabolic process is most probable, but it is not yet proved. The data do not prove or disprove reports of changes of cerebral blood flow (CBF) during controlled hypotension with sodium nitroprusside, because quantitative data on CBF are not available from our investigations. The vasodilatation parallel with or after the fall in blood pressure would make it difficult for us to understand a parallel decrease in cerebral blood flow, since this would require a greater vasodilator than hypotensive action of the drug, and hence a more powerful action on brain vessels than on other vessels of the body. Moreover, the contrary can be shown, namely that pial vessels react more slowly than other vessels. Otherwise, the dilatation of pial vessels after the blood pressure has fallen can hardly be explained. Another explanation for conflicting results could be the use of various animal species. This appears possible because of the widely differing amounts of the drug necessary to achieve the hypotensive effect. The relative vasodilator phase after sodium nitroprusside therapy might then be interpreted as a reactive hyperaemia after a phase of decreased flow, as measured by Crockard e t al. 6 who observed also a loss of autoregulatory ability with nitroprusside in rhesus monkeys. Furthermore, it is possible to assume a change of cerebrovascular autoregulation to blood pressure changes immediately after administration of the drug. The discrepancy between the photometric vessel diameter curve and the blood pressure curve inicates clearly that regeneration of pial vascular tone comes after the return of blood pressure to normal after hypotension. This would mean that the local metabolic processes leading to decrease of vascular tone last longer in piaI vessels than in other vessels of the body. The time delay between the two vascular beds evidently necessitates a period of decreased contractility of brain vessels.
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This is an important observation of clinical medicine for two reasons, firstly because the rate of administration must be decreased very slowly to prevent the patient from a vasodilator phase due to the transient autoregulatory failure, and secondly because patients tend to have reactive hypertension after controlled hypotension. These observations are one more argument for handling the drug with great care and exclusively under continuous blood pressure control. The vessel diameter decrease in the one animal made hypotensive after a spontaneous hypertensive crisis with break through of autoregulation does not mean preserved autoregulation and increase of vascular tone with pressure normalization, but an inversion of the drug action. It was an interesting observation to see pial arterioles continuing to constrict during controlled hypotension induced by Nipride | after the hypertensive crisis. This would mean a failure of the substance to act normally on the pial vessels which are altered by the preceeding hypertension. This reaction was in contrast to vessels in other regions of the body, because the hypotensive phase indicated dilatation of resistance vessels. Although one experiment does not allow us to draw conclusions, it will be interesting to study the action of this substance in hypertensive animals to see if it fails to cause vasodilatation in conditions of disturbed autoregulation and to lower CBF when cerebral perfusion is increased.
Acknowledgement I am grateful to Dr. Neuhold for organization and care of experimental animals, Mr. I. Georgiev for special development of the photographical material, and K. Wachter for skilful technical assistance. References
1. Auer, L., The pathogenesis of hypertensive encephalopathy. Acta Neurochir. (Wien) in press. 2. Auer, L., Intravitalmikroskopische Beobachtung der pialen Gef~if~e im Tierexperiment. Zentralblatt f. Neurochir. 38 (1977), 175--184. 3. Auer, L., A method for continous monitoring of pial vessel diameter changes. Pfliigers Archly 373 (1978), 195--198. 4. Auer, L., Photometrische Auswertung yon Mikrogef~i~reaktionen im Intravitalmikroskop am Beispiel der pialen Hirnges In press, Wiss. Mitteilungen Leitz, 1977. 5. Auer, L., Pial arterial reactions to hyper- and hypocapnia, a dynamic study in cats. Europ. Neurol., in press. 6. Crockard, H. A., et aL, Effects of trimetaphan and sodium-nitro prusside on cerebral blood flow in rhesus monkeys. Acta Neurochir. (Wien) 35 (1976), 85--89.
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7. Forbes, H. S., The cerebral Circulation. I. Arch. Neurol. Psychiat. 19 (1928), 751--760. 8. Gifford, R. W., Hypertension: Mechanismus and Management, pp. 809--817. New York: Grune & Stratton. 1973. 9. Hermann, L., L~ber die Wirkung des Nitroprussidnatriums. Arch. ges. Physiol. 39 (1886), 419. 10. Johnson, C. C., The action and toxicity of sodium nitroprusside. Arch. Int. Pharmacodyn. Ther. 35 (1929), 480--496. ll, Kaplan, N. M., Clinical Hypertension, p. 169. New York: Medcom Press. 1973. 12. Katz, R. L., Wolf, C. E., In: Highlights of Clinical Anestesiology, pp. 48--54. New York: Harper & Row. 1971. 13. Koch-Weser, J. N., Hypertensive Emergencies. N. Engl. J. Med. 290 (1974), 211--214. 14. Page, I. H., et al., Cardiovascular actions of sodium nitroprusside in animals and in hypertensive patients. Circulation 11 (1955), 188--198. 15. Sidgwick, N. V., Chemical Elements and Their Compounds. Vol. 2, pp. 1343-1346. London: Oxford University Press. 1950. 16. Stoyka, W. W., Schutz, H., The cerebral response to sodium nitroprusside and trimethapan controlled hypotension. Canad. Anaesth. Soc. J. 22 (1975), 275--283.
17. Wildsmith, J. A. W., et al., Hemodynamic effects of sodium nitroprusside, during nitrous-oxide: halothane anaesthesia. Brit. J. Anaesth. 45 (1973), 71--82. Author's address: Dr. L. Auer, Universit~itsklinik fiir Neurochirurgie, Auenbruggerplatz 5, A-8010 Graz, Austria.
