Anesth Analg 2003;96:1139-1144
© 2003 International Anesthesia Research Society
NEUROSURGICAL ANESTHESIA
The Comparative Effects of Prostaglandin E1 and Nicardipine on Cerebral Microcirculation in Rabbits
Motoyasu Takenaka, MD*,
Hiroki Iida, MD
,
Mami Iida, MD
,
Masayoshi Uchida, MD, and
Shuji Dohi, MD
*Department of Anesthesia, Ibi General Hospital, Ibi County, Gifu, and
Department of Anesthesiology and Critical Care Medicine and
Internal Medicine, Gifu University School of Medicine, Gifu, Japan
Address correspondence and reprint requests to Hiroki Iida, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, 40 Tsukasamachi, Gifu City, Gifu 500-8705, Japan. Address e-mail to iida{at}cc.gifu-u.ac.jp
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Abstract
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We compared the effects of the systemic hypotensive drugs prostaglandin E1 (PGE1) and nicardipine on the cerebral microcirculation and on the cerebrovascular reactivities to hypercapnia and hypoxia. In isoflurane-anesthetized rabbits (n = 48), we measured cerebral pial vessel diameters using a cranial-window preparation: (a) during IV PGE1- or nicardipine-induced mild or moderate hypotension (to 80% or 60% of initial mean arterial blood pressure), (b) after topical administration of these drugs, and (c) during hypercapnia or hypoxia induced during such mild or moderate hypotension. Pial arteriolar diameters were (a) unchanged when hypotension (mild or moderate) was induced by PGE1 but increased when it was induced by nicardipine and (b) increased dose-dependently by topical administration of nicardipine but not PGE1. Only small changes in cerebral venular diameter were observed in these experiments. The pial arteriolar dilator response to hypercapnia was potentiated during hypotension (mild or moderate) when it was induced by PGE1 but decreased when it was induced by nicardipine, whereas the response to hypoxia was maintained during PGE1-induced hypotension but decreased during nicardipine-induced hypotension. In conclusion, as a systemic hypotensive drug, PGE1 does not dilate cerebral arterioles and maintains cerebrovascular reactivities to hypercapnia and hypoxia, whereas nicardipine dilates such vessels and reduces these cerebrovascular reactivities.
IMPLICATIONS: When given systemically to produce mild or moderate hypotension, prostaglandin E1 does not induce cerebral vasodilation and maintains cerebrovascular reactivity to hypercapnia and hypoxia, whereas nicardipine dilates cerebral vessels and reduces both reactivities.
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Introduction
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Drugs used to control systemic blood pressure during anesthesia may affect blood vessels within the central nervous system (1–3) in which flow must be kept sufficiently high to maintain cerebral activity. Such vessels are known to be influenced by hypercapnia and by hypoxia. Prostaglandin E1 (PGE1) and nicardipine, a calcium-channel blocker, are potent vasodilators that can be used often for the treatment of hypertension or for inducing hypotension during anesthesia in the clinical setting. In previous reports, local cerebral blood flow (CBF) was reported to be unchanged by IV PGE1 (4–6) but increased by nicardipine (7,8) , although CO2 reactivity was maintained by both drugs (9–12) . However, the literature is deficient in studies involving direct observations of the comparative effects of PGE1 and nicardipine on the cerebral microcirculation and on the reactivities of cerebral vessels to hypercapnia and hy-poxia in in vivo experiments. The aim of the present study was to investigate, in rabbits fitted with a cranial window, the changes occurring in the cerebral microcirculation during periods of hypotension induced by IV PGE1 or nicardipine and those occurring after their topical administration. In addition, we evaluated the cerebrovascular reactivities to hypercapnia and hypoxia during such periods of induced hypotension.
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Materials and Methods
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The procedures used in this study conformed to the Guiding Principles in the Care and Use of Animals approved by the Council of the American Physiologic Society, and the experimental protocols were approved by our Institutional Committee for Animal Care. The experiments were performed on 48 anesthetized rabbits weighing 2.3–2.5 kg. In each rabbit (anesthetized with pentobarbital sodium [20 mg/kg IV] and maintained with 0.5% isoflurane) the lungs were mechanically ventilated through a tracheotomy tube with oxygen-enriched room air to maintain arterial O2 content between 14 and 16 vol%. The tidal volume and respiratory rate were adjusted to maintain PaCO2 between 35 and 40 mm Hg. Catheters were placed in the femoral vein for the administration of fluid and drugs and in the femoral artery for the continuous monitoring of mean arterial blood pressure (MAP) and heart rate (HR) and for blood sampling. Rectal temperature was maintained between 38.0°C and 39.0°C by means of a heating blanket.
A closed cranial window was used to observe the cerebral pial microcirculation. Each rabbit was placed in the sphinx posture, the scalp was retracted, and a hole 10 mm in diameter was made in the bone over the right parietal cortex. The dura and arachnoid membranes were opened carefully, and a ring with a glass coverslip was placed over the hole and secured using dental acrylic. The space under the window was filled with artificial cerebrospinal fluid (aCSF) of the following composition: Na+ 151 mEq/L, K+ 4 mEq/L, Ca2+ 3 mEq/L, Mg2+ 1.3 mEq/L, Cl- 110 mEq/L, HCO3- 25 mEq/L, urea 40 mg/dL, and glucose 67 mg/dL. The pH value was adjusted to 7.48. The solution was freshly prepared each day and bubbled with 5% CO2 in air at 38.5°C for 15 min just before use.
Four catheters were inserted into the ring. One was attached to a reservoir bottle containing aCSF to allow a constant pressure to be maintained within the window (5 mm Hg), the second was used to monitor the pressure within the window, the third was for the administration of experimental drugs and aCSF, and the fourth for draining the fluid. The volume below the window was between 0.5 and 1 mL. The temperature within the window, which was monitored using a thermistor (Model 6510; Mallinckrodt Medical, St Louis, MO), was maintained at 38.0°C–39.0°C. The diameters of three pial arterioles (or venules) were measured in each cranial window using a videomicrometer (Olympus Flovel videomicrometer, Model VM-20; Flovel, Tokyo, Japan) on a television monitor, which received pictures from a microscope (Model SHZ-10; Olympus, Tokyo, Japan). The data from the pial views were stored on videotape for later playback and analysis. The percentage changes recorded for individual arteriolar and venular segments were averaged for each type of vessel in each rabbit, and this average value was used in the statistical analysis. The pial arterioles and venules examined were 70–110 µm in diameter.
The study was divided into four parts. In the first set of experiments, we evaluated the effects of IV administration of PGE1 or nicardipine on cerebral arterioles and venules. Pial arteriolar and venular diameters and the levels of various physiologic variables (including MAP, HR, rectal temperature, arterial blood gas tensions, and pH [STAT Profile-5; NOVA Biomedicals, Waltham, MA]) were recorded before and during the mild (to 80% of initial MAP) and moderate (to 60% of initial MAP) levels of hypotension induced by continuous IV administration of PGE1 (n = 6) or nicardipine (n = 6). In the second set of experiments, we evaluated the direct effects of the topical administration of PGE1 or nicardipine on cerebral arterioles and venules. To this end, pial arteriolar and venular diameters and the levels of various physiologic variables were recorded before and during the topical administration of 3 different concentrations (10-9, 10-7, and 10-5 mol/L) of PGE1 (n = 6) or nicardipine (n = 6). In the third set of experiments, we evaluated the cerebral vasodilator response to hypercapnia during periods of mild or moderate hypotension induced by IV administration of PGE1 (n = 6) or nicardipine (n = 6)(details as for the first experiment). Hypercapnic challenges (PaCO2, approximately 60 mm Hg) were delivered by adding CO2 gas to the inspiratory gases before (baseline) and during mild and moderate hypotension, with a stable level of PaCO2 being maintained for 5 min. Pial arteriolar diameters and the levels of various physiologic variables were recorded before and after such a hypercapnic challenge under baseline conditions and during mild and moderate hypotension. In the fourth set of experiments, we evaluated the cerebral vasodilator response to hypoxia (arterial O2 content, 8–10 vol%) (OSM3; Radiometer, Copenhagen, Denmark) during periods of mild and moderate hypotension induced by IV administration of PGE1 (n = 6) or nicardipine (n = 6)(details as for the first experiment). These arterial oxygen content levels were produced by adding supplementary nitrogen to the inspired gas. Pial arteriolar diameters and the levels of various physiologic variables were recorded before and after such a hypoxic challenge under baseline conditions and during mild and moderate hypotension. All experiments were performed after at least a 30-min recovery from the surgical preparation.
All data about the changes of vessel diameters relating to the effects of the degree of hypotension and the concentration-dependent effects of PGE1 and nicardipine were tested by a one-way analysis of variance (ANOVA) for repeated measurements followed by Scheffé test for post hoc comparisons. The group effects of PGE1 or nicardipine on pial vessel diameters were compared with each other by a two-way ANOVA, and the differences at a given dose or a degree of hypotension were tested by an unpaired t-test. All physiologic variables within groups were examined using a one-way ANOVA for repeated measurements followed by Scheffé test for post hoc comparisons. Significance was set at P < 0.05. All values are expressed as mean ± SD.
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Results
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The baseline vessels diameters in each experiment are shown in Table 1.
Experiment 1
Pial arteriolar diameters were unchanged during both mild and moderate hypotension when these were induced by PGE1, but when the same levels of hypotension were induced by nicardipine, there was cerebral vasodilation (P < 0.05 compared with the response to PGE1) (Fig. 1A). Only small changes in cerebral venular diameter were observed during the periods of mild and moderate hypotension induced by IV PGE1 or nicardipine (Fig. 1B). There was no significant change in any of the physiologic values, except MAP (data not shown).
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Figure 1. Percentage change in pial arteriolar (A) and venular (B) diameters during mild (to 80% of initial mean arterial blood pressure [MAP]) and moderate (to 60% of initial MAP) hypotension induced by IV administration of prostaglandin E1 (PGE1) or nicardipine (n = 6 each). Values are mean ± SD. *P < 0.05 PGE1 versus nicardipine.
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Experiment 2
Cerebral pial arteriolar diameters were not significantly altered by topical administration of PGE1 but were increased dose-dependently by topical administration of nicardipine (Fig. 2A). Small changes in cerebral venular diameter were observed on topical administration of both PGE1 and nicardipine, the latter responses being significantly larger than the former at each concentration tested (Fig. 2B). There was no significant change in any of the physiologic values on topical administration of either drug (data not shown).
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Figure 2. Percentage change in pial arteriolar (A) and venular (B) diameters after topical administration of prostaglandin E1 (PGE1) or nicardipine (n = 6 each). Values are mean ± SD. #P < 0.05 compared with corresponding value at 10-9 mol/L. $P < 0.05 compared with corresponding value at 10-7 mol/L. *P < 0.05 PGE1 versus nicardipine.
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Experiment 3
The pial arteriolar dilator responses to hypercapnia seen under baseline conditions were significantly potentiated during periods of mild and moderate hypotension when these were induced by IV PGE1 but significantly reduced when the same levels of hypotension were induced by IV nicardipine (P < 0.05 in each case; Fig. 3). MAP was not changed significantly by the hypercapnia in any of the groups (Table 2), although HR decreased significantly in response to hypercapnia in each group (P < 0.05; Table 2). Arterial pH decreased significantly in response to hypercapnia without changes in arterial O2 tension (Table 2).
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Figure 3. Percentage change in pial arteriolar diameter in response to hypercapnia during mild (to 80% of initial mean arterial blood pressure [MAP]) and moderate (to 60% of initial MAP) hypotension induced by IV administration of prostaglandin E1 (PGE1) or nicardipine (n = 6 each). Values are mean ± SD. P < 0.05 compared with corresponding baseline value. *P < 0.05 PGE1 versus nicardipine.
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Experiment 4
The pial arteriolar dilator responses to hypoxia seen under baseline conditions were not altered when periods of mild and moderate hypotension were induced by IV PGE1. In contrast, they were significantly reduced when hypotension was induced by IV nicardipine (P < 0.05 in each case; Fig. 4). MAP did not change in response to hypoxia during mild or moderate hypotension (Table 3), although HR was decreased significantly by hypoxia during both mild and moderate hypotension whether induced by PGE1 or nicardipine (P < 0.05 in each case; Table 3). Arterial pH was not changed by hypoxia during either mild or moderate hypotension.
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Figure 4. Percentage change in pial arteriolar diameter in response to hypoxia during mild (to 80% of initial mean arterial blood pressure [MAP]) and moderate (to 60% of initial MAP) hypotension induced by IV administration of prostaglandin E1 (PGE1) or nicardipine (n = 6 each). Values are mean ± SD. P < 0.05 compared with corresponding baseline value.
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Discussion
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The major findings of the study were that when either drug is administered at doses sufficient to induce mild-to-moderate hypotension, PGE1 is unlikely to affect cerebral arterioles, but nicardipine will dilate them. Topical administration of nicardipine dilated cerebral arterioles in a concentration-dependent manner, but topical administration of PGE1 did not induce any significant changes in such vessels. Only small changes in cerebral venules were observed after the systemic or topical administration of either drug. Although cerebrovascular reactivities to hypercapnia and hypoxia were maintained during PGE1 administration, nicardipine reduced both reactivities when given systemically to induce either mild or moderate hypotension.
A major concern with the use of induced hypotension is that CBF may decrease to a critically low level, resulting in ischemic brain damage. Although PGE1 reduces blood pressure by relaxing vascular smooth muscle, mainly by dilating resistance vessels, it has been variously reported to dilate (13,14) , not to affect (15) or to constrict (16), cerebral vessels. In the present study, PGE1 had little or no effect on cerebral vessels. Because PGE1 is likely, on this basis, to preserve an adequate CBF and intracranial pressure (ICP), it may be a safe drug to use for inducing hypotension. However, a previous report demonstrated that pial arteries dilated by approximately 15% when MAP was decreased to 70 mm Hg by hemorrhage (17). Thus, the absence of an effect of PGE1 in the present study may disguise an attenuation of such an autoregulatory response to induced hypotension. On the contrary, Endoh et al. (18) demonstrated that nicardipine, but not PGE1, attenuated cerebral autoregulation during propofol-fentanyl anesthesia in humans. Further study is required on this point.
However, nicardipine increases CBF in both human and rabbit studies (19–21) . Moreover, it has been used for the treatment of cerebral vasospasm (22). It has been speculated that systemic administration of nicardipine might increase ICP because of its cerebral vasodilator effect. Koyama et al. (8) reported that nicardipine causes dilation of cerebral arterioles, increases CBF and cellular oxidation, but causes constriction of cerebral veins, thus decreasing cerebral venous blood volume. In the present study, when nicardipine was directly applied into the window, cerebral pial arterioles dilated dose-dependently, but cerebral venules showed only small changes. There is few information about the effects of PGE1 (14) and nicardipine on venules. Because most of the blood volume is contained in the venous compartment, the effects on cerebral venular diameter induced by these drugs may contribute to ICP changes. Although we did not measure ICP, it is possible that neither PGE1 nor nicardipine would produce much increase in ICP because of their minimal effects on pial venules observed in the present study. With regard to both PGE1 and nicardipine, this speculation is consistent with the observation of previous studies (14,23) .
Hyperventilation is recommended as a way of reducing CBF and cerebral blood volume in patients with brain protrusion, and it is required to preserve CO2 reactivity during induced hypotension. Abe et al. (9,10,12) indicated that both PGE1 and nicardipine would maintain CO2 reactivity during cerebral-aneurysm surgery, and thus, both drugs should be useful and safe for inducing hypotension or for the treatment of intraoperative hypertension during such surgery. Kawaguchi et al. (11) demonstrated that nicardipine-induced hypotension resulted in increased middle cerebral artery blood flow velocity with maintenance of CO2 reactivity to hypocapnia in patients under fentanyl-diazepam-nitrous oxide anesthesia.
In the present study, cerebrovascular reactivity to hypercapnia was maintained during PGE1 administration, whereas nicardipine attenuated it. Likewise, Oishi et al. (24) reported that nicardipine decreased cerebrovascular reactivity to hypercapnia (in their case in cats). Endoh et al. (25) also demonstrated that both PGE1 and nicardipine attenuated cerebrovascular reactivity to hypercapnia during propofol-fentanyl anesthesia in humans. The discrepancy between some previous reports and ours may be because of different methods used for the evaluation of cerebrovascular reactivity (thermal-gradient blood flowmeter or transcranial Doppler versus direct observation of cerebral vessels) or to a species difference (human versus animal). However, we cannot be sure of the exact reason. At present, there is no clinical evidence as to the effects of PGE1 and nicardipine on the reactivity of cerebral vessels to hypoxia. The present study indicates that at least in the rabbit, the effects of PGE1 and nicardipine on the cerebrovascular reactivity to hypoxia are similar to their effects on hypercapnia, although the mechanism underlying the cerebrovascular dilation induced by hypoxia is believed to be different from the mechanism underlying that induced by hypercapnia.
In conclusion, when given systemically to produce mild or moderate levels of hypotension, PGE1 does not dilate cerebral vessels, and the cerebrovascular reactivities to both hypercapnia and hypoxia are maintained. In contrast, when nicardipine is given systemically to produce similar levels of hypotension, it dilates cerebral vessels and decreases the cerebrovascular reactivities to hypercapnia and hypoxia.
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Acknowledgments
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Supported, in part, by Grant-in Aid for Scientific Research No. 13671570 from the Ministry of Education, Science, and Culture, Japan.
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Footnotes
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Presented, in part, at the annual meeting of the American Society of Anesthesiologists, Dallas, TX, October 9–13, 1999.
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Accepted for publication December 3, 2002.
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Abstract
Introduction
