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NEUROSURGICAL ANESTHESIA

The Comparative Effects of Intravenous Nicardipine and Prostaglandin E1 on the Cerebral Pial Arteriolar Constriction Seen After Unclamping of an Aortic Cross-Clamp in Rabbits

Masahiko Kumazawa, MD^*, Hiroki Iida, MD^*, Masayoshi Uchida, MD, Mami Iida, MD, Motoyasu Takenaka, MD^*, and Shuji Dohi, MD^*

From the Departments of *Anesthesiology and Pain Medicine, and Cardiology, Gifu University Graduate School of Medicine, Gifu City, Gifu; Department of Anesthesia, Chubu Rosai Hospital, Nagoya; and Department of Nutrition and Food Science, Faculty of Home Economics, Gifu Women's University, Gifu, Japan.

Address correspondence and reprint requests to Hiroki Iida, MD, Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan. Address e-mail to iida{at}gifu-u.ac.jp.

	Abstract

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BACKGROUND: The potent vasodilators nicardipine and prostaglandin E1 (PGE1) are useful for the treatment of systemic hypertension or pulmonary hypertension during aortic surgery.

METHODS: We measured cerebral pial arteriolar diameters, using a rabbit closed cranial window preparation: before (baseline) and 15 min after the start of an IV infusion (preclamp) (0.9% saline [control group], nicardipine [at 0.1, 1.0, or 10 µg·kg^–1·min^–1], or PGE1 [at 0.1 or 1.0 µg·kg^–1·min^–1]), just after aortic clamping, 20 min after clamping, and at 0–60 min after unclamping.

RESULTS: In the control group, a significant decrease in diameter persisted for at least 60 min after unclamping (maximum [at 60 min], –16% for large [75 µm], and –27% for small [<75 µm] arterioles versus baseline). Although the aortic unclamping-induced vasoconstriction was unaffected under the smallest dose of nicardipine, it was significantly attenuated under larger doses in both large and small arterioles (residual vasoconstriction, –10% and –6% for large and –18% and –10% for small arterioles; at 60 min). The pial arteriolar constriction observed at 5 min or more after unclamping in the control group was not altered by PGE1 in either large or small arterioles.

CONCLUSIONS: The larger doses of nicardipine, but neither dose of PGE1, attenuated aortic unclamping-induced sustained cerebral pial arteriolar constriction.

	Introduction

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Abrupt changes in systemic hemodynamics occur during aortic surgery in association with aortic cross-clamping and unclamping. Such hemodynamic instability would be expected to affect the cerebral circulation, and drugs used to control systemic and pulmonary blood pressures during such surgery and anesthesia may affect the reactivity of blood vessels within the central nervous system (CNS) (1,2).

Nicardipine, a calcium-channel blocker, and prostaglandin E1 (PGE1) are vasodilators. These drugs are used for the treatment of systemic hypertension or pulmonary hypertension (3–6), which may occur during aortic surgery. We previously reported (a) that unclamping of an abdominal aortic cross-clamp causes a sustained pial arteriolar constriction, and (b) that concomitantly administered milrinone or colforsin daropate attenuate such vasoconstriction (7,8). In the present study, we hypothesized that nicardipine and PGE1 would attenuate the sustained constriction of pial vessels seen after unclamping of an abdominal aortic cross-clamp, effects that could be favorable for the maintenance of the cerebral circulation. We therefore sought to examine the effect of various doses of each drug on the cerebral microcirculation during and after unclamping of an abdominal aortic cross-clamp. For this, we used a closed cranial window technique in anesthetized rabbits.

	METHODS

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Experimental Animals
The procedures used in the present 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 36 anesthetized rabbits weighing 2.0–2.2 kg. Each animal was initially anesthetized with pentobarbital sodium (25 mg/kg body weight, IV). Anesthesia was maintained using a continuous infusion of the same drug (5 mg·kg^–1·h^–1). Mechanical ventilation was achieved through a tracheotomy tube using oxygen-enriched room air (arterial O₂ content; 14–17 vol %). The tidal volume and respiratory rate were continually adjusted so as to maintain end-tidal carbon dioxide tension at between 35 and 40 mm Hg, end-tidal carbon dioxide tension being monitored throughout the experiment. Polyvinyl chloride catheters were placed in the femoral vein for administration of fluid (lactate Ringer's solution: 5 mL·kg^–1·h^–1), in the right axillary and left femoral arteries for the continuous monitoring of proximal and distal aortic pressures (PrAP and DiAP) and heart rate (HR), and also for blood sampling (from the right axillary artery). Rectal temperature was maintained between 38.5°C and 39.5°C by means of a heating blanket and warming lamp. A skin incision was made in the lateral abdomen. After the abdominal aorta had been freed from the surrounding tissues, tapes were passed around it to permit tightening in preparation for clamping just distal to the renal arteries.

In the present study, a closed cranial window was used to observe the cerebral pial microcirculation (n = 36). Each animal was placed in the sphinx posture, the scalp was retracted, and a 10-mm diameter hole was made in the parietal bone. The dura and arachnoid membranes were opened carefully, and a polypropylene ring with a glass coverslip placed over the hole was secured with dental acrylic. The space under the window was filled with artificial cerebrospinal fluid, the composition of which was Na⁺ 151 mEq/L, K⁺ 4 mEq/L, Ca²⁺ 3 mEq/L, Mg²⁺ 1.3 mEq/L, Cl^– 134 mEq/L, HCO₃ 25 mEq/L, urea 40 mg/dL, and glucose 67 mg/dL. This solution was freshly prepared each day, and bubbled with 5% CO₂ in air at 39.0°C for 15 min just before use. Three polyethylene catheters were inserted through the ring: one was attached to a reservoir bottle containing artificial cerebrospinal fluid to maintain the desired level of intra-window pressure (5 mm Hg), while the second was used to monitor intra-window pressure, and the third for draining the fluid. The temperature within the window was monitored using a thermometer (Model 6510; Mallinckrodt Medical, St. Louis, MO) and was between 38.5 °C and 39.5°C.

The diameters of two large (75 µm) and two small (<75 µm) pial arterioles were measured in each cranial window using a videomicrometer (Olympus Flovel videomicrometer, Model VM-20; Flovel, Tokyo, Japan) on a television monitor attached to a microscope (Model SZH-10; Olympus, Tokyo, Japan). We selected the vessels from which data would be collected as the first step in the experiment; that is, before drug administration. This was done to eliminate any bias that might occur if vessels were selected after drug administration. The data from the pial views were stored on videotape for later playback and analysis. The percentage changes recorded for individual arterial segments were averaged for each type of vessel (large or small) in each rabbit, and this average value was used in the statistical analysis.

Experimental Protocol
Rabbits were assigned to one of six groups (see later). All experiments were performed after at least 30 min recovery from the surgical preparation. After baseline measurements had been made, each rabbit was infused IV with one of the following: saline (control group, n = 6), nicardipine (N-0.1 group, 0.1 µg·kg^–1·min^–1, n = 6; N-1.0 group, 1.0 µg·kg^–1·min^–1, n = 6; N-10 group, 10 µg·kg^–1·min^–1, n = 6), PGE1 (P-0.1 group, 0.1 µg·kg^–1·min^–1, n = 6; P-1.0 group, 1.0 µg·kg^–1·min^–1, n = 6). All infusions were continued throughout the experiment. At 15 min after the start of the IV infusion, aortic clamping was performed (duration, 20 min). The clamping and subsequent unclamping were done gradually (each taking about 30 s to perform) so as to minimize the hemodynamic changes induced by these maneuvers. Measurements of cerebral pial arteriolar diameter, hemodynamic variables (PrAP, DiAP, and HR), and various physiologic variables (rectal temperature, intra-window temperature, arterial blood gas tensions, electrolytes, blood glucose, and blood pH) were taken at the following time-points: just before the start of IV administration (baseline), 15 min after the start of the IV infusion (preclamp), just after aortic clamping (after clamp), 20 min after clamping (preunclamp), and at 0, 2, 5, 15, 30, and 60 min after unclamping (the time-point "0 min after unclamping" was actually 30 s after the start of unclamping, which took about 30 s to perform; see above).

Statistical Analysis
All variables used to assess time-dependent effects within groups (versus baseline) were tested by a one-way analysis of variance (ANOVA) for repeated measurements followed by a paired t-test with Bonferroni correction for post hoc comparisons. Differences between groups (drug group versus control group) were examined by a two-way ANOVA and then by a one-way ANOVA for factorial measurements followed by an unpaired t-test with Bonferroni correction. Significance was considered to be demonstrated at P < 0.05. All results are expressed as mean ± sd.

	RESULTS

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There were no significant differences in baseline hemodynamic or physiological variables among the groups, nor did HR vary significantly throughout the experiment in any group. In addition, rectal and intra-window temperatures did not alter at any stage of the experiments in any group. Moreover Pao₂, Na⁺, K⁺, and blood glucose were stable at all stages of the experiment in each group. In every group: (a) PrAP was significantly reduced at time-point "0 min after unclamping" (by 10% for control, 10% for N-0.1, 15% for N-1.0, 15% for N-10, 11% for P-0.1, and 15% for P-1.0 [each, P < 0.05]), (b) DiAP was significantly reduced after clamping (by 80% for control, 81% for N-0.1, 80% for N-1.0, 79% for N-10, 79% for P-0.1, and 80% for P-1.0 [each, P < 0.05]), but then recovered after unclamping (Table 1), (c) arterial pH was significantly reduced at both 0 and 2 min after unclamping (maximum change: 1.4% for control, 1.1% for N-0.1, 1.4% for N-1.0, 1.2% for N-10, 1.2% for P-0.1, and 1.0% for P-1.0 [each, P < 0.05]), and (d) Paco₂ was significantly increased at both 0 and 2 min after unclamping (maximum change: 13% for control, 16% for N-0.1, 17% for N-1.0, 11% for N-10, 11% for P-0.1, and 13% for P-1.0 [each, P < 0.05]) (Table 2).

There were no significant differences among groups in the baseline diameter of either of the two sizes of arterioles (for large and small arterioles, respectively: control, 95 ± 8 µm and 62 ± 6 µm; N-0.1, 94 ± 6 µm and 59 ± 7 µm; N-1.0, 97 ± 9 µm and 66 ± 5 µm; N-10, 92 ± 8 µm and 60 ± 5 µm; P-0.1, 92 ± 9 µm and 60 ± 4 µm; P-1.0, 91 ± 8 µm and 64 ± 6 µm). In the following paragraphs, all percentage values represent changes in diameter with respect to baseline.

In the control group, neither large nor small pial arterioles showed significant changes in diameter after clamping, but both types of arterioles dilated significantly just after unclamping (maximum increases in diameters, 6% and 10%, respectively). They then constricted significantly, starting at 5 min after unclamping (–5% and –6%, respectively). The constrictions were still significant (and, indeed, appeared still to be increasing) at 60 min after unclamping (–16% and –27%, respectively), as in a previous study (7,8).

In the N-0.1, N-1.0, N-10, P-0.1, and P-1.0 groups, baseline pial arteriolar diameters (large and small) did not change after IV administration of drug. In all groups, both large and small pial arterioles showed significant dilations just after unclamping, the maximum increases in diameter for these two sizes of arterioles being, respectively, by 7% and 8% for N-0.1, by 9% and 10% for N-1.0, by 13% and 14% for N-10, by 7% and 8% for P-0.1, and by 7% and 12% for P-1.0 (each, P < 0.05 vs baseline.). These dilations were not significantly different from those seen in the control group.

Although the aortic unclamping-induced vasoconstriction was not different between the N-0.1 group and the control group, it was significantly attenuated in the N-1.0 and N-10 groups in both large and small arterioles (N-1.0 group: residual vasoconstriction, –11% and –15% at 30 min, and –10% and –18% at 60 min after unclamping for large and small arterioles, respectively; N-10 group: residual vasoconstriction, –8% and –10% at 30 min, and –6% and –10% at 60 min after unclamping for large and small arterioles, respectively). The constrictions observed in large and small pial arterioles at 5 min or more after unclamping in the control group were not altered by prostaglandin E1 (in either the P-0.1 or P-1.0 group) (Figs. 1 and 2).

View larger version (21K): [in this window] [in a new window]   Figure 1. (a) The effects of IV infusion of nicardipine (N-0.1 group, 0.1 µg·kg–1·min–1; N-1.0 group, 1.0 µg·kg–1·min–1; N-10 group, 10 µg·kg–1·min–1) or (b) prostaglandin E1 (PGE1) (P-0.1 group, 0.1 µg·kg–1·min–1; P-1.0 group, 1.0 µg·kg–1·min–1) on responses of large diameter (75 µm) cerebral pial arterioles to aortic clamping and unclamping in 36 rabbits. Data are expressed as percentage change from the diameter measured just before IV administration of drug (baseline). Data are shown for: 15 min after IV administration (preclamp), just after clamping (after clamp), 20 min after clamping (preunclamp), and 0, 2, 5, 15, 30, and 60 min after unclamping. Values are mean ± sd. *P < 0.05 vs baseline in same group. P < 0.05 as indicated.

View larger version (20K): [in this window] [in a new window]   Figure 2. (a) The effects of IV infusion of nicardipine (N-0.1 group, 0.1 µg·kg–1·min–1; N-1.0 group, 1.0 µg·kg–1·min–1; N-10 group, 10 µg·kg–1·min–1) or (b) prostaglandin E1 (PGE1) (P-0.1 group, 0.1 µg·kg–1·min–1; P-1.0 group, 1.0 µg·kg–1·min–1) on responses of small diameter (<75 µm) cerebral pial arterioles to aortic clamping and unclamping in 36 rabbits. Data are expressed as percentage change from the diameter measured just before IV administration of drug (baseline). Data are shown for: 15 min after IV administration (preclamp), just after clamping (afterclamp), 20 min after clamping (preunclamp), and 0, 2, 5, 15, 30, and 60 min after unclamping. Values are mean ± sd. *P < 0.05 vs baseline in same group. P < 0.05 as indicated.

	DISCUSSION

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During an abdominal aortic aneurysmectomy, abrupt changes in hemodynamics and a significant increase in pulmonary artery pressure, with an increase in pulmonary vascular resistance, can be induced both by aortic cross-clamping itself and by the release of the aortic cross-clamp (9,10). Anesthesiologists occasionally use vasodilators, such as nicardipine and PGE1, to control any systemic or pulmonary hypertension during or after aortic cross-clamping and unclamping. We previously reported first that unclamping of an abdominal aortic cross-clamp causes a sustained cerebral pial arteriolar constriction in rabbits, and second that a concomitantly administered vasoactive drug (such as milrinone or colforsin daropate, which have been commonly used in critical situations, such as that occurs in aortic surgery) can attenuate this unclamping-induced cerebral vasoconstriction (7,8), a favorable interaction in the clinical setting. We therefore thought it important to establish the effects of nicardipine and PGE1 on the cerebral alterations induced during aortic cross-clamping or after aortic unclamping, because this may be crucial if we are to reduce the incidence of neurologic complications in the CNS during aortic surgery. Although such complications related to abdominal aortic surgery are not particularly common, similar phenomena can occur upon any unclamping during aortic surgery (including thoracic aortic aneurysmal surgery), leading to CNS complications. The present model is suitable for the investigation of the cerebrovascular disturbances induced by the production of humoral factors associated with the ischemia and reperfusion caused by any aortic clamping and unclamping.

First, it was necessary to consider the direct effects of nicardipine and PGE1 on cerebral blood flow and vessel diameter. Although PGE1 decreases arterial blood pressure by relaxing vascular smooth muscle, mainly by dilating resistance vessels, it has variously been reported to dilate (2), not to affect (11,12), or to constrict (13) cerebral vessels. On the other hand, nicardipine has been reported to increase cerebral blood flow in both human and rabbit studies (14–16), and indeed it has been used for the treatment of cerebral vasospasms (17). We previously observed, in a rabbit cranial window study, that PGE1 had little or no effect on cerebral vessels during the hypotension induced by its IV administration, but that when essentially the same experiment was performed using nicardipine, the same level of hypotension was associated with a dilation of cerebral vessels (12). However, in the present study none of the clinically relevant doses of nicardipine or PGE1 (smaller doses than in our previous study; namely, at 0.1,1.0, or 10 µg·kg^–1·min^–1 for nicardipine, and at 0.1 or 1.0 µg·kg^–1·min^–1 for PGE1) by themselves significantly altered the diameter of cerebral vessels, nor did they induce a significant hypotension.

In a previous study, cross-clamping of the infrarenal aorta in humans was shown to be associated with an increase in thromboxane A2 (TxA2) synthesis and also with time-related increases in mean pulmonary artery pressure and pulmonary vascular resistance (18). Moreover, reperfusion of the ischemic lower torso after aortic unclamping also leads to a synthesis of TxA2, resulting in neutrophil and platelet activation, and pulmonary dysfunction (19,20). We previously obtained evidence suggesting that such an increased level of TxA2, after its washout from the ischemic region in experiments involving clamping and cross-clamp release, could contribute, at least in part, to the sustained pial arteriolar constriction that is seen after the unclamping of an abdominal aortic cross-clamp (7). Feng et al. (21) indicated that PGE1 (28 nmol/L) inhibited the release of cardiac-derived TxA2 induced by reperfusion of the isolated rat heart, while Terashita et al. (22) showed that PGE1 (2.8–280 nmol/L) inhibited the platelet-activating factor-induced release of TxA2 in the isolated rat heart and lung. Moreover, nicardipine has been reported to induce concentration-dependent (10^–10 to 10^–3 M) relaxation of TxA2 analog (U46619)-preconstricted human umbilical arteries (23) and human internal mammary arteries (24). In contrast, in the present study neither dose of PGE1 had any significant effect on the sustained pial arteriolar constriction seen after aortic unclamping, and only the two larger doses of nicardipine attenuated it. Although the estimated plasma concentrations of the two drugs used in the present study (4,25) may have been relatively low when compared with the values attained in the previous experimental studies mentioned earlier, the precise explanation for the small effects of these drugs on unclamping-induced cerebrovascular constriction remains unclear. Our previous data showed that in rabbits, IV PGE1 did not dilate cerebral pial arterioles, although on direct application PGE1 did dilate such arterioles, whereas nicardipine had a vasodilator effect upon either IV or topical administration (12). Thus, the implication is that the blood-brain barrier permeability of PGE1 may be less than that of nicardipine. If that is indeed so, then it is possible that the difference between these drugs in blood-brain barrier permeability or in the effective dose (plasma concentration) needed to relax the unclamp-induced constriction of cerebral vessels might contribute to their different effects on cerebral vasoactivity after aortic unclamping.

The following points must be considered in the assessment of the clinical relevance of the present results: First, the "clinical" infusion doses of nicardipine and PGE1 (including the highest dose used here of each drug, which may induce systemic hypotension in humans) did not cause any significant decrease in systemic blood pressure in the pentobarbital-anesthetized rabbit. It is possible that the species difference might help explain this discrepancy. If we were to use much larger doses of these drugs, which would presumably induce significant hypotension in the present model, the results might be different. Second, as the basal anesthetic state achieved using pentobarbital might affect the tone of the cerebral arterioles, we cannot exclude the possibility that the observed effects on pial arteriolar tone might have been modulated by our use of pentobarbital. Moreover, if we were to use a volatile anesthetic instead of pentobarbital as the basal anesthetic, the decreases in the pial arteriolar diameter after unclamping might be smaller.

In conclusion, a sustained pial arteriolar constriction was induced in pentobarbital-anesthetized rabbits when the aorta was unclamped following a 20-min aortic cross-clamp. Only the larger doses of nicardipine used (1.0 and 10 µg·kg^–1·min^–1), but neither dose of PGE1, attenuated this unclamping-induced pial vasoconstriction. Thus, we suggest that if the vasodilators nicardipine and PGE1 were given IV at the present doses during aortic surgery, they would not aggravate unclamping-induced cerebral vasoconstriction, and nicardipine (at the larger doses) might even attenuate it.

	Footnotes

 
Accepted for publication November 2, 2006.

Supported by Ministry of Education, Science, and Culture, Tokyo, Japan Grants 13671570 and 18591697.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kumazawa, M. Articles by Dohi, S. Search for Related Content PubMed PubMed Citation Articles by Kumazawa, M. Articles by Dohi, S. Related Collections Neuroanesthesia Physiology Pharmacology