Anesth Analg 2008; 106:910-915
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31816195bc
NEUROSURGICAL ANESTHESIOLOGY
The Effects of Transient Cerebral Ischemia on Vasopressin-Induced Vasoconstriction in Rabbit Cerebral Vessels
Masahiko Kumazawa, MD*,
Hiroki Iida, MD*,
Masayoshi Uchida, MD ,
Mami Iida, MD ,
Motoyasu Takenaka, MD*,
Naokazu Fukuoka, MD*,
Tomohiro Michino, MD*, and
Shuji Dohi, MD*
From the *Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu City, Gifu, Japan; Department of Anesthesiology and Critical Medicine, Oregon Health and Science University, Portland, Oregon; and Department of Cardiology, Gifu University Graduate School of Medicine; Gifu City, 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
BACKGROUND: Vasopressin is a drug of choice for use during cardiopulmonary resuscitation because several experimental studies have shown that it is better than epinephrine at increasing systemic perfusion pressure and improving cerebral perfusion pressure without increasing myocardial oxygen consumption. We used a pial window preparation to determine the effects of vasopressin when applied topically to pial vessels and whether any effects were altered after cerebral ischemia in rabbits (n = 27).
METHODS: We first examined the effects of topical application of arginine-vasopressin (AVP) (10–11 M, 10–9 M, 10–7 M, and 10–5 M, sequentially). We then examined the effects of topical application of AVP (10–9 M and 10–7 M, sequentially) before and after a 5-min intervention consisting of cerebral ischemia produced by inflation of a neck tourniquet plus systemic hypotension or systemic hypotension alone.
RESULTS: Pial arteriolar diameters were (a) dilated by 10–11 M AVP [7% ± 11% (P = 0.014 versus baseline)], but constricted by 10–9 M, 10–7 M, and 10–5 M AVP [7% ± 14%, 20% ± 14%, and 16% ± 16% (each P < 0.05), respectively], and (b) constricted before hypotension (7% ± 10% at 10–9 M, 20% ± 15% at 10–7 M) or ischemia (7% ± 11% at 10–9 M, 21% ± 15% at 10–7 M). However, after the 5-min of ischemia, the decrease in diameter induced by 10–7 M AVP was significantly reduced but not by hypotension alone [hypotension control group: 7% ± 10% at 10–9 M, 19% ± 14% at 10–7 M; ischemia group: 5% ± 11% at 10–9 M, 10% ± 13% at 10–7 M (P = 0.35 versus hypotension control)].
CONCLUSIONS: Topical application of AVP (except at the lowest concentration used here) induced concentration-dependent vasoconstriction of pial arterioles in anesthetized rabbits. The vasoconstrictor effect of 10–7 M AVP was reduced after transient (5-min) cerebral ischemia.
Vasopressin, a potent vasoconstrictor neuropeptide in peripheral arteries, is often used for the treatment of critical arrhythmia or cardiopulmonary arrest in the clinical setting.1–4 This is because several experimental studies have shown that even during the severe acidosis induced by cardiopulmonary arrest or after resuscitation, vasopressin increases systemic perfusion pressure without increasing myocardial oxygen consumption, which is, in contrast, increased by the β-adrenergic inotropic effects induced by catecholamines such as epinephrine.5 For this reason, vasopressin is accepted as a drug of choice for use during cardiopulmonary resuscitation (CPR).
The vasoconstrictor effect of vasopressin varies according to the target organ. Vessels in major organs, such as brain, heart, and liver, are constricted less strongly by IV vasopressin than those in other, less crucial, peripheral tissues, suggesting that vasopressin might improve blood flow and oxygen supply to major organs after cardiac arrest and CPR.6–8 On this basis, vasopressin would be more favorable for the cardiac oxygen balance between demand and supply than epinephrine, and could lead to a greater improvement in cerebral perfusion pressure than epinephrine.
However, we know of no studies involving direct observations of the effects of vasopressin on the cerebral microcirculation before and after transient ischemia in vivo. The aims of the present study were therefore to investigate, in rabbits fitted with a cranial window: (a) the direct effect on the cerebral vessels of topical administration of various concentrations of arginine-vasopressin (AVP), and (b) whether responses are altered after transient cerebral ischemia produced by the neck-tourniquet method.
METHODS
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 27 anesthetized rabbits weighing 2.0–2.4 kg. Each animal was initially anesthetized with pentobarbital sodium (20 mg/kg body weight, IV) and maintained using inhalation of 0.5% isoflurane. Mechanical ventilation was achieved through an orotrachial tube using oxygen-enriched room air so as to maintain the inspiratory oxygen concentration at about 50%. The tidal volume and respiratory rate were adjusted to keep the end-tidal carbon dioxide tension (Petco2) at between 35 and 40 mm Hg, with Petco2 being monitored throughout the experiment. Polyvinyl chloride catheters were placed in the femoral vein for administration of fluid (lactated Ringer's solution: 5 mL · kg–1 · h–1), and in the femoral artery for blood sampling and continuous monitoring of systolic and mean arterial blood pressures (SAP and MAP) and heart rate (HR). Rectal temperature was maintained between 38.0°C and 39.0°C with a heating blanket and warming lamp.
In the present study, a closed cranial window was used to observe the cerebral pial microcirculation, as in our previous studies.9,10 Each animal was placed in the sphinx position, the scalp was retracted, and a hole 10-mm in diameter was made in the bone over the left parietal cortex. The dura and arachnoid membranes were opened carefully, and a polypropylene ring with a coverslip glass was placed over the hole and secured using dental acrylic. The space under the window was filled with artificial cerebrospinal fluid (aCSF), 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. Four polyethylene catheters were inserted through the ring: one was attached to a reservoir bottle containing aCSF to maintain the desired level of intrawindow pressure (5 mm Hg), whereas the second was used to monitor intrawindow pressure, the third for the administration of experimental drugs and aCSF, and the fourth 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 three pial arterioles and three pial venules 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 segments were averaged for each type of vessel (arteriole or venule) in each rabbit, and this average value was used in the statistical analysis. The diameters of these pial arterioles and venules were within the range 30–120 µm.
Measurements of cerebral pial vessel diameter, hemodynamic variables (SAP, MAP, and HR), and various physiologic variables (rectal temperature, intrawindow temperature, arterial blood gas tensions, electrolytes, blood glucose, and blood pH) were taken at set time-points.
Experimental Protocol
The study was divided into two parts. In the first experiment, we evaluated the cerebrovascular responses to topical application of various concentrations of AVP in normal rabbits (n = 12). After baseline measurements had been made, each rabbit was infused under the window with AVP (Sigma, St. Louis, MO), the various concentrations (10–11 M, 10–9 M, 10–7 M, and 10–5 M) being infused for 10 min each, sequentially. A 20-min infusion of aCSF was used to completely wash out each concentration of AVP from the space under the window. Throughout the experiment, all infusions were at a rate of 0.25 mL/min. Each solution was freshly dissolved in aCSF for the present study. Measurements were taken just before the start of topical application of AVP (baseline) and at 10 min after the start of the infusion of a given concentration of AVP.
In the second experiment, we evaluated the effects of transient cerebral ischemia on the responses to AVP (n = 15) using two concentrations of AVP (10–9 M and 10–7 M) that had been found to induce typical concentration-dependent cerebral vasoconstriction in the first experiment. The following additional preparation was performed in each rabbit before the closed cranial window was prepared: A tourniquet was placed snugly around the neck to permit later occlusion of four arteries (bilateral common carotid arteries and bilateral vertebral arteries) instantaneously. This was done by inflating a cuff using compressed air (INFLATOMATIC 3000 REGULATOR; Zimmer) so as to produce transient cerebral ischemia. Rabbits were assigned to one of two groups [ischemia group (n = 9) or control group (n = 6)]. As in the previous experiment, baseline measurements were made and each rabbit was topically administered AVP (10–9 M or 10–7 M) for 10 min each concentration sequentially, with aCSF being infused for 20 min to wash out each AVP application (preintervention period). Then, at the end of the 20-min wash out of 10–7 M AVP that followed the infusion, a 5-min period of cerebral ischemia was produced (ischemia group). This was done by inflating the neck tourniquet to 760 mm Hg while inducing systemic hypotension (MAP <40 mm Hg) by giving phentolamine (0.5 mg, IV). In the control group, a 5-min period of hypotension was induced as in the ischemia group (MAP <40 mm Hg) without tourniquet inflation. We confirmed that cerebral blood flow ceased upon inflation of the neck tourniquet in the ischemia group by viewing the exposed cranial field through a microscope and by electrocardiogram monitoring. After this 5-min intervention period, a 30-min interval of normotension was allowed. Then, the previous sequence [10-min infusions of AVP (10–9 M and 10–7 M) with 20-min aCSF washouts] was repeated in each group (postintervention period). To maintain the hypotensive or normotensive state, and so as to minimize hemodynamic changes, bolus IV administrations of phenylephrine (0.05 mg) or phentolamine (0.5 mg) were given intermittently throughout the experiment. Measurements were taken just before the start of the topical applications of AVP (baseline) and at 10 min after the start of infusion with each concentration of AVP. All experiments were begun after at least a 30-min recovery from the surgical preparation.
Statistical Analysis
Putative changes in all variables relating to the concentration-dependent effects of AVP and the effects of cerebral ischemia and/or hypotension within a given group were tested using a one-way analysis of variance for repeated measurements, followed by a paired t-test with a Bonferroni correction for post hoc comparisons. The differences between the two groups were assessed using a two-way analysis of variance, with differences at a given dose being examined by an unpaired t-test. Significance was set at P < 0.05. All values are expressed as mean ± sd.
RESULTS
In the first experiment (under control conditions), there were no significant differences in hemodynamic or physiologic variables among the various topical concentrations of AVP. The values obtained for SAP, MAP, HR, and Petco2 did not differ significantly from baseline at any concentration of AVP (Table 1). Arterial blood gas tensions, electrolytes, blood glucose, and blood pH were stable throughout the experiment, as were rectal temperatures and intrawindow temperatures. Pial arterioles responded to the topical infusions of AVP by constricting at 10–9 M, 10–7 M, and 10–5 M AVP [by 7.2% ± 14.4%, 20.3% ± 14.1%, and 16.3% ± 16.4% (P = 0.038, P < 0.01, P < 0.01 versus baseline), respectively], but by dilating at 10–11 M AVP [by 7.4% ± 10.9% (P = 0.014)]. Each of these changes was a significant difference from baseline (Fig. 1a). In contrast, pial venules showed no significant changes in diameter in response to any concentration of AVP (Fig. 1b).
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Figure 1. (a) Effects of topical infusion of arginine-vasopressin (10–11 M, 10–9 M, 10–7 M, and 10–5 M) on cerebral pial arterioles in 12 rabbits. Data are expressed as percentage change from the diameter measured just prior to topical administration of drug (baseline). Values are mean ± sd. *P < 0.05 versus baseline; **P < 0.01 versus baseline; (b) Effects of topical infusion of arginine-vasopressin (10–11 M, 10–9 M, 10–7 M, and 10–5 M) on cerebral pial venules in 12 rabbits. Data are expressed as percentage change from the diameter measured just before topical administration of drug (baseline). Values are mean ± sd. No statistically significant differences.
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In the second experiment, there were no significant changes in any of the physiologic values except a 5-min period of cerebral ischemia or systemic hypotension (Table 2). HR did not change significantly regardless of the imposition of cerebral ischemia or systemic hypotension. Rectal temperatures, intrawindow temperatures, arterial blood gas tensions, electrolytes, blood glucose, and blood pH were stable at all time-points throughout the experiment. The values of SAP and MAP obtained during the ischemia or hypotension period were significantly reduced compared with those obtained at the other time-points (data not shown). In the preintervention period, the arterioles were constricted by topical infusion of AVP to a similar extent as in the first experiment (control group: 7.3% ± 9.6% and 19.9% ± 15.1% at 10–9 M and 10–7 M, respectively; ischemia group: 7.4% ± 10.5% and 20.9% ± 15.0% at 10–9 M and 10–7 M, respectively). In the postintervention period, the arterioles were again constricted by AVP, but the decreases in diameter induced by 10–7 M AVP was significantly reduced in the ischemia group only [control group: 6.9% ± 9.6% and 19.2% ± 13.9% at 10–9 M and 10–7 M, respectively; ischemia group: 5.4% ± 10.5% and 10.5% ± 12.7% at 10–9 M and 10–7 M (P = 0.035 versus control group), respectively] (Fig. 2).
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Figure 2. Effects of the 5-min intervention period on responses of cerebral pial arterioles to topical infusion of arginine-vasopressin (10–9 M or 10–7 M) in 15 rabbits. The intervention entailed an induced systemic hypotension with (n = 9) or without (n = 6) cerebral ischemia. Data are expressed as percentage change from the diameter measured just before topical administration of drug (baseline). Values are mean ± sd. P < 0.05.
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The cumulative infused doses of phenylephrine and phentolamine were not significantly different between the control and ischemia groups.
DISCUSSION
The major findings made in the present study were that, in rabbits: 1) topical applications of AVP induced a dual response in pial arterioles viz. the lowest concentration used (10–11 M) caused a dilation, whereas all higher concentrations (10–9 M, 10–7 M, and 10–5 M) caused a constriction, and 2) after transient (5-min) cerebral ischemia, the vasoconstrictor effect of 10–7 M AVP was significantly reduced. There was no effect on venules. Such an attenuation of the vasoconstrictor response to AVP after transient ischemia could be favorable for the maintenance of cerebral blood flow when AVP is used to increase systemic and cerebral perfusion pressures during CPR.
It has been demonstrated that the effect of AVP is biphasic, an initial peripheral vasoconstriction followed by a vasodilation.11 Although AVP is a potent vasopressor by virtue of its endothelium-independent, V1-receptor-mediated contraction of vascular smooth muscle,12 it also increases the release of products of nitric oxide (a potent vasodilator) from vascular endothelial cells via the same receptor.13 Reportedly, these opposing effects of vasopressin vary according to the target vessels in the brain. Indeed, vasopressin has variously been reported to dilate the basilar artery,13,14 not to affect the middle cerebral artery,13 or to constrict the canine vertebral artery14 or pial arteries in cats or rats.15–17 According to Lluch et al., the vasoconstrictor effects of vasopressin on cerebral arteries are particularly prominent in human vessels,18 and so it is important for us to understand the direct effects of AVP on cerebral blood flow and vessel diameter. The results obtained here differ from those previously reported in other animals or in human vessels (in vitro or in vivo).13–18 The reason for this discrepancy is not yet clear, but it is possible that species differences, regional differences between brain vessels, and/or experimental design may explain it.
With regard to the plasma concentrations of AVP, it has been reported that patients who suffered a subsequent cardiac arrest had endogenous AVP concentrations of up to 193 pg/mL before CPR.19 Unfortunately, we know of no data concerning the concentration of exogenous AVP in the plasma used for CPR. When AVP is administered by bolus injection, its plasma concentration will increase substantially, possibly leading to cerebral vasoconstriction under normal conditions. Neither hemodynamic nor physiologic values were significantly changed by the present ischemic intervention, yet in the postintervention period the vasoconstriction induced by 10–7 M AVP was significantly attenuated in the ischemia group. Before the study, we were concerned that a brief ischemia might disturb the endothelium-dependent, more than the endothelium-independent, vascular regulation, with the release of nitric oxide perhaps being attenuated by the endothelial dysfunction induced by the ischemia. This would have led to the endothelium-independent vasoconstrictor effect of AVP being enhanced and, if true, this could be a contraindication for the use of AVP in maintaining the cerebral circulation during and after CPR. However, the actual results did not match our initial expectation, for reasons not explained or investigated in the present study. Nevertheless, such an alteration in the cerebrovascular response to AVP could be favorable for maintaining cerebral blood flow in the cerebral reperfusion state during CPR.
In the present study, we used a neck tourniquet to produce transient cerebral ischemia. The tourniquet was inflated rapidly using compressed air with the intention of occluding all cerebral arteries instantaneously without inducing blood stasis or extravasation, which might have affected cerebrovascular reactivity. Indeed, we observed that pial arterial blood flow ceased in the ischemia group by viewing the field under the window through a microscope. Systemic tissue damage during cardiac arrest and resuscitation in animal models leads to an activation of the arachidonic acid cascade and release of other humoral factors.6–8,20,21 These could affect cerebrovascular reactivity and, in addition, cardiac function after CPR and have powerful effects on cerebral perfusion pressure, with consequent effects on the cerebral circulation. In such models, it could therefore be difficult to be sure that the observed changes in the cerebral microcirculation result from the transient cerebral ischemia itself. In contrast, the present model allows direct investigation of any changes in the cerebrovascular responses to AVP induced by transient total cerebral ischemia without an actual circulatory arrest preparation.
When cerebral autoregulation is retained, cerebral arteriolar diameter can be altered by changes in MAP or the partial pressure of arterial carbon dioxide (Paco2). To minimize the MAP or Paco2 changes caused by the present intervention, and to avoid such unwanted changes in the cerebral microcirculation, we carefully used (a) bolus IV administrations of phenylephrine (0.05 mg; to increase MAP) or phentolamine (0.5 mg; to decrease MAP), and (b) adjustments in minute ventilation to maintain Petco2 at between 35 and 40 mm Hg throughout the experiment. In fact, except for the intervention period (inflation of the neck tourniquet and/or systemic hypotension), changes in MAP or Petco2 were insignificant in all groups throughout the experimental period.
A further potential concern is whether the basal anesthetic state achieved using pentobarbital and isoflurane might affect the tone of the cerebral arterioles, and we cannot exclude the possibility that the observed effects on pial arteriolar tone might have been modulated by our use of pentobarbital and isoflurane. It is possible that the species difference and basal anesthetics might affect the vasoconstrictor effects of AVP on the cerebral vessels. Similarly, we applied the AVP topically to the abluminal surface of the vessels and not intravascularly. This must be considered in the assessment of the clinical relevance of the present study.
In conclusion, topical application of AVP, except at the lowest concentration used, induced vasoconstriction of pial arterioles in anesthetized rabbits, and the greatest constriction occurred at an AVP concentration of 10–7 M. The vasoconstrictor effect of 10–7 M AVP was reduced after transient (5-min) cerebral ischemia. Such an alteration in the response to AVP after transient ischemia could be favorable for the maintenance of cerebral blood flow when AVP is used during CPR.
Footnotes
Accepted for publication November 6, 2007.
Supported by the Ministry of Education, Science and Culture, Tokyo, Japan (Grant-in-Aid for Scientific Research Nos. 13671570 and 18591697).
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