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Anesth Analg 2001;93:1580-1586
© 2001 International Anesthesia Research Society

REGIONAL ANESTHESIA

Endogenous Endothelin and Vasopressin Support Blood Pressure During Epidural Anesthesia in Conscious Dogs

Olaf Picker, MD, Achim W. Schindler, MD, and Thomas W. L. Scheeren, MD

Department of Anesthesiology, Heinrich-Heine-University, Duesseldorf, Germany

Address correspondence and reprint requests to Olaf Picker, MD, Department of Anesthesiology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Address e-mail to olaf.picker{at}uni-duesseldorf.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We studied whether endogenous endothelin, like endogenous vasopressin, helps to maintain blood pressure during high epidural anesthesia when efferent sympathetic drive is diminished. On different days, six awake dogs underwent each of the following five interventions: blockade of vasopressin V1a receptors using [d(CH2)5Tyr(Me2)]AVP, (40 µg/kg) or endothelin receptors using tezosentan (3 mg/kg followed by 3 mg · kg-1 · h-1) with or without epidural anesthesia (1% lidocaine, intraindividual dose did not differ between experiments), and epidural saline (n = 5). The effects of endothelin- or vasopressin-receptor blockade were analyzed (means ± SEM) and compared by an analysis of variance for repeated measures (paired Student’s t-test, {alpha}-adjusted, P < 0.05). Vasopressin-receptor blockade decreased blood pressure (10 ± 2 mm Hg) only in the presence of epidural anesthesia, whereas endothelin-receptor blockade reduced blood pressure both in the presence and absence of epidural anesthesia (12 ± 3 versus 10 ± 1 mm Hg). During baseline and each intervention, plasma concentrations of vasopressin and big-endothelin were measured and compared by a Wilcoxon’s rank sum test; P < 0.05. Vasopressin concentrations increased during epidural anesthesia and after additional endothelin receptor blockade, but big-endothelin concentrations remained unchanged during each intervention. We conclude that vasopressin acts as a reserve system, as it stabilizes blood pressure specifically during epidural anesthesia, whereas the unchanged concentrations of big-endothelin indicate that the endothelin system is not specifically activated to support blood pressure during epidural anesthesia.

IMPLICATIONS: We studied in awake dogs whether endogenous endothelin, like endogenous vasopressin, helps to maintain blood pressure during resting conditions and epidural anesthesia. Only vasopressin was specifically activated to support blood pressure during epidural anesthesia, whereas endothelin supported blood pressure to the same extent during epidural anesthesia and during resting conditions.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
During resting conditions the sympathetic nervous system and the renin-angiotensin system predominate in the maintenance of blood pressure. The blood concentrations of the vasoactive peptides endothelin and vasopressin are small, so they can be characterized as a reserve system of blood pressure control. In contrast, during high epidural anesthesia widespread sympathetic blockade occurs, leading to a depression of the renin-angiotensin system (1,2), thus eliminating the two major vasoconstrictor mechanisms. Accordingly, during epidural anesthesia, endogenous vasopressin and endothelin are capable of maintaining blood pressure. Although the release of endogenous vasopressin is a key mechanism to maintain blood pressure during epidural anesthesia (2), the role of endothelin is unknown. However, in view of the increased endothelin concentrations during hypotensive challenges induced by hypovolemia (3), mesenteric ischemia (4), or pharmacologically (5), it is likewise plausible that endothelin contributes to the maintenance of blood pressure during epidural anesthesia. Therefore, we hypothesized that during epidural anesthesia the release of endogenous endothelin supports blood pressure in a similar fashion as vasopressin. To test this we studied the cardiovascular response to blockade of either endothelin or vasopressin receptors in combination with epidural anesthesia in awake dogs and compared these effects with those elicited by a sole blockade of either endothelin or vasopressin receptors.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The data derive from 29 experiments on 6 trained dogs (foxhounds weighing 28–35 kg) studied with approval of the District Governmental Animal Investigation Committee and treated in accordance with the Guiding Principles on the Care and Use of animals of the American Physiologic Society.

Several weeks before the experiments the dogs were operated under general anesthesia (enflurane/nitrous oxide + fentanyl) and sterile conditions. For blood pressure recording and blood sampling, both carotid arteries were exteriorized in skin loops. Ultrasound transit-time flow transducers (T101, Transonic Systems, Ithaca, NY) were implanted around the pulmonary artery for the continuous recording of cardiac output (CO) and calibrated in vivo at least three weeks after implantation as previously described (6). During convalescence the dogs were trained to lie quietly and unrestrained on their right side and to become familiar with the experimenters and the laboratory.

During the experiments the following variables were recorded continuously on an eight-channel polygraph (RS 3800, Gould Inc., Cleveland, OH) and simultaneously stored on the hard disk of a conventional personal computer for further analysis after analog-to-digital conversion with a rate of 1 kHz per channel.

Mean arterial pressure (MAP) and central venous pressure (CVP) were measured electromanometrically (Statham P-23ID; Elk Grove, IL) through catheters in the carotid artery and in the superior caval vein. Correct position of the central venous catheter, which was advanced from the animal’s hind limb, was checked by fluoroscopy and adequacy of the venous pressure curve. The electromanometers were referenced to the processus spinosus of the seventh vertebra and calibrated with a mercury manometer. CO was measured continuously and systemic vascular resistance (SVR) was calculated as quotient of (MAP - CVP) and CO. We also measured (intermittently) arterial blood gas tensions, O2 saturation, and pH (ABL3®, Radiometer, Copenhagen, Denmark).

To determine the plasma concentrations of vasopressin, endothelin, and big-endothelin, arterial blood samples were collected during baseline and at the end of each intervention (epidural anesthesia, receptor blockade) in chilled EDTA-tubes and placed immediately in crushed ice. Within 10 min plasma was separated by centrifugation and stored at -20°C until analysis. Vasopressin was measured by means of radioimmunoassay (125I Vasopressin, Bühlmann Laboratories AG, Allschwil, Switzerland) using rabbit anti-vasopressin antiserum. The minimum detectable dose was calculated to be 0.35 ng/L. Of note, vasopressin concentrations could not be measured after injection of the V1a-receptor antagonist because the blocker interferes with the test assay. Endothelin and big-endothelin, a sensitive measure of endothelin system activation (7), were measured by means of enzyme immunoassay (Biomedica, Boston, MA) using immunoaffinity purified polyclonal capture antibody and a monoclonal detection antibody. The detection limit for endothelin and big-endothelin is 0.05 pmol/L and 0.025 pmol/L, respectively.

At least 2 h before each experiment an epidural catheter was introduced percutaneously into the epidural space (usually between L5 and L6) through a 16-gauge Tuohy needle under sterile conditions during short-term sedation with propofol (3–4 mg/kg). The catheter was advanced rostrally into the epidural space and sutured to the skin. Exact position of the catheter tip (approximately T10) was verified by fluoroscopy with contrast medium, and care was taken that in successive experiments the catheter position did not vary for more than one intervertebral space in one animal.

Lidocaine 1% was injected into the epidural space; the volume injected depending on the dog’s length and individual spread of nerve block. Although the volume of lidocaine differed slightly between dogs (9–13 mL), it was identical in each animal in successive experiments. Cranio-caudal spread of epidural anesthesia was assessed as described previously (1,2) by paresis of the nictitating membrane of the eyes, absence of blood pressure increase to bilateral occlusion of the exteriorized carotid arteries (duration 45 s), sensory blockade up to the lower neck region, complete motor blockade of the hind limbs at the end of the experiments, and changed mode of respiration from a thoracic to a diaphragmatic pattern, indicating at least partial blockade of the intercostal musculature.

Endothelin was prevented from acting at its receptors by injecting tezosentan (3 mg/kg, followed by 3 mg · kg-1 · h-1, Actelion Ltd., Allschwil, Switzerland), an endothelin receptor antagonist with high affinity to ETA and ETB receptors (8). Vasopressin(V1a)-receptors were blocked by [d(CH2)5Tyr(Me2)]AVP (V-2255; Sigma Chemicals) (9) at a dose of 40 µg/kg.

Completeness of receptor blockade was assessed by injecting 2.5 and 5 µg of endothelin-1 (E-7764; Sigma Chemicals) or 200 and 400 mU of Arg-Vasopressin (V-0377; Sigma Chemicals), respectively, after the experiments. MAP increased after injection of 5 µg of endothelin-1 by 22 ± 1 mm Hg and remained constant (1 ± 3 mm Hg) after previous receptor blockade. In parallel, 400 mU vasopressin increased MAP by 20 ± 2 mm Hg without and -2 ± 2 mm Hg after blocking of the vasopressin receptors.

All experiments were performed with the awake dogs in the basal metabolic state (food withheld for 12 h with free access to water) and under standardized experimental conditions (dogs lying on their right side, lightly dimmed laboratory at thermoneutral temperature for dogs of 24°C) always beginning at 8 AM. During the experiments the dogs remained unrestrained on their right side on a cushioned table.

After connecting the animals to the recording system, we waited for approximately 30 min until all variables had reached a steady state as the animals calmed down. The actual experiments started with baseline measurements for a further 30 min. Thereafter, the dogs were randomly assigned to one of the following interventions:

1. Endothelin receptor blockade alone (n = 6). Tezosentan was injected to assess the role of endothelin during resting conditions.
2. Vasopressin receptor blockade alone (n = 6). The V1a-blocker was injected to assess the role of vasopressin during resting conditions.
3. Epidural anesthesia followed by endothelin receptor blockade (n = 6). Lidocaine 1% (9–13 mL) was injected into the epidural space over 5 min and the data were recorded for further 30 min, i.e., for a time sufficient to allow full spreading of epidural blockade. Thereafter, the endothelin receptor antagonist was injected as described above.
4. Epidural anesthesia followed by vasopressin receptor blockade (n = 6). After epidural injection of lidocaine 1% as described above, the V1a-blocker was injected IV.
5. Sham epidural anesthesia (n = 5). Saline (9–13 mL) was injected into the epidural space to exclude time-related changes during the experiments for the duration of 30 min.

After these interventions all variables were recorded for further 20 min. An interval of at least 2 wk was interspaced between successive experiments in one and the same animal.

Data for all results are given as means ± SEM. Comparisons were made by an analysis of variance for repeated measures (ANOVA), followed by a paired Student’s t-test and {alpha}-adjusted according to the Bonferroni procedure. The change in blood pressure after vasopressin or endothelin receptor blockade was compared by a paired Student’s t-test. Plasma concentrations of endothelin, big-endothelin and vasopressin were compared by Wilcoxon’s rank sum test. A P value < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
In general, endogenous endothelin maintains MAP during resting conditions and during epidural anesthesia, whereas endogenous vasopressin stabilizes MAP only during epidural anesthesia. This is detailed in Figure 1 in which the time course of MAP is summarized over the entire experimental period. First, baseline measurements apparently did not differ between study groups, which is a prerequisite for meaningful comparison. During resting conditions (Fig. 1A), MAP declined for approximately 10 mm Hg after endothelin receptor blockade, whereas it remained unchanged after vasopressin receptor blockade. During epidural anesthesia (Fig. 1B) MAP decreased similarly in the V1a- and Tezosentan group after injection of the respective blocker. In detail, starting from the same baseline, MAP decreased for approximately 20 mm Hg with the onset of epidural anesthesia and for a further 10 mm Hg during injection of the blockers. In contrast, MAP was almost unchanged throughout the experiment during sham epidural anesthesia (epidural saline).



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  		Figure 1. Time course of blood pressure during physiological conditions (A) and during epidural anesthesia (B) after injection of either an endothelin or a vasopressin receptor antagonist. Means ± SEM from six awake dogs in each group and five dogs in the "epidural saline" group. a indicates P < 0.05 against baseline; b indicates P < 0.05 against epidural anesthesia.

 
Vasopressin, big-endothelin, and endothelin plasma concentrations (Table 1) mirror the course of MAP. Vasopressin concentrations increased during epidural anesthesia, and increased further as MAP decreased after additional endothelin receptor blockade. In contrast, big-endothelin concentrations remained unchanged during all interventions and only endothelin concentrations increased after injection of tezosentan (with or without epidural anesthesia).


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  		Table 1. Plasma Concentrations
 
The effects on MAP elicited by endothelin receptor blockade in the presence or absence of epidural anesthesia are summarized in Table 2, and it is apparent that endothelin supports MAP during both conditions, whereas vasopressin supports MAP only during epidural anesthesia. After the injection of the endothelin receptor blocker, MAP decreased from 100 ± 2 mm Hg to 90 ± 3 mm Hg in the absence of epidural anesthesia and from 88 ± 3 mm Hg to 76 ± 3 mm Hg in its presence (P < 0.05 for both conditions). Although this decrease in MAP during resting conditions was mainly a result of a 10% decrease of SVR from 35 ± 3 mm Hg · min · L-1 to 32 ± 2 mm Hg · min · l-1 (P < 0.05), a 10% reduction of CO from 81 ± 4 mL · kg-1 · min-1 to 70 ± 7 mL · kg-1 · min-1 mainly accounted for the decrease of MAP during epidural anesthesia (P < 0.05). In contrast, V1a receptor blockade decreased MAP from 87 ± 1 to 79 ± 3 mm Hg only in the presence of epidural anesthesia; this was a result of a reduction of SVR (P < 0.05) at an unchanged CO. The injection of the V1a receptor blocker during resting conditions did not change any of these hemodynamic variables.


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  		Table 2. Hemodynamic Variables
 
For comparison of the effect size on MAP elicited by the blockers, relative changes to the respective control are given in Figure 2. MAP did not change after V1a receptor blockade but did so in all the other groups to a similar extent.



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  		Figure 2. Changes in blood pressure from the respective baseline values after injection of the vasopressin- (V1a) or the endothelin (ET) receptor antagonist. Values are means ± SEM from six awake dogs. Note that blood pressure deceased to almost the same extent after endothelin or vasopressin receptor blockade during epidural anesthesia (EPID) as well as after sole endothelin receptor blockade.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our results show that during epidural anesthesia both endogenous endothelin and vasopressin contribute to the same extent to the maintenance of MAP, whereas during resting conditions mainly endothelin supports MAP. However, the increase in vasopressin plasma concentrations during epidural anesthesia and the unchanged big-endothelin concentrations indicate that endogenous vasopressin supports MAP specifically during epidural anesthesia.

Our conclusion rests primarily on the tenable premises of a sufficient blockade of either the endothelin or the vasopressin system and the presence of almost complete and comparable sympathetic denervation in the animals.

There is little information in the literature about the amount of tezosentan required to obtain complete blockade of the endothelin receptors in dogs. However, like others (10) we observed a substantial increase in MAP after IV injection of endothelin-1, whereas in our experiments MAP remained unchanged after the same dose of endothelin-1 during endothelin receptor blockade. Moreover, the dosage used in our study is nearly identical to that used by others to completely block endothelin receptors in dogs (11,12).

Vasopressin is a very potent vasoconstrictor even at "physiological" concentrations. These effects are mediated via V1a receptors that are selectively blocked by the antagonist used in our study (13). This is additionally confirmed by the absence of any vasopressor response after injection of 200–400 mU of arg-vasopressin in the presence of the antagonist used here, whereas without this antagonist blood pressure increased by 20 mm Hg with a corresponding decrease in heart rate (2). Therefore, from a methodological point of view, the chosen dosages of the vasopressin and the endothelin antagonists used in our study should have been appropriate to block the respective receptors sufficiently.

Epidural anesthesia almost eliminated sympathetic activity as already discussed (see Methods). Sympatholysis should have been nearly complete, but even if sympathetic activity was not completely blocked this effect was identical in each individual animal, and it would only reduce the quantity but not the quality of the effects.

Thus, our study design was appropriate to detect changes in MAP related to the injection of either the endothelin or the vasopressin receptor blocker in the presence or absence of epidural anesthesia.

The endothelins are a group of potent vasoconstrictive peptides that is comprised of 21 amino acids. Until now three different isoforms (endothelin 1–3) have been identified, of which endothelin-1 is the original endothelin that is produced exclusively by endothelial cells. Within the synthesis of endothelin-1 several precursor peptides are involved, including big-endothelin, which is further cleaved to endothelin-1. The physiological role of endogenous endothelin in the maintenance of blood pressure is unclear because, for instance, in anesthetized dogs endothelin receptor blockade did not change blood pressure (14). However, it is now accepted that endogenous endothelin does contribute to blood pressure regulation under resting conditions (15), as blockade of its receptors decreased blood pressure in healthy volunteers (16) as well as in awake dogs (17). Consistent with our experiments, this was accompanied by a decrease in SVR as a measure of vasomotor tone. This may be explained by the fact that resistance arteries, which are the main determinant of vasomotor tone, are particularly sensitive to the effects of endothelin (18). Compared with the vasoactive properties of endothelin, vasopressin is less potent but nevertheless causes vasoconstriction even at "physiological" concentrations (19,20). However, under these conditions, most of its direct vascular actions are buffered by baroreflexes and are only unmasked after baroreceptor denervation (19) or after destruction of the central nervous system (21). In accordance with our results, sole blockade of the V1a-receptors failed to exert demonstrable cardiovascular effects not only in dogs (22) but also in humans (23). Thus, endogenous endothelin, but not vasopressin, contributes substantially to maintain blood pressure during resting conditions.

These resting conditions differ substantially from the situation during epidural anesthesia. Concomitant with the reduction of sympathetic tone during epidural anesthesia the renin angiotensin system does not counterbalance the hypotension associated with epidural anesthesia, as seen by the absence of any increase in renin concentration during epidural anesthesia (1,2). Thus, during epidural anesthesia, endothelin as well as vasopressin could act as a reserve system for blood pressure control. The role of vasopressin was unmasked by the injection of the V1a-blocker, which elicited a reduction in SVR resulting in a substantial decrease of MAP at an unchanged CO. This is in accordance with the view that during hypotensive challenges vasopressin is released, as indicated by the increase in vasopressin plasma concentrations in our experiments not only during epidural anesthesia but also during hemorrhage (24,25), when it acts as a vasopressor (26). Vasopressin plasma concentrations increased in our experiments and thus mirrored the reduction of MAP, as indicated by the largest vasopressin concentrations during a combination of epidural anesthesia and endothelin receptor blockade in association with the lowest MAP. Several receptor sites, like cardiopulmonary afferents, are sensitive to heart volume (24) as well as arterial baroreceptors (27) and thus are involved in the control and release of endogenous vasopressin. Nevertheless, the increased vasopressin concentrations in our study were most probably driven by unloading of arterial baroreceptors, as shown by the absence of this effect after sinoaortic denervation during graded hypotension (27) in contrast to an unchanged increase in vasopressin after sole cardiopulmonary denervation.

During epidural anesthesia, the role of endogenous endothelin to support MAP seems to be similar to vasopressin. Again, this was unmasked after injection of the respective antagonist, which reduced MAP slightly larger in the presence of epidural anesthesia than in the absence. However, there are substantial differences compared to the effects of vasopressin. Whereas MAP decreased after injection of the vasopressin blocker only in the presence of epidural anesthesia, endothelin receptor blockade elicited almost the same reduction in MAP in the presence as well as in the absence of epidural anesthesia. Surprisingly, endothelin did not support MAP to a much larger extent during epidural anesthesia than during resting conditions, as did vasopressin. This is in accordance with the unchanged concentrations of big-endothelin during the experiments, whereas the increase in endothelin concentration after endothelin receptor blockade most probably indicates displacement of endothelin from the receptors by tezosentan (15). This interpretation is likewise supported by the unchanged endothelin and big-endothelin concentrations during epidural anesthesia with concomitant vasopressin receptor blockade, although the reasons for the unchanged endothelin concentrations are unclear. In contrast to these results, hypotensive challenges induced pharmacologically (5), by hypovolemia (3), or by mesenteric ischemia (4) elicited increases in endothelin plasma concentrations, indicating that probably the integrity of the sympathetic nervous system is required to elicit increases in endothelin concentrations to counterbalance hypotensions. Nevertheless, endothelin receptor blockade elicited a decrease in MAP during epidural anesthesia and during resting conditions. This reduction in MAP was almost the same during both interventions, but was caused mainly by a decrease in CO during epidural anesthesia in contrast to a decrease in SVR during resting conditions.

In addition to the physiological understanding of blood pressure control during epidural anesthesia, the results of our study are of potential interest to clinicians because endothelin- and perhaps vasopressin receptor antagonist are on the rise as antihypertensive drugs. Accordingly, if an epidural anesthesia is performed within patients receiving such drugs, they are likely to expect a more severe hypotension.

Regardless of these speculations, we showed for the first time that during epidural anesthesia both endothelin and vasopressin contribute to the same extent to the maintenance of MAP, whereas during resting conditions endothelin, but not vasopressin, supports MAP. However, the different response of the endothelin and vasopressin plasma concentrations indicate that the endothelin system does not specifically support MAP during epidural anesthesia, whereas vasopressin acts as a reserve system for blood pressure control because it stabilizes MAP specifically during epidural anesthesia.


   Acknowledgments
 
Supported, in part, by a grant from the Deutsche Forschungsgemeinschaft (DFG) Az. SCHE 479/1.

We want to thank Dr. Martine Clozel, Actelion Ltd, for kindly providing us with the endothelin receptor antagonist.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication July 24, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press