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Cardiovascular Research 1997 36(1):111-117; doi:10.1016/S0008-6363(97)00145-4
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Copyright © 1997, European Society of Cardiology

Effects of sympathetic nerve blockade on vasoconstrictive properties of nitric oxide synthase inhibition in sheep

Michael Booke, Rene Waurick, Hugo Van Aken*, Hans-Georg Bone, Andreas Meißner, Thomas Prien and Jörg Meyer

Department of Anesthesiology and Intensive Care Medicine, University of Münster, Albert-Schweitzer-Str. 33, 48129 Münster, Germany

* Corresponding author. Tel. +49 251 837255; Fax: +49 251 88704.

Received 1 August 1996; accepted 20 May 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Inhibition of nitric oxide synthase causes intense vasoconstriction. This effect is thought to be dependent on sympathetic nerve activity. Thus, we investigated the vasoconstrictive effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in sheep, in which a reversible sympathetic block was established by thoracic epidural anesthesia. Methods: Sheep (n = 11) were surgically prepared for chronic study. After at least 5 days of recovery, L-NAME was continuously administered and hemodynamics were monitored. This was done in sheep with and without sympathetic blockade in randomized order. Results: The vasoconstrictive effects of L-NAME were similar in sheep with and without sympathetic blockade. Conclusion: The obtained results suggest that the vasoconstrictive properties of nitric oxide synthase inhibitors are independent of sympathetic tone.

KEYWORDS Nitric oxide synthase inhibition; Epidural anesthesia; Sympathetic nerve activity; Hemodynamics; Sheep


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Controversy exists about whether the hemodynamic effects of nitric oxide synthase (NOS) inhibition are beneficial or deleterious. However, there is general agreement regarding the vasoconstrictive properties of compounds inhibiting NOS. Nitric oxide (NO) is produced by the constitutive nitric oxide synthase (cNOS). It stimulates soluble guanylate cyclase (GC), thus causing an increase of intracellular cyclic guanosine monophosphate (cGMP), which in turn produces relaxation of vascular smooth muscle cells [1, 2]. Inhibition of NOS thus causes intense vasoconstriction (for review see [3, 4]).

Most interesting, in terms of hemodynamics, is the interaction of NO with the sympathetic nervous system: NO can be synthesized by sympathetic nerves [5, 6]and inhibits the sympathetic nerve activity in the central nervous system [7–9]as well as in peripheral sympathetic nerve fibers [10–12]. Fig. 1 gives a schematic description of NO as a mediator for vascular smooth muscle relaxation and sympathetic nerve activity. Recently, it was reported that in cats, in which any sympathetic nerve activity was blocked by reversible cooling of the medulla, the administration of a NOS inhibitor failed to increase blood pressure [13]. A normal pressor response was obtained after NOS inhibition in cats with preserved sympathetic nerve activity. This study suggested that the vasoconstrictive effects of NOS inhibitors are dependent on sympathetic nerve activity. By contrast, the vasoconstrictive properties of NOS inhibitors have been shown in in vitro studies on denervated tissues [14, 15].


Figure 1
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  		Fig. 1 Schematic description of the NO–cGMP pathway and its interaction with the sympathetic nervous system. NO is produced by three different NO synthases (NOS). Under physiologic conditions, NO is synthesized by a constitutive isoform (cNOS) located in endothelial cells, and by an isoform located in the nervous system (brain NOS, bNOS). The NO produced diffuses into vascular smooth muscle cells and activates the soluble guanylate cyclase (GC), which in turn converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), thus causing vascular relaxation. Stimulation of sympathetic nerve fibers causes norepinephrine release and NO production by bNOS. Norepinephrine binds to receptors on the vascular smooth muscle cell and causes vasoconstriction. NO released from bNOS firstly stimulates GC and thus attenuates the norepinephrine-induced vasoconstriction, and secondly inhibits sympathetic nerve activity by a negative feedback mechanism.

 
In an attempt to resolve this controversy, we investigated the effects of NOS inhibition and its dependence on sympathetic nerve activity. We gave the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) to awake sheep in which a reversible sympathetic block (SB) was induced by epidural anesthesia [16, 17]. Thus, the effects of sympathetic nerve activity on the cardiovascular response to NOS inhibition could be analyzed in vivo.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
After appropriate approval, 11 ewes (mean body weight 35.2±1.2 kg) were prepared for chronic study. After premedication with ketamine (Ketanest, Parke Davis, Freiburg, FRG; 20 mg/kg, i.m.) the animals were anesthetized with halothane in oxygen using an animal anesthesia face mask until the depth of anesthesia allowed endotracheal intubation (Rüschelit i.d. 10 mm, Willy Rüsch GmbH, Kernen, FRG). The sheep were then mechanically ventilated with 1.5–2.5 vol.% halothane in oxygen. The respiratory frequency was adjusted to maintain paCO2 levels within the normal range (30–35 mmHg), and the tidal volume was fixed at 12 ml/kg. Under sterile conditions, a flow-directed pulmonary artery catheter was inserted through the right jugular vein and floated into the pulmonary artery. An arterial catheter (Cavafix 355, Braun AG, Melsungen, FRG) was positioned transcutaneously into the femoral artery. An epidural catheter was placed into the epidural space using the loss of resistance technique. The epidural space was transcutaneously punctured at the L5/S1 level using an 18-gauge Tuohy needle and then a silastic catheter was inserted into the epidural space and forward into the thoracic part of the spine. Spinal or intravascular position of the silastic catheter was excluded in case neither spinal fluid nor blood was aspirable through this catheter. All catheters were sutured to the skin. The sheep were then allowed to awaken and had at least 5 days to recover from the operation. During these days, they were held in metabolic cages and all vascular catheters were flushed with heparin solution (500 IU/ml NaCl 0.9%). Each day, a local anesthetic (bupivacaine 0.5%, Astra Chemicals GmbH, Wedel, FRG) was injected through the epidural catheter until the sheep exhibited a complete motoric blockade of all four extremities, verifying the efficacy of the epidural drug application.

After at least 5 days, during which the sheep had been accustomed to the paralytic state, the experiments were begun. A continuous infusion of Ringer's lactate at a rate of 2 ml/kg/h was started. All catheters were attached to pressure transducers and connected to a monitor (pressure transducers, DTXX, Ohmeda AG, Erlangen, FRG; physiological recorders, Servomed, PPG Hellige, Freiburg, FRG). A cardiac output computer (Model 9529, American Edwards Laboratory, Irvine, CA) was used for cardiac output measurements by thermodilution technique. The indicator, 5% dextrose (10 ml, 0–2°C), was injected in triplicate into the proximal port of the Swan–Ganz catheter, and the cardiac index was calculated as the average of these three measurements.

2.1 Experimental protocol
2.1.1 Control experiments
When the sheep had been connected to pressure transducers, baseline data (hemodynamics and blood gases) were obtained. Then NG-nitro-L-arginine methyl ester (L-NAME) was given as a bolus of 2.5 mg/kg, followed by a continuous infusion of 0.5 mg/kg/h (low L-NAME). All hemodynamic parameters were measured after 30 min. Then another bolus of 2.5 mg/kg/h L-NAME was given, and the infusion rate was increased to 1 mg/kg/h L-NAME (high L-NAME). Again, hemodynamic and blood gases data were collected after 30 min. The L-NAME-infusion was then stopped.

2.1.2 Sympathetic block experiments (SB)
This part differs from control experiments in that all measurements, except the baseline readings, were performed during blockade of the sympathetic nervous system on spinal level. After baseline measurements were made, bupivacaine 0.5% was injected into the epidural space through the previously positioned silastic catheter. Usually, after a total dose of 10–15 ml of bupivacaine, the animals' extremities became paralytic with a delay of approximately 10–15 min. The height of the pressure transducers was adjusted for the prostrate sheep. As in the standing animal, the elbow served as reference height. The infusion rate of Ringer's lactate was adjusted to keep the central venous pressure (CVP) at baseline level ±3 mmHg during the development of sympathetic block experiments (SB). Then, Ringer's lactate was infused at a rate of 2 ml/kg/h, as in control experiments. In two sheep, the skin temperature of the extremities was recorded while the epidural local anesthetic induced a SB (YSI 400 series probe, Servomed, PPG Hellige, Freiburg, FRG). After 60 min of SB, L-NAME was given as a bolus of 2.5 mg/kg, followed by 0.5 mg/kg/h (low L-NAME). After 30 min, all hemodynamic parameters were recorded, and another bolus of 2.5 mg L-NAME was given. The infusion rate of L-NAME was then increased to 1.0 mg/kg/h (high L-NAME). After another 30 min, the final measurements were taken and the L-NAME-infusion was stopped.

All sheep underwent both parts of the experimental protocol in randomized order, with at least 4 days in between to allow the animals to recover and to ensure that any remaining L-NAME was eliminated from the circulation. The entire investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No 85-23, revised 1985).

2.1.3 Statistics
All data are presented as mean±s.e.m. A probability of less than 5% was defined as significant. Significance was tested by the use of an ANOVA for repeated measurements with post-hoc Scheffe's F-test (Statview® II, Version 1.04, Abacus Concepts Inc., Berkeley, CA).


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
In all sheep, L-NAME caused a significant, dose-dependent decrease in cardiac index (CI), and an increase in mean arterial pressure (MAP), systemic and pulmonary vascular resistance (SVRI and PVRI, respectively) (Fig. 2). Mean pulmonary artery pressure (PAP) also increased significantly. The decrease in CI was related to a reduction in heart rate (HR), while stroke volume index (SVI) remained unchanged.


Figure 2
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  		Fig. 2 Hemodynamic data during NOS inhibition in control sheep (solid squares) and sheep with SB induced by epidural anesthesia (open circles). L-NAME administration during SB caused a significant increase in LVSWI, and a more pronounce drop in HR compared with control sheep. CI=cardiac index; MAP=mean arterial pressure; SVRI=systemic vascular resistance index; PAP=mean pulmonary artery pressure; PVRI=pulmonary vascular resistance index; HR=heart rate; SVI=stroke volume index; LVSWI=left ventricular stroke work index; RVSWI=right ventricular stroke work index; PaO2=arterial oxygen tension. *P<0.05 vs. baseline; {dagger}P<0.05 vs. control.

 
Epidural anesthesia was satisfactory in all sheep as judged by muscular relaxation and lack of response to a moderate pain stimulus (placement of a surgical clamp between the hoofs of the foreleg). The effects of SB induced by epidural anesthesia are summarized in Table 1. SB caused a significant reduction in HR and MAP. Furthermore, it resulted in a significant reduction in arterial oxygen tension (paO2) with simultaneous increase in carbon dioxide tension (paCO2). Skin temperature was measured in two animals and increased after the epidural administration of bupivacaine by 1.6 and 1.3°C, respectively, while body core temperature measured at the tip of the Swan–Ganz catheter remained unaffected (±0.0 and +0.1°C, respectively).


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  		Table 1 Hemodynamic effects of epidural anesthesia in awake sheep

 
The hemodynamic effects of L-NAME given to sheep during SB were similar to those obtained in control sheep. However, the drop in HR during SB was more pronounced compared with controls. Viewed separately, the changes in MAP and SVI during SB were not significantly different from controls. In combination, however, they caused a significant increase in the left ventricular stroke work index (LVSWI) after L-NAME administration during SB, a phenomenon not seen in controls.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
All experiments were performed in awake sheep, since interactions between NO synthase inhibitors and anesthetics are well described [18–22]. As anesthesia reduces sympathetic tone [23, 24], the observed interactions between anesthetic drugs and NOS inhibitors may be related to a suppressed sympathetic nerve activity rather than to direct drug interactions. To avoid such interactions, the presented study was performed in unanesthetized, chronically instrumented animals.

The hemodynamic effects of NOS inhibition in sheep are well documented [25–28]. However, the (patho-) physiologic background is not completely understood. L-NAME and other NOS inhibitors competitively block NOS [29–36]. Consequently, less NO is produced, causing a decrease in intracellular cGMP, which finally causes vasoconstriction. However, NO is also produced in sympathetic nerve fibers by another constitutive isoform of NOS [5, 6]. High sympathetic nerve activity is associated with a progressively increasing NO release from the sympathetic nerve fiber [37, 38]. NO then not only causes vasodilation through increasing intracellular cGMP, but also by inhibiting the presynaptic release of norepinephrine from the sympathetic nerve terminal, thus counterbalancing the vasoconstriction induced by sympathetic stimulation [39]. Consequently, NO also serves as a mediator in a negative feedback loop, preventing extensive vasoconstriction. Blocking NOS consequently implies an inhibition of this negative feedback loop, leading to an increased sympathetic nerve activity with subsequently pronounced vasoconstriction [40]. Recently, this mechanism was suggested to be mainly responsible for vasoconstriction after NOS inhibition, since in cats without any sympathetic nerve activity, NOS inhibition did not cause any increase in blood pressure [13]. Unfortunately, in the cat model no cardiac output measurements are available, thus a vasoconstriction with an increased systemic vascular resistance and decreased cardiac output could not be ruled out. Lacolley et al. demonstrated, that after ganglionic blockade, the administration of a NOS inhibitor had no effect on blood pressure [41]. May be, as suggested by the authors, that after ganglionic blockade the basal NO production was downregulated, so that the inhibition of NOS could not further reduce NO production, and thus could not cause any vasoconstriction. If the blood pressure of these animals was elevated to normal levels with phenylephrine, NOS inhibition caused the blood pressure increase normally seen. Consequently, NO production, at normal blood pressure, is largely independent of sympathetic nerve activity. However, several other studies suggest that NOS inhibition, at least in part, causes vasoconstriction through an increase in sympathetic tone [42–44], suggesting that continued vasoconstriction after NOS inhibition depends on sympathetic nerve activity. Sakuma et al. found in rats sympathectomized by spinal C1–C2 transection that the increase in blood pressure after NOS inhibition was significantly smaller than before transection [7].

In an attempt to resolve these issues, the study presented here was designed to examine in vivo the interactions between NOS inhibition and sympathetic nerve activity. Epidural anesthesia is a reliable and well-described method for induction of a sympathetic blockade [16, 17]that is familiar to any anesthetist. Local anesthetics given into the epidural space not only block motoric and sensoric nerve fibers, but also sympathetic nerve fibers. The SB causes vasodilation and is responsible for the fall in blood pressure observed during spinal/epidural anesthesia. SB also leads to an improved perfusion of the skin, since the skin perfusion is sympathetically reduced in order to minimize heat loss through the large skin surface. Thus, an elevation in skin temperature as found in the presented study, is a reliable indicator for SB when core temperature remains stable or slightly decreases [45]. Sympathetic nerve fibers lack a myelin sheath and thus are blocked much earlier and by lower concentrations of local anesthetics than motoric or sensoric nerve fibers. Furthermore, sympathetic nerve fibers leave the spinal cord between thoracic 1 and lumbar 3 (sheep differ from humans (T1–L1)), while the motoric innervation for front and back legs originates from cervical and lumbar segments, respectively. Thus a complete motoric blockade of all extremities during epidural anesthesia is accompanied by SB. Furthermore, a motoric and/or sensoric blockade (judged by muscular relaxation and lack of response to a moderate pain stimulus) may thus serve as an indicator for SB. We chose epidural anesthesia to induce SB, because firstly, the implantation of the epidural catheter can be easily performed and does not require any postoperative pain medication, and secondly, the SB is completely reversible. In all sheep, the SB resulted in a reduction in HR and MAP. Furthermore, epidural anesthesia caused a significant reduction in arterial oxygenation (paO2) and a simultaneous increase in arterial carbon dioxide tension (paCO2), most likely related to hypoventilation, caused by incomplete paralysis of respiratory muscles. Although each of these parameters given alone is no direct proof for a complete SB, all together they indicate an effective and more or less complete SB.

In all sheep, L-NAME caused a vasoconstriction with subsequent increase in MAP and SVRI. In the pulmonary circulation, the same changes took place. The reduction in CI was mainly related to a reduction in HR rather than to a reduction in SVI.

L-NAME given to sheep during SB caused similar hemodynamic effects (see Fig. 2). These data prove that NOS inhibition causes a vasoconstriction despite sympathetic blockade, suggesting that the hemodynamic effects of NOS inhibition are largely independent of sympathetic nerve activity. The drop in CI after L-NAME administration was no different in sheep with SB than in controls, although the HR was significantly lower in sheep with SB. Stroke volume index (SVI) thus was significantly higher in sheep with SB. This is most likely related to the prolonged diastolic phase: ventricular filling is slightly reduced after NOS inhibition, since the diastolic ventricular relaxation may be impaired [46]. A prolonged diastolic phase may give enough time for ventricular filling, despite a certain ventricular stiffness after NOS inhibition, thus leading to a higher SVI. That SVI remained high despite both the reduction in CI and the increase in MAP. Thus, the LVSWI was significantly elevated. In controls, however, this phenomenon could not be seen. Again, the only reasonable explanation is that the prolonged diastolic phase during SB allowed adequate ventricular filling despite a possibly impaired ventricular relaxation after NOS inhibition. During control conditions, the reduction in HR may not have been sufficient to compensate for this phenomenon.

One limitation of this study is that NOS activity has not been measured. As a consequence, the hemodynamic effects of L-NAME in this study cannot be directly related to an inhibition of NOS. However, the vasoconstrictive properties of L-NAME in vivo were confirmed by in vitro experiments, using isolated ovine vessels: the obtained vasoconstriction was solely related to the reduction in NO synthesis and could be completely reversed by the administration of an NO-donor [36]. Although the dose of 2.5 mg/kg did not completely block NOS, the dose of 5.0 mg/kg certainly blocked the majority of these enzymes. First, this dose is able to completely restore the vasodilation seen in ovine sepsis [47], a disease known to be characterized by a more than 1000-fold increase in NO production compared to the healthy state [32, 48]. Second, a 5-fold dose (25 mg/kg L-NAME) had comparable hemodynamic effects [49]. This was confirmed by a dose–response curve (unpublished data). Furthermore, a complete blockade of NOS is not absolutely necessary to assess the effects of SB on the hemodynamic effects of L-NAME, since L-NAME is known to have no intrinsic activity, no hormonal side effects and to act only through NOS inhibition [50].

In summary, despite its complex interactions with the sympathetic nervous system, NOS inhibition has the same vasoconstrictive properties in sheep with SB as in sheep without SB.

Time for primary review 26 days.


   References
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 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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