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Am J Physiol Heart Circ Physiol 294: H190-H197, 2008. First published October 26, 2007; doi:10.1152/ajpheart.00366.2007
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Direct and reflexive effects of nitric oxide synthase inhibition on blood pressure

Jill M. Wecht,1,2 Joseph P. Weir,3 David S. Goldstein,4 Annmarie Krothe-Petroff,1 Ann M. Spungen,1,2 Courtney Holmes,4 and William A. Bauman1,2

1Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York; 2Departments of Medicine and Rehabilitation Medicine, Mount Sinai School of Medicine, New York, New York; 3Des Moines University-Osteopathic Medical Center, Des Moines, Iowa; and 4Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Submitted 22 March 2007 ; accepted in final form 21 October 2007


   ABSTRACT
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Direct effects of vasoactive substances on blood pressure can be examined in individuals with tetraplegia due to disruption of descending spinal pathways to sympathetic preganglionic neurons, as cervical lesions interfere with baroreceptor reflex buffering of sympathetic outflow. In this study, we assessed effects of the nitric oxide synthase inhibitor nitro-L-arginine methyl ester (L-NAME) on mean arterial pressure, heart rate, and plasma norepinephrine concentrations in individuals with tetraplegia vs. effects shown in a neurologically intact control group. Seven individuals with tetraplegia and seven age-matched controls received, on separate visits and in the following order, placebo (30 ml normal saline) and 0.5, 1, 2, and 4 mg/kg L-NAME intravenously over 60 min. Supine hemodynamic data were collected, and blood was sampled at the end of each infusion and at 120, 180, and 240 min thereafter. L-NAME increased mean arterial pressure, and the relative increase was greater in the tetraplegia group than in the control group. Heart rate was reduced after L-NAME administration in both groups. L-NAME decreased plasma norepinephrine in the control group but not in the group with tetraplegia. These findings suggest that reflexive sympathoinhibition normally buffers the pressor response to nitric oxide synthase inhibition, an effect that is not evident in individuals with tetraplegia as a result of decentralized sympathetic vasomotor control.

spinal cord injury; nitro-L-arginine methyl ester; norepinephrine; sympathetic nervous system

FLUCTUATIONS IN BLOOD PRESSURE (BP) are normally buffered by the baroreceptor reflex, through modulation of norepinephrine (NE) release from postganglionic sympathetic nerves. Individuals with tetraplegia, due to disruption of descending spinal pathways to sympathetic preganglionic neurons, have low circulating plasma NE and manifest partial to complete interruption of this neurocirculatory reflex (5, 8, 17). In those with tetraplegia, BP responses to vasoactive substances more readily provide evidence for direct vascular effects, independent of reflexive baroreceptor control.

Nitric oxide (NO), one of the most potent endogenous vasodilators, is derived from the action of NO synthase (NOS) on its substrate, L-arginine. In neurologically intact models, NO modulates vascular tone directly by relaxing vascular smooth muscle (27) and indirectly by restraining central sympathetic outflow (10) and NE release from nerve terminals (23). Thus inhibition of NOS would be expected to increase BP by inhibiting vascular smooth muscle relaxation and by releasing central sympathetic outflow from tonic inhibition (16). In support of the latter mechanism, in intact subjects, {alpha}-adrenoceptor blockade by phentolamine blunts the delayed rise (60+ min) in BP after administration of a NOS inhibitor, suggesting a contribution from the postganglionic sympathetic nerves (21). If this mechanism were operative, the late rise in BP after NOS inhibition would be blunted in individuals with tetraplegia. In contrast, two recent publications have reported that ganglionic autonomic blockade with trimethaphan (7) or thoracic sympathectomy (15) potentiates pressor responses to NOS inhibition, suggesting baroreceptor reflex buffering in the unblocked state. Based on these latter studies, we hypothesized that, compared with able-bodied controls, individuals with tetraplegia would have accentuated BP responses to NOS inhibition, due to a limited ability to buffer BP via reflexive sympathoinhibition.

The present study assessed the BP and plasma NE responses to NOS inhibition in individuals with tetraplegia vs. responses in able-bodied controls. An augmented BP response and little to no change in plasma NE after NOS inhibition in those with tetraplegia were hypothesized to occur; in addition, an attenuated rise in BP in the control group due to baroreceptor reflex buffering, which would be evidenced by reduced plasma NE in response to NOS inhibition, was also hypothesized.


   METHODS
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Subjects. Demographic data are presented in Table 1. All subjects (n = 14) were between the ages of 22 and 51 yr, and they had no known history of cardiovascular disease, pulmonary disease, or diabetes mellitus. All were nonsmokers for a minimum of 1 yr before the investigation and were not taking medications known to affect autonomic cardiovascular function. Subjects with tetraplegia (n = 7) were healthy outpatients, at a minimum of 6 yr postinjury (18 ± 11 yr); all were nonambulatory and capable of maintaining an independent lifestyle. Using the American Spinal Injury Association (ASIA) classification of neurological impairment, two individuals were diagnosed with a complete injury (ASIA A) and the other five with an incomplete injury (ASIA B and C). The control subjects (n = 7) were matched for age, height, and weight to the subjects with spinal cord injury (SCI).


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  		Table 1. Subject characteristics

 
This study was approved by the Institutional Review Board for Human Studies of the James J. Peters Veterans Affairs Medical Center, and informed consent was obtained before subject participation.

Protocol procedures. Subjects were instructed to be well hydrated and to avoid heavy exertion, caffeine, and alcohol for a minimum of 24 h before they were tested. Data collection commenced between 8:00 and 9:00 AM, and subjects visited the laboratory on as few as 3 and as many as 5 days for intravenous administration of placebo and nitro-L-arginine methyl ester (L-NAME) in the following escalating dose order: placebo (30 ml normal saline) followed by 0.5, 1, 2, and 4 mg/kg L-NAME. The dose regimen was not randomized; if the BP response to one dose of L-NAME exceeded a systolic pressure of 150 mmHg and/or a diastolic pressure of 90 mmHg, the next higher dose was not administered. After data were collected from three individuals with tetraplegia at the highest dose of L-NAME (4 mg/kg), and because increased sensitivity to NOS inhibition was noted, further data collection at this dose level was precluded because of safety considerations (Table 3). After this decision, the protocol was modified to include a low dose of L-NAME (0.5 mg/kg); therefore, the numbers of subjects who received each dose of L-NAME varied by date of enrollment (Table 1).


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  		Table 3. Peak pressure with 4.0 mg/kg L-NAME

 
After arrival to the laboratory, subjects were placed in the supine position and were allowed to rest quietly while ECG electrodes were applied to the chest for continuous heart rate (HR) monitoring (742 Mennen Medical ECG monitor, Bio-Medical Equipment Service, Louisville, KY). BP was measured by a trained clinician at the brachial artery using a standard adult BP cuff (WA Baum, Copiague, NY) placed around the left upper arm and was continuously monitored at the finger arterioles by photoplethysmography (Portapres; Finapres Medical Systems, Amsterdam, The Netherlands). An intravenous catheter was placed in the right anticubital vein and secured for administration of placebo and L-NAME (Clinalfa-Bachem, Bubendorf, Switzerland) and for sequential blood draws for NE (HPLC; National Institute of Health) (11). After 20 min of supine rest, baseline HR and BP data were collected, and the 60-min infusion was initiated. During data collection, subjects remained in the supine position for 240 min [1 h of infusion (60 min) and 3 h postinfusion (120, 180, and 240 min)]. HR and BP were continuously monitored and recorded every 15 min, and blood was drawn at baseline and at 30, 60, 120, 180, and 240 min.

Data analyses. Group differences at baseline were analyzed by unpaired t-test for demographic, cardiovascular, and NE data (Tables 1 and 2). Postinfusion data are presented as individual responses across the observation period for mean arterial pressure (MAP), HR, and NE during placebo and each L-NAME administration (Figs. 1, 3, 5). Differences in the mean responses to placebo or L-NAME infusion in the control group and the tetraplegia group were calculated, and 95% confidence intervals (CI) were constructed for the differences in mean responses between groups at each dose level for the average (averaged across time) postinfusion value for each of the dependent variables. The 95% CI represents the range of scores around the group mean difference (control – tetraplegia) for the average postinfusion results for MAP, HR, or NE (see Table 4).


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  		Table 2. Baseline characteristics

 

Figure 1
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  		Fig. 1. Individual mean arterial pressure (MAP) responses to placebo and nitro-L-arginine methyl ester (L-NAME) infusion in subjects with tetraplegia (left) and in controls (right). Responses to placebo and 0.5, 1.0, 2.0, and 4.0 mg/kg L-NAME are displayed from top to bottom, respectively. The mean group response is depicted by the solid line.

 

Figure 3
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  		Fig. 3. Individual heart rate (HR) responses to L-NAME in subjects with tetraplegia (left) and in control subjects (right). Responses to placebo and to 0.5, 1.0, 2.0, and 4.0 mg/kg L-NAME are displayed from top to bottom, respectively. Mean group response is depicted by the solid line. bpm, Beats/min.

 

Figure 5
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  		Fig. 5. Individual plasma norepinephrine (NE) responses to L-NAME in subjects with tetraplegia (left) and in control subjects (right). Responses to placebo and to 0.5, 1.0, 2.0, and 4.0 mg/kg L-NAME are displayed from top to bottom, respectively. Mean group response is depicted by the solid line.

 

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  		Table 4. Mean group responses and 95% CI for the mean group difference

 
Postinfusion responses to placebo or L-NAME were also quantified by calculating the area under the curve (AUC) for the change in the dependent variables (MAP, HR, NE) relative to baseline for each individual subject (6, 18). That is, for each postinfusion time point, a delta score was calculated from the baseline score, and AUC data of the delta scores were treated as dependent variables in the statistical analyses of MAP, HR, and NE. The AUC data for each variable was statistically analyzed by mixed modeling via PROC MIXED in SAS, which allows for the analysis of data with missing values. The factors in the analysis were group (tetraplegia, control), dose (placebo, 0.5, 1.0, 2.0, and 4.0 mg), and group-by-dose interaction effect. Examination of the covariance structure for each variable showed that the compound symmetric structure was the best fit relative to other structures available for comparison in SAS.


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There were no significant differences among the groups for subject demographics (Table 1). In general, baseline MAP was lower in the tetraplegia group than in the control group, although a statistically significant group difference was only observed at the placebo and 1.0 mg/kg L-NAME visits (Table 2). Individual MAP responses after L-NAME administration were, on average, greater in those with tetraplegia than in control subjects (Figs. 1 and 2). With increases in L-NAME dose, there was a modest effect on MAP in the control group but a marked increase in MAP in the tetraplegia group (Tables 3 and 4; Figs. 1 and 2). Of note, the 95% CI does not span zero during placebo infusion, indicating that MAP is increased in the control compared with that in the tetraplegia group. However, with each dose of L-NAME, group differences for MAP are eliminated (95% CI includes zero); in fact, the trend reverses, such that at the 4.0 mg/kg dose the group mean difference is largely negative, indicating a higher MAP in the tetraplegia than in the control group (Table 4). The results of the mixed model analysis for MAP indicate significant group [F(1,12) = 7.4, P = 0.019], dose [F(4,39) = 18.5, P < 0.0001], and interaction [F(4,39) = 3.82, P = 0.01] effects (Fig. 2). The significant interaction effect demonstrates that the response to placebo or L-NAME differed among the groups; specifically, the MAP response to escalating L-NAME dose was heightened in subjects with tetraplegia.


Figure 2
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  		Fig. 2. Group average area under the curve (AUC) for the MAP change from baseline ({Delta}MAP) at each time point postinfusion across placebo or L-NAME dose. There was a significant group, dose, and interaction effect for {Delta}MAP.

 
Baseline HR did not differ among the groups (Table 2). HR was reduced in a dose-response manner after L-NAME infusion, and this response was similar in the tetraplegia and control groups (Table 4; Figs. 3 and 4). As such, the 95% CI for the group difference in average postinfusion HR included zero for all L-NAME doses (Table 4). Similarly, the results of the mixed model analysis for HR indicated a significant main effect for dose [F(1,39) = 22.4, P < .0001], whereas neither the main effect for group [F(1,12) = 2.4, P = 0.15] nor the group x time interaction effect [F(4,39) = 0.6, P = 0.64] was significant.


Figure 4
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  		Fig. 4. Group average AUC for the {Delta}HR from baseline at each time point postinfusion across placebo and L-NAME dose. There was a significant group effect for {Delta}HR.

 
Baseline plasma NE was significantly reduced in the tetraplegia group compared with the control group (Table 2). Individual plasma NE responses to placebo or L-NAME infusion varied within the groups (Fig. 5). After L-NAME administration, plasma NE was reduced in a dose-dependent manner in the control group, whereas plasma NE levels were low at baseline in the tetraplegia group, and no further decrease was noted after L-NAME (Table 4; Figs. 5 and 6). Although the control group had higher plasma NE than the tetraplegia group at each dose of L-NAME, the 95% CI for group mean differences approached or included zero (Table 4). The results of the mixed model analysis for plasma NE demonstrated significant main effects for group [F(1,12) = 8.46, P = 0.013] and dose [F(4,38) = 3.57, P = 0.014]. Although the interaction effect approached but did not attain statistical significance [F(4,38) = 2.24, P = 0.083], it should be noted that, given the small sample size at the highest L-NAME dose (due to safety issues), a significant finding may have been undetectable because of low statistical power.


Figure 6
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  		Fig. 6. Group average AUC for the plasma {Delta}NE from baseline at each time point postinfusion across placebo and L-NAME dose. There was a significant group and dose effect for plasma {Delta}NE.

 

   DISCUSSION
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 ABSTRACT
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In individuals with tetraplegia, L-NAME caused a dose-dependent increase in MAP without a change in plasma NE, suggesting a direct pressor effect of NOS inhibition independent of sympathetic nervous system activity. In the control group, the MAP response to L-NAME was smaller than in the tetraplegia group and was accompanied by reduced plasma NE. Thus baroreceptor buffering caused reflexive sympathoinhibition, which constrained the pressor response to NOS inhibition in the control group.

It has been proposed that the central nervous system contributes substantially to the pressor response to NOS inhibition by modulating sympathetic preganglionic outflow. This has been examined after baroreflex deafferentation and cervical SCI in rodents (1, 20, 26). Initial elevations in BP after intravenous infusion of the NOS inhibitor N{omega}-methyl-L-arginine accompanied a reduction in sympathetic nerve activity, which was thought to reflect baroreflex buffering. NOS inhibition after baroreflex deafferentation unmasked a slow but significant increase in sympathetic activity, which potentiated the pressor response to N{omega}-methyl-L-arginine. In this rodent model, cervical SCI abolished the increase in sympathetic activity and diminished the pressor response to NOS inhibition (12, 20, 26). The authors concluded that increased sympathetic nerve activity contributes substantially to the pressor response after NOS inhibition.

The substantial rise in BP after L-NAME infusion at the 1 and 2 mg/kg doses in the tetraplegia group is comparable to that reported by Halliwill et al. (9) following intravenous phentolamine administration and argues against a synergistic sympathetic component to the pressor response. Although only two of the seven individuals with tetraplegia were classified as having a complete spinal lesion, plasma levels of NE were uniformly low in this group and were significantly reduced at baseline compared with values in the control group. Furthermore, plasma NE levels were suppressed in control subjects and remained low for 240 min after L-NAME administration, whereas increases in MAP persisted. A similar relationship has been reported between muscle sympathetic traffic and BP in able-bodied subjects after infusion of the NOS inhibitor N-monomethyl-L-arginine (L-NMMA) (4), and reductions in plasma NE have been documented for up to 60 min after cessation of L-NMMA infusion (3). Although the number of subjects that received the 4 mg/kg dose of L-NAME was small, the striking fall in plasma NE at this dose (Fig. 6) in the control group suggests that baroreflex buffering of BP resulted in withdrawal of sympathetic nervous system activity, and it has been demonstrated that intravenous infusion of L-NAME results in an increased pressor response following complete autonomic blockade in conscious rats (19).

There are several reports documenting the contribution of the sympathetic nervous system to the postinfusion (60+ min) pressor effects of NOS inhibition (1, 3, 20–22, 26, 29). Attenuation of the late rise in BP after intravenous L-NAME administration was reported in sympathectomized rats (50 mg guanethidine·kg–1·day–1) and in normotensive humans after {alpha}-adrenergic blockade with phentolamine (0.1 mg/kg) (21, 22). As such, the authors (21, 22) suggest that the sympathetic nervous system is partly responsible for the magnitude and duration of the effect of NOS inhibition on BP and postulate that this may relate to the time required for systemically administered L-NAME to cross the blood-brain barrier and inhibit NOS centrally. Our finding of a sustained elevation in MAP in individuals with tetraplegia does not support this postulate because plasma NE was uniformly low over the 240-min observation period in this group.

Mechanisms other than an impaired baroreceptor-mediated peripheral efferent vasomotor withdrawal may have contributed to the heightened BP response to NOS inhibition in the tetraplegia group. Although not measured in this study, previous reports have indicated that individuals with tetraplegia have reduced cardiac output (13, 24) compared with control subjects, which may have contributed to the augmented pressor response after NOS inhibition in this group (4). Although the vagal efferent arm of the baroreceptor is anatomically intact, functionally, this reflex may also be impaired in those with tetraplegia as the bradycardic response to the magnitude of BP elevation was relatively reduced compared with that shown in the controls, possibly indicating an attenuated cardiac output response. Increased baseline leg vascular resistance has been reported in individuals with SCI in conjunction with a preservation of {alpha}-adrenergic and NO contributions to basal vascular tone (2, 14, 25). Inhibition of NOS activity with L-NMMA caused an increase in leg vascular resistance in individuals with SCI similar to a non-SCI control group; although at higher doses (0.2 and 0.4 mg·min–1·dl–1 leg tissue) there appeared to be an augmented response in the SCI subjects, this was not statistically confirmed (2). To our knowledge, there is no information regarding NO bioavailability or vascular sensitivity to NO in a human model of SCI, although our group has reported increased inducible NOS expression 14 days postsurgical SCI in rodents (30) and suggested increased sensitivity to L-NAME infusion in men and women with tetraplegia (28).

There are several limitations to consider when interpreting the results reported herein. The model of tetraplegia is a heterogeneous example of autonomic disruption, and the extent of autonomic impairment for a particular level and completeness of SCI are unclear from clinical examination. This may have influenced intraindividual differences in the BP response to NOS inhibition, which might confound data interpretation. In addition, because of safety considerations, the sample size varied across the dose range, precluding statistical verification of group-by-dose interaction effects on plasma levels of NE. Despite these limitations, the BP response to L-NAME was observed to be increased in subjects with tetraplegia compared with controls, and this pressor response was independent of the sympathetic nervous system, as evidenced by the lack of change in plasma NE with NOS inhibition. In the control group, the reduced plasma NE in response to NOS inhibition suggests baroreceptor reflex buffering, which attenuated the rise in MAP compared with the tetraplegia group.


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This research was supported by the Veterans Affairs Rehabilitation Research and Development Service (B3203R), by the United Spinal Association, and by the National Institute of Neurological Disorders and Stroke intramural research program.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. M. Wecht, Center of Excellence: Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center; Rm. 1E-02, 130 West Kingsbridge Rd., Bronx, NY 10468 (e-mail: jm.wecht{at}va.gov)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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