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Division of Cardiology, 1Department of Internal Medicine, and 2Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97239
Submitted 15 August 2003 ; accepted in final form 25 November 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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nitric oxide synthase; sympathetic tone; heart rate
Thus the primary aim of the current study was to test the hypothesis that in conscious rats, as in anesthetized rats, NOS activity tonically provides a net inhibitory input to basal sympathetic tone by determining the effects on RSNA and heart rate (HR) of systemic NOS inhibition in conscious, unrestrained rats. We reasoned that if NO tonically inhibits basal sympathetic outflow, then abrupt inhibition of NOS would result in a prompt increase in RSNA and HR. Because nonspecific systemic NOS inhibition produces profound arterial hypertension, which would reflexly decrease sympathetic activity and HR, a key feature of this experiment was that confounding increases in arterial pressure were prevented by simultaneous infusion of a direct vasodilator, hydralazine.
The second aim of the study was to determine whether the action of NO on renal sympathetic outflow was altered by increases in endogenous angiotensin II (ANG II). It has been shown in conscious rabbits that while systemic NOS inhibition has no effect on basal RSNA in normal animals, in animals that received ANG II intravenously, NOS inhibition resulted in a net increase in nerve activity, suggesting that ANG II stimulates NOS-mediated sympathoinhibition in that species (25). However, whether increases in endogenous ANG II enhance NO-mediated sympathoinhibition in conscious animals is not known. We reasoned that if NO inhibits sympathetic outflow more in conscious rats with chronically elevated endogenous ANG II, then abrupt inhibition of NOS would result in a greater increase in RSNA and HR in animals on a low-salt (LS) diet, with high levels of circulating ANG II, than in animals on a high-salt (HS) diet.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Surgery. Twenty-four hours before the experiment, animals were anesthetized (25 mg ip pentobarbital sodium) for placement of vascular catheters and a renal sympathetic nerve electrode, as previously described (37, 43). In brief, a single polyethylene (PE) femoral arterial catheter (PE-10 heat-welded to a length of PE-50), and one or two femoral venous catheters (Tygon, Norton Performance Plastics; Akron, OH) were first implanted. A flank incision was then made, and a multifiber nerve bundle projecting to the left kidney was isolated and placed on a bipolar stainless steel electrode (0.005 in. diameter, A-M Systems; Everett, WA). The signal-to-noise ratio was assessed on an oscilloscope, and viable nerve bundles were embedded on their electrode in quick-drying, lightweight dental silicone (Bisico; Bielefield, Germany). The electrode leads, ground wire, and the vascular catheters were tunneled subcutaneously, and externalized at the nape of the neck. All incisions were closed in layers, and animals on NS and HS diets received isotonic saline (10 ml/kg iv) on completion of surgery, to counteract surgically induced intravascular fluid loss and maintain between group differences in ANG II levels.
Chemicals. Pentobarbital sodium for anesthesia was obtained from Abbott Laboratories (North Chicago, IL). Sodium nitroprusside (Elkins-Sinn; Cherry Hill, NJ) was used to determine maximal hypotension-induced RSNA. N
-nitro-L-arginine methyl ester (L-NAME) and its inactive D-isomer (D-NAME) were obtained from Sigma (St. Louis, MO). Fresh 10 mg/ml solutions of each chemical were made at the time of each experiment and titrated to pH between 7.3 and 7.4. Hydralazine was obtained from American Regent Laboratories (Shirley, NY), diluted to 2 mg/ml in 5% dextrose in water, and was used to prevent hypertension in animals receiving L-NAME. Phenylephrine (American Regent Laboratories), diluted to 1 mg/ml in 0.9% saline, was used in some animals to maintain arterial pressure. Hexamethonium chloride (30 mg/kg iv; Sigma) was used to block transmission at sympathetic ganglia to determine the noise level of the nerve recording.
Data acquisition. The arterial line was connected to a Grass bridge amplifier (7P1; Grass Instruments; Quincy, MA) for determination of phasic and mean arterial pressure (MAP). This signal was fed to a Grass tachograph (7P4) for determination of HR. Raw nerve activity was filtered, and frequencies between 100 and 3,000 Hz were then amplified, displayed on an oscilloscope, and fed to a Grass integrator (7P10), where the signal was whole wave rectified, and integrated in 1-s bins. The maximal RSNA was determined as the average nerve activity over 5 s during the phase of maximal hypotension after administration of a bolus of nitroprusside (70 µg) that lowered arterial pressure by >50 mmHg. At the end of each experimental protocol, background noise was determined by blockade of ganglionic transmission with hexamethonium (30 mg/kg), and the level of background noise was subtracted from values obtained for RSNA during the course of the experiment. RSNA was normalized to baseline nerve activity before the first intervention in the protocol (%baseline).
Experimental protocols. After overnight recovery after surgery, the vascular catheters and electrode leads were connected to their respective lines and recording equipment between 8 and 9 AM, while the animals rested unrestrained in their home cages. A minimum of 2 h was allowed to elapse after this before any interventions were performed. Baseline HR, MAP, and RSNA were then recorded, and the animals were administered nitroprusside to determine maximal hypotension-induced RSNA and HR. At least 30 min after this intervention, a 350-µl arterial blood sample was taken for determination of plasma renin activity (PRA), hematocrit, and plasma protein concentration. The blood withdrawn was immediately replaced with an equal volume of isotonic saline. At least 30 min thereafter, one of the protocols below was performed. HR, MAP, and RSNA were continuously recorded during all experiments. Nerve activity was quantified for 15- to 30-s periods at 
15-min intervals, at times when the animals rested quietly and MAP and HR were stable.
Protocol 1 was performed to test the hypothesis that NOS activity tonically inhibits basal sympathetic tone in conscious rats by determining whether nonselective NOS inhibition increases RSNA in conscious rats, when increases in arterial pressure are prevented. This was done by determining the responses of HR and RSNA to the administration of L-NAME, 10 mg/kg iv, given over 30 min in NS rats (n = 6). This dose of L-NAME is the lowest that achieves maximal NOS inhibition in the rat brain when given systemically and causes sustained NOS inhibition for several days (18). However, intravenous L-NAME causes a marked elevation in arterial pressure (15), which confounds interpretation of changes in HR and RSNA. Therefore, in this protocol hydralazine was simultaneously administered with L-NAME, via the second intravenous line, to prevent an increase in arterial pressure as a result of the vascular effects of L-NAME. The rates of hydralazine and L-NAME infusion were titrated as necessary to maintain resting MAP usually within 5 mmHg of baseline, while simultaneously infusing the complete dose of L-NAME within 30 min. MAP, HR, and RSNA were monitored for 60 min after drug administration.
Protocol 2 was performed as a time control and to control for potential nondrug effects of the administration of the L-NAME solution, including the effects of fluid volume and pH. In this protocol, D-NAME (10 mg/kg) was given at a fixed infusion rate over 30 min, without hydralazine, and MAP, HR, and RSNA were monitored for 60 min postinfusion (n = 10).
Protocol 3 was performed to test the hypothesis that endogenous ANG II enhances NO-induced sympathoinhibition, by determining whether NOS inhibition causes a greater rise in basal sympathetic activity in rats with high-circulating ANG II (LS rats, n = 5) compared with rats with low levels of circulating ANG II (HS rats, n = 6). In this protocol, HS and LS animals received L-NAME (10 mg/kg iv) over 30 min, as in protocol 1, again using simultaneous hydralazine infusion to keep arterial pressure at baseline.
Protocol 4 was performed to test the hypothesis that the expected differences in the effect of NOS inhibition on RSNA and HR in HS and LS rats were the result of differences in ANG II in these groups (as opposed to effects resulting from, for example, differences in plasma volume). We reasoned that any difference between these groups that resulted from the differences in circulating ANG II would be abolished by pretreatment with an ANG II receptor antagonist (AIIRA). In this protocol, LS (n = 5) and HS (n = 5) animals were administered the AIIRA L-158809 (1 mg/kg iv) over 1 min, 30 min before the infusion of L-NAME (10 mg/kg iv over 30 min) was initiated. In this protocol, PE was infused post-AIIRA as needed to maintain MAP, and then was weaned during L-NAME administration, with concomitant use of hydralazine, as needed, to keep MAP at baseline.
Hematocrit was determined from duplicate blood-filled hematocrit tubes that were spun at 5,000 rpm for 5 min and read with a microhematocrit reader (Adams; New York, NY). The tubes were then broken, and the plasma therein was used for duplicate determinations of plasma protein using a Hitachi protein refractometer (National Instruments; Baltimore, MD). PRA was determined by radioimmunoassay as the amount of angiotensin I produced in 1 ml of plasma incubated for 1 h (39); the ANG I antibody was generously provided by Dr. Ian A. Reid.
Data analysis. All data are presented as group means ± SE. Two-way ANOVA with repeated measures was used to assess MAP, HR, and RSNA responses to experimental and control interventions. Data were grouped to answer the following specific questions: 1) whether MAP differs over time (two-way ANOVA) between animals receiving L-NAME and D-NAME, or between HS and LS animals administered L-NAME, with or without prior ANG II receptor blockade; 2) whether RSNA or HR differ between NS animals given L-NAME or D-NAME; 3) whether RSNA or HR differ between HS and LS animals given L-NAME; 4) whether HR or RSNA differ between HS and LS rats given L-158809; and 5) whether RSNA or HR differ between HS and LS animals given L-NAME after pretreatment with AIIRA. Where significant differences (P < 0.05, time or interaction) were found, post hoc Newman-Keuls tests were performed to determine specific between- and/or within-group differences. ANOVA (and the post hoc Newman-Keuls test) was also used to test for differences between groups in baseline MAP, hematocrit, plasma protein concentration, and PRA. P values provided in the text are for the interaction, unless indicated otherwise. All analyses were performed using GB-STAT software (Version 7, Dynamic Microsystems; Silver Spring, MD).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The effects of administration of L-NAME on RSNA and HR in NS rats were markedly different from the effects of D-NAME (Fig. 1, B and C; P < 0.001, ANOVA). While D-NAME had no significant effect on RSNA or HR, RSNA fell to 42 ± 11% of baseline (P < 0.01) at completion of the L-NAME infusion. This effect was not sustained, and 60-min postdrug infusion RSNA was not statistically different from control (88 ± 7% vs. 87 ± 6% for D-NAME group). In contrast to this nonsustained effect on RSNA, L-NAME administration in NS animals also caused a profound bradycardia, which was sustained over the entire subsequent period of observation (Fig. 1C). HR fell from 432 ± 23 beats/min at baseline to 372 ± 11 beats/min immediately after L-NAME (P < 0.01, whether compared with control or own baseline), and 60 min later remained markedly reduced, at 338 ± 12 beats/min (P < 0.01, compared with control or own baseline).
These findings indicate that, in contrast to our hypothesis, in conscious rats on NS diet, NOS activity provides a stimulatory input to RSNA and tonically supports HR.
Effects of NOS inhibition in LS and HS groups. As anticipated, PRA was significantly higher in animals receiving a LS diet compared with animals on a HS or NS diet (Table 1). Hematocrit and plasma protein concentration were also significantly higher in the LS group compared with the NS group. Resting MAP did not differ between HS, LS, and NS animals (P 
0.1), although resting MAP was lower in the subset of HS animals used for protocol 4 compared with those used in protocol 3 (Fig. 3A).
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MAP did not change in LS and HS animals given L-NAME (protocol 3; Fig. 2A; P > 0.5, ANOVA, interaction and time); thus again hydralazine administration prevented arterial hypertension. The dose of hydralazine required to maintain MAP at baseline did not differ among NS (1.1 ± 0.1 mg/kg), LS (1.3 ± 0.3 mg/kg), and HS (0.9 ± 0.1 mg/kg) groups (ANOVA, P > 0.3 for all comparisons). While the changes in RSNA in response to L-NAME did not differ between the LS and HS groups (or between these groups and NS rats; ANOVA, P > 0.5), as in the NS group, RSNA initially declined and subsequently returned to baseline values (Fig. 2B; P < 0.0001, ANOVA, time). Similarly, while the response of HR was not different between LS and HS rats (or between these groups and NS rats; P > 0.5, ANOVA), a sustained fall was observed in both groups (Fig. 2C; P < 0.0001, ANOVA, time). These data do not support the hypothesis that endogenous ANG II enhances a sympathoinhibitory effect of NO.
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Effects of NOS inhibition in LS and HS groups pretreated with AIIRA. As expected, administration of AIIRA produced differing effects on RSNA in LS and HS rats (P < 0.05, ANOVA). With arterial pressure held constant, RSNA fell to 78 ± 10% of baseline 30 min post-AIIRA in the LS group (P < 0.05, compared with HS group); no significant change in RSNA occurred in the HS group. HR was not significantly changed by AIIRA in either HS or LS groups (P > 0.3, ANOVA): HR was 420 ± 11 and 419 ± 11 beats/min in the LS and HS groups at baseline, respectively, and 30 min post-AIIRA was 415 ± 14 beats/min in the LS group and 431 ± 22 beats/min in the HS group.
The effects of subsequent L-NAME administration in LS and HS animals pretreated with AIIRA (protocol 4) are shown in Fig. 3, normalized to pre-AIIRA baseline. Again, MAP was maintained (P > 0.5, ANOVA) by coinfusion of hydralazine (1.2 ± 0.2 mg/kg, HS; 1.4 ± 0.3 mg/kg, LS; ANOVA, P > 0.5). The changes in RSNA and HR differed significantly between LS and HS animals pretreated with AIIRA (P < 0.005 for each, ANOVA). The difference between HS and LS groups in the response of HR was due entirely to a difference in heart rate 1-h post-L-NAME (Fig. 3C). In contrast, the entire pattern of change in RSNA after L-NAME was different between HS and LS animals pretreated with AIIRA (Fig. 3B). Whereas L-NAME caused an immediate and significant fall in RSNA in the HS animals, it did not in the LS group. Subsequently, whereas RSNA returned only to baseline in the HS group, in the LS group a significant rise in RSNA occurred, so that at 60-min postdrug, RSNA was 122 ± 11% of the baseline (P < 0.01, whether compared with own baseline or to HS group). Similarly, when the RSNA data were expressed instead as a percentage of the post-AIIRA baseline, RSNA rose to 162 ± 12% of control in LS animals but only to 75 ± 9% in the HS rats (P < 0.01).
To determine whether endogenous ANG II altered the actions of L-NAME, we also compared, for both LS and HS groups, the responses to L-NAME in untreated rats versus rats pretreated with AIIRA. Differences in the responses of RSNA to L-NAME were only observed in the LS group (P < 0.05, ANOVA; Fig. 4); pretreatment with AIIRA altered the pattern of change following L-NAME from an initial fall with a subsequent return to baseline, to a pattern in which RSNA was not significantly different from baseline immediately after L-NAME administration, but by 60 min after L-NAME infusion was significantly above the baseline. In contrast, pretreatment with AIIRA had no effect on the responses to L-NAME in the HS group (P > 0.5, ANOVA; Fig. 5). Thus after blockade of ANG II receptors in LS rats, but not HS rats, the sympatho-excitatory action of NOS is lost.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The novel findings in this study are that, in conscious, intact rats, when the confounding effect of arterial hypertension is effectively prevented 1) systemic NOS inhibition, adequate to cause suppression of central NOS activity, causes a marked initial fall in RSNA, with a subsequent rise to control values and no demonstrable net effect on RSNA at the time when NOS inhibition is maximal (18); 2) systemic NOS inhibition causes profound and sustained bradycardia; 3) in animals with elevated PRA due to salt deprivation, there is no difference in the effect of NOS inhibition on RSNA compared with rats on a normal or high-salt intake; and 4) however, if LS animals are pretreated with an AIIRA, the initial decrease in RSNA following NOS blockade is eliminated, and a net increase in RSNA is produced. These findings do not support the hypotheses that in intact rats the net effect of NO is sympathoinhibition or that ANG II enhances this inhibitory effect. Instead, the data suggest that a major action of NO is sympathoexcitation. Moreover, whereas the net effects of NO do not vary with dietary salt intake in conscious rats, it appears that the excitatory NOS-dependent input to RSNA is reduced during salt deprivation but that this NOS action is enhanced by the elevated endogenous ANG II that occurs.
Two previous studies (11, 23) have examined the effect of nonspecific, systemic NOS inhibition in conscious rats. However, to our knowledge, there has been no previous report of the effect of nonspecific NOS inhibition on sympathetic tone in conscious rats in which arterial pressure has been "clamped." Kumagai et al. (23) also noted a biphasic response to L-NAME in spontaneously hypertensive rats, with net sympatho-inhibition resulting, but the arterial hypertension that occurred after L-NAME in their study confounds interpretation of their results. In contrast, in the study by Fujisawa et al. (11), a very low dose of L-NAME, chosen to avoid systemic arterial hypertension, was given to intact, conscious rats: no effect on RSNA was seen. However, the dose of L-NAME used is unlikely to have had a significant effect on central NOS activity (18).
The finding that systemic NOS inhibition caused a marked biphasic response in RSNA in all animal groups suggests that both excitatory and inhibitory NOS inputs to RSNA are present in conscious, intact rats, and these inputs are of similar magnitude. The possibility that both inhibitory and excitatory NOS inputs to renal sympathetic tone are active at baseline in conscious rats, while novel, is not entirely surprising given the multiple loci at which NOS is present in the mammalian nervous system (2, 19) and the previous reports that NOS can be both excitatory (27, 28, 31) and inhibitory (20, 41). Nevertheless, an alternative interpretation is that L-NAME blocks only an excitatory input, and the delayed increase in RSNA is due to an independent compensatory response. However, this interpretation seems less likely, because the rebound increase was not observed for heart rate, and because RSNA actually increased above control values in low-salt animals pretreated with the AIIRA.
The bradycardia that followed NOS inhibition in this study was profound. This finding indicates that NOS activity supports basal heart rate in conscious rats. Bradycardia was not noted in anesthetized sinoaortic-denervated rats administered L-NAME (16) or in conscious intact rats receiving low-dose (50 µg) L-NAME (11). Thus this effect appears to be a function both of the conscious state and of the high dose of L-NAME used in this study. The bradycardia noted may be the result of interruption of basal sympathetic outflow to the heart, activation of cardiac vagal efferents, a direct action of L-NAME on atrial cardiomyocytes, or a combination of these mechanisms. Chronic NOS inhibition has been shown to augment vagal outflow (36) in rats; however, because vagal and cardiac sympathetic nerve activity was not measured in this study, it is not possible to determine whether the bradycardia seen was the result of a reduction in sympathetic outflow or due to vagal activation. We doubt that the bradycardia is the result of a direct actions of NOS inhibition on atrial cardiomyocytes as has been reported in some species (12, 14), because NOS inhibition does not affect HR in isolated rat heart (21).
The interaction between ANG II and NO in the generation of sympathetic tone revealed in this study is, to say the least, highly complex. At face value there was no apparent difference between the effects of NOS inhibition in HS and LS animals (Fig. 2), suggesting that endogenous ANG II has no effect on the actions of NO on the sympathetic nervous system. However, in LS animals after AIIRA, both the decrease and subsequent rise of RSNA after NOS blockade were modified, suggesting that ANG II modifies excitatory and possibly also inhibitory inputs to RSNA that are dependent on NOS activity. When ANG II-mediated sympathoexcitation was absent, NOS inhibition in LS animals did not produce the immediate decline in RSNA seen in all other groups. This implies that, in LS but not HS animals, NO-mediated sympathoexcitation is dependent on the presence of ANG II (or the sympathoexcitatory effect of ANG II is via NO). Alternatively, a less likely possibility is that the processes that cause the second phase of rise in RSNA begin earlier in these animals. Similarly, in LS animals pretreated with AIIRA, the net rise in RSNA 1 h after L-NAME suggests that ANG II reduces a greater inhibitory NO-dependent input present in LS animals. Collectively, these findings suggest that part of the mechanism by which ANG II promotes sympathoexcitation in salt-deprived animals may be mediated through its stimulatory effect on a sympathoexcitatory NO-mediated input and possibly also by attenuating NO-mediated sympathoinhibition.
Limitations. These studies in conscious rats have limitations that have the potential of modifying the conclusions that can be made. First, because of the difficulty in maintaining viable nerve recordings in rats, experiments were performed the day after surgery, a time at which full recovery was not attained. Thus it is possible that the existence of physical or psychological stress altered NO production and its impact on control of RSNA. Second, the vasodilator hydralazine was used to counteract the pressor effect of NOS blockade, and a concern is that the drug, independent of its effects on arterial pressure, altered responses in RSNA and HR. However, the doses of hydralazine used did not vary, suggesting that between group differences were not secondary to varying nonspecific actions of the drug. Moreover, the available evidence indicates that hydralazine acts independently of NO and its intracellular signaling pathway in the vascular endothelium (42); instead, hydralazine appears to directly cause vasodilation by inhibiting inositol 1,4,5-trisphosphate-induced release of calcium from the sarcoplasmic reticulum of vascular smooth muscle (9). Third, to minimize between animal differences in absolute levels of nerve activity, in microvolts, RSNA was quantified as change from control. As a result, both basal RSNA and the manner in which it is being achieved [i.e., the particular pool(s) of sympathetic neurons that are activated (17), and the manner in which they have been activated (30)] may have differed between groups. Indeed, DiBona et al. (8) have shown that the absolute level of RSNA, measured in microvolts, is greater in salt-deprived than salt-loaded animals. Thus the absolute decrease in RSNA after L-NAME may be greater in LS than HS animals in this study, although, expressed as a percentage of the baseline, the magnitude of effect was the same. Nonetheless, this assessment does not alter the fact that our hypothesis, that the net effect of NO is sympathoinhibition, is not supported by the present results. Fourth, because of the nature of these whole animal studies, we are unable to pinpoint the site(s) of action of NO and ANG II. NO may act at sympathetic ganglia (3), the spinal cord (1), and the brain stem (2, 19). Similarly, ANG II may be acting from the circulation at receptors in sympathetic ganglia (6, 26) or brain circumventricular organs (10). Alternatively, because the action of ANG in brain may also be increased during salt deprivation (7), and because nonpeptide ANG antagonists appear to cross the blood-brain barrier (24), endogenous ANG II may also interact with NO in brain.
In summary, the findings of this study on conscious rats challenge the widespread view (based on prior work in anesthetized animals) that NO exerts a predominantly inhibitory influence on basal sympathetic outflow in normal rats. Instead, we found that NOS provides a stimulatory input to RSNA. Furthermore, in contrast to the findings in ANG II-infused conscious rabbits (25) in which acute ANG II infusion resulted in an enhanced sympathoinhibitory NOS input, in rats with chronically elevated endogenous ANG II, the hormone instead increases a sympathoexcitatory effect of NO. Indeed, if the later rise in RSNA after its initial decline is the result of the interruption of a sympathoinhibitory NOS input, then elevated endogenous ANG II appears to instead decrease a sympathoinhibitory NO input in the LS animals. Together, these findings suggest a novel hypothesis, that the sympathoexcitatory effect of chronically elevated ANG II may be mediated via its interactions with NO.
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ACKNOWLEDGMENTS |
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GRANTS
This study was supported by National Heart, Lung, and Blood Institute Grants HL-35872 and HL-70962 (to V. L. Brooks). This work was done during D. F. McKeogh's fellowship from the American Heart Association, Northwest Affiliate.
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FOOTNOTES |
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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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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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P < 0.05, 
