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(Hypertension. 1995;26:691-695.)
© 1995 American Heart Association, Inc.

Articles

Sympathetically Mediated Hypertension Caused by Chronic Inhibition of Nitric Oxide

Mikael Sander; Pernille G. Hansen; Ronald G. Victor

From the Division of Cardiology, Molecular Cardiology Laboratories, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.

Correspondence to Ronald G. Victor, MD, Molecular Cardiology Laboratories, Room NB11.116, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-8573.

	Abstract

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Abstract Pharmacological inhibition of nitric oxide synthase causes sustained hypertension in many animal species. Although this hypertension has been attributed to inhibition of endothelium-dependent vasodilation, short-term studies in anesthetized preparations have advanced the hypothesis that there could be a sympathetic component to this hypertension. To test this hypothesis we measured intra-arterial pressure directly before and after 1 week of treatment with the nitric oxide synthesis inhibitor N-nitro-L-arginine methyl ester (L-NAME, approximately 80 mg/kg per day in drinking water) in conscious unrestrained rats with or without chronic guanethidine-induced sympathectomy. The major new finding is that the hypertensive response to L-NAME was greatly attenuated by sympathectomy. With L-NAME, mean arterial pressure increased from 101±3 to 152±6 mm Hg in rats without sympathectomy (n=11) but only from 96±2 to 122±3 mm Hg in rats with sympathectomy (n=15, +52±5 versus +27±4 mm Hg, P<.01). Sympathectomy did not alter maximal endothelium-dependent vasodilation assessed by femoral vascular responses to intra-arterial acetylcholine or bradykinin, indicating that the differing hypertensive responses to L-NAME in rats with versus without sympathectomy could be related to inhibition of neuronal rather than endothelial nitric oxide synthesis. We also found that L-NAME–induced hypertension, once developed, is completely reversed by acute ganglionic blockade. In conclusion, these findings identify an important sympathetic neural component to the sustained hypertension produced by pharmacological inhibition of nitric oxide in the rat.

Key Words: nitric oxide • sympathetic nervous system • sympathectomy • rats • hypertension

	Introduction

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Pharmacological inhibition of NO synthesis is firmly established to produce acute and chronic hypertension in many animal species,^{1 2 3 4 5} but the underlying mechanisms mediating the hypertension are incompletely understood. Although this hypertension has been attributed solely to inhibition of endothelial NO,^{5 6 7} an emerging body of literature suggests that inhibition of neuronal NO also is involved.^{8 9 10 11 12 13}

Short-term studies in anesthetized animals provide the conceptual framework for hypothesizing a major neurogenic component to the hypertensive response evoked by NO inhibition. Administration of methyl-arginine inhibitors of NO synthesis by intravenous injection,^{9 14} by intracisternal injection,¹⁰ or by direct injection into the nucleus tractus solitarius¹¹ or rostral ventrolateral medulla⁸ evokes short-term increases in both renal SNA and BP. An important unanswered question is whether these data can be extrapolated to the conscious state and to chronic hypertension. In conscious as compared with anesthetized rats, acute intravenous infusion of L-NMMA causes a much smaller increase in BP¹⁵ that at least in spontaneously hypertensive rats is accompanied by decreased (not increased) SNA.¹⁶ We recently found that acute L-NMMA–induced increases in BP also are accompanied by decreased SNA in conscious humans.¹⁷

The latter observations prompted us to critically reevaluate the hypothesis that sympathetic activation contributes to chronic hypertension during inhibition of NO synthesis.^{18 19 20 21} To test this hypothesis we measured intra-arterial pressure directly before and after 1 week of treatment with L-NAME in conscious unrestrained rats with or without chronic sympathectomy.

	Methods

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Methods used were in accordance with institutional guidelines, and all protocols were approved by the Institutional Animal Care and Research Advisory Committee at the University of Texas Southwestern Medical Center.

Chronic Sympathectomy
Chronic sympathectomy was induced by repeated daily subcutaneous injections of guanethidine (50 mg/kg) to newborn Sprague-Dawley rats (Charles River, Kingston, Mass) from the 5th through the 27th day after birth.²² This procedure causes irreversible immunologic destruction of postganglionic sympathetic nerves,^{23 24 25} which we documented in each rat by marked attenuation of the BP increase in response to tyramine. Rats without sympathectomy received an equal volume of subcutaneous vehicle (normal saline). All experimental protocols were performed with female rats 8 to 12 weeks of age weighing 220 to 300 g.

Surgical Procedures
Survival surgery was performed with the use of sodium pentobarbital anesthesia (40 mg/kg IP). For intravenous injections and measurement of arterial pressure the left jugular vein and carotid artery were cannulated, the tubing was exteriorized at the neck, and the patency was maintained with heparin.

For nonsurvival surgery anesthesia was induced with ketamine HCl (80 mg/kg IM) and maintained with -chloralose (60 mg/kg IV), which was supplemented as needed. Atropine sulfate (0.5 mg/kg SC) was given to prevent excessive tracheal secretions. The trachea was cannulated and the rat artificially ventilated (Harvard Apparatus) with room air and supplementary oxygen. Arterial blood gasses were measured periodically (ABL-3, Radiometer) and kept within normal limits. The urethra was catheterized to allow free urine flow. Core temperature was monitored by a thermocouple in the rectum and maintained at 37±1°C. Left carotid artery and jugular vein catheters were inserted for BP measurements and intravenous injections. The right femoral artery was cannulated (PE10, Clay Adams) and the catheter tip advanced to the level of the aortic bifurcation for close-arterial injections into the left femoral artery in which blood velocity was measured with a pulsed Doppler flow probe (VF-1, Crystal Biotech), as previously described.²⁶

Recording of Arterial Pressure in Conscious Rats
All measurements were performed at least 5 days after surgery with rats in individual cages in a quiet room. Carotid artery catheter-extensions were placed on a counterweighted lever system, allowing rats to move freely. Catheters were connected to a P23ID pressure transducer (Gould Inc) for intra-arterial pressure recordings (RS3400, Gould Inc). At least 30 minutes were allowed for acclimation. Arterial pressure was then measured continuously for 60 minutes, with the reported values being obtained during periods in which the rats were not moving. MAP was calculated from the phasic arterial pressure tracing as one half pulse pressure plus diastolic pressure. Heart rate was measured directly from the arterial pressure tracing.

Drugs
All drugs used were obtained from Sigma Chemical Co, with the exception of chlorisondamine (CIBA-GEIGY).

Experimental Protocols
Protocol 1: Effects of Chronic Sympathectomy on L-NAME–Induced Hypertension
The aim of this protocol was to determine whether sympathectomy would attenuate the subsequent development of hypertension in response to chronic NO inhibition. Arterial pressures were measured at baseline and again after 7 days of continuous administration of L-NAME (0.67 mg/mL drinking water) or vehicle (drinking water without L-NAME). We studied four groups of rats: L-NAME/sympathectomy (n=15), L-NAME/no sympathectomy (n=11), vehicle/sympathectomy (n=5), and vehicle/no sympathectomy (n=7).

At the baseline study we first measured resting arterial pressures and then documented the completeness of sympathectomy by measuring the short-term increases in arterial pressure evoked by tyramine (250 mg/kg IV) (MAP: 7±1 versus 45±2 mm Hg in rats with versus without sympathectomy, P<.01) or the -adrenergic agonist phenylephrine (2 µg/kg IV), the latter to establish denervation supersensitivity (MAP: 42±2 versus 16±2 mm Hg in rats with versus without sympathectomy, P<.01). Rats were then housed individually and treated with either L-NAME or vehicle for 7 days, after which end point measurements of resting arterial pressure were obtained.

Protocol 2: Reversal of L-NAME–Induced Hypertension by Ganglionic Blockade
In a subset of the rats without sympathectomy we determined whether L-NAME–induced hypertension could be reversed by ganglionic blockade. Resting arterial pressure was measured before and after chlorisondamine (5 mg/kg IV).

Protocol 3: Effects of Chronic Sympathectomy on Endothelium-Dependent Vasodilation
The aim of this protocol was to validate the underlying assumption that chronic sympathectomy has no effect on the expression of endothelial NO synthase and thus on maximal endothelium (NO)-dependent vasodilation. In anesthetized rats femoral artery blood velocity and systemic arterial pressure were recorded during close-arterial injection of acetylcholine (1 µg) or bradykinin (450 ng) in rats with (n=4) or without (n=4) sympathectomy. In preliminary studies we documented that these intra-arterial doses of acetylcholine and bradykinin produce maximal regional vasodilator responses while causing minimal decreases in systemic arterial pressure compared with similar intravenous injections. The percent change in femoral vascular resistance was calculated as the change in MAP (in millimeters of mercury) divided by the change in Doppler shift (in kilohertz).

Data Analysis
Student's t test for nonpaired data was used for comparisons between rats with and without sympathectomy and between L-NAME– and vehicle-treated rats. Within each experimental group Student's t test for paired data was used to detect values that were significantly different from baseline. The significance level was set at a value of P<.05, using the Bonferroni adjustment for multiple comparisons. Results are expressed as mean±SEM.

	Results

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L-NAME treatment produced significantly smaller increases in MAP in rats with versus without sympathectomy (96±2 to 122±3 versus 101±3 to 152±6 mm Hg; change, 27±4 versus 52±5 mm Hg; P<.01) (Fig 1). The volumes of drinking water ingested were equivalent in rats with versus without sympathectomy (225±17 versus 225±10 mL/wk). Body weights were not significantly different in rats with versus without sympathectomy (267±7 versus 254±6 g), and correspondingly, there was no significant difference between the daily doses of L-NAME ingested in rats with versus without sympathectomy (80±8 versus 84±3 mg/kg per day). Vehicle treatment produced no changes in MAP over time in either group (Fig 1). L-NAME produced minimal changes in heart rate that were not significantly different in rats with versus without sympathectomy (438±10 to 404±12 versus 402±15 to 390±9 beats per minute; change, -34±13 versus -12±18 beats per minute).

View larger version (15K): [in this window] [in a new window]   Figure 1. Plots show individual and summary data (mean±SEM) of MAP at baseline and after 7 days of oral ingestion of L-NAME (added to drinking water) (left) or vehicle (plain drinking water) (right) in rats with or without sympathectomy. *Significant responses to L-NAME vs baseline (P<.01); indicates significant differences in responses to L-NAME between rats with vs without sympathectomy (P<.01). The hypertensive response to L-NAME was significantly attenuated by sympathectomy.

In the subset of rats without sympathectomy that received chlorisondamine, ganglionic blockade produced much larger decreases in MAP in L-NAME– versus vehicle-treated rats (153±5 to 74±2 versus 108±4 to 70±1 mm Hg; change, -80±6 versus -38±5 mm Hg, P<.01) (Fig 2). Thus, although arterial pressures were higher in L-NAME– versus vehicle-treated rats before ganglionic blockade, the nadir values of arterial pressure in the two groups were comparable after ganglionic blockade.

View larger version (16K): [in this window] [in a new window]   Figure 2. Plots show individual and summary data (mean±SEM) of effects of acute ganglionic blockade on MAP in rats treated with L-NAME or vehicle. *Significant responses to ganglionic blockade (P<.01); indicates significant differences in responses to ganglionic blockade between rats treated with L-NAME vs vehicle (P<.01). Acute ganglionic blockade evoked a much larger decrease in arterial pressure in L-NAME– vs vehicle-treated rats.

Maximal femoral artery vasodilator responses to close-arterial injections of acetylcholine or bradykinin were not different in rats with versus without sympathectomy (Fig 3). In rats with versus without sympathectomy femoral vascular resistance decreased by 47±3% versus 53±4% with acetylcholine and by 50±4% versus 56±2% with bradykinin. These changes in regional vasomotor tone were accompanied by minimal and comparable decreases in MAP in rats with versus without sympathectomy (acetylcholine, -8±2 versus -8±3 mm Hg; bradykinin, -8±1 versus -10±3 mm Hg).

View larger version (39K): [in this window] [in a new window]   Figure 3. Top, Tracings show continuous measurements of blood velocity in the left femoral artery (phasic Doppler shift) immediately before and after close-arterial injection of 450 ng bradykinin (BK) in one rat with and one without sympathectomy. Bottom, Plots show individual and summary data (mean±SEM) for relative changes in femoral vascular resistance after close-arterial injections of 450 ng bradykinin and 1 µg acetylcholine (ACh) in rats with and without sympathectomy. There were no differences between the two groups in the local vasodilation caused by acetylcholine and bradykinin.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The major new finding from this study is that chronic sympathectomy greatly attenuates the development of L-NAME–induced hypertension in the rat. Because sympathectomy had no discernible effect on endothelium-dependent vasodilation, these results identify an important sympathetic neural component to the sustained hypertension produced by pharmacological inhibition of NO.

Previous studies have provided compelling evidence that chronic L-NAME–induced hypertension is not caused by an expanded plasma volume but rather by widespread vasoconstriction^{3 4} involving the renal, mesenteric, and hind limb vascular beds.^{27 28} Is this vasoconstriction sympathetically mediated? Some studies have found that L-NAME treatment is accompanied by a progressive attenuation in sinoaortic baroreflexes, which might contribute to neurogenic vasoconstriction and hypertension.^{19 20} However, those studies did not prove that baroreflex attenuation is the cause rather than the consequence of the hypertension, and other studies have found that L-NAME treatment is accompanied by normal²⁹ or even augmented³⁰ baroreflexes. L-NAME–induced hypertension has been found to be accompanied by either decreased³¹ or increased^{4 32} plasma renin activity, the latter possibly reflecting increased renal SNA. Indeed, the recent study by Matsuoka et al²¹ suggests that renal denervation delays the onset of L-NAME–induced hypertension, at least as assessed by indirect tail-cuff measurements of BP. However, when intra-arterial pressures were measured directly, renal denervation was found to cause no attenuation in L-NAME–induced hypertension.²¹ Thus, the previous studies have not answered the question of whether the sympathetic nervous system plays an important role in mediating the vasoconstriction and hypertension produced by chronic NO inhibition.

Chronic sympathectomy provides a straightforward approach to this question. We found that guanethidine-induced sympathectomy attenuates the hypertensive response to L-NAME by approximately 50%. The large magnitude of this attenuation is remarkable, because guanethidine treatment destroys most but not all of the peripheral sympathetic nerves^{23 24 25} and leaves intact adrenomedullary release of catecholamines.^{22 33} Compensatory mechanisms evidently cannot compensate for the loss of sympathetically mediated vasoconstriction in the production of this form of hypertension. Guanethidine-induced sympathectomy also attenuates the development of hypertension in spontaneously hypertensive rats,³⁴ the Dahl strain,³⁵ and Goldblatt hypertension³⁵ but not in other experimental models of hypertension, including Lyon genetic hypertension³³ and one-kidney, one-clip hypertension.³⁶ Thus, our results strongly suggest that L-NAME–induced hypertension is at least in part sympathetically mediated.

This interpretation is further strengthened by two additional observations. First, sympathectomy did not alter maximal endothelium-dependent vasodilation in response to either acetylcholine or bradykinin. This suggests that expression of endothelial NO synthase is comparable in rats with and without sympathectomy, and thus the differing hypertensive responses to L-NAME in the two groups are related to effects of L-NAME on neuronal rather than endothelial NO synthesis. Second, we found that L-NAME–induced hypertension, once developed, is completely reversed by acute ganglionic blockade, which extends previous work of Cunha et al,¹⁸ who found that this form of hypertension is not completely reversed by ganglionic blockade. The even larger effect of ganglionic blockade in our study compared with theirs is likely related to the use of chlorisondamine, which produces complete and irreversible ganglionic blockade,^{26 37 38} versus trimethaphan, which produces rapidly reversible ganglionic blockade and lowers BP in part by mechanisms (eg, histamine release) unrelated to ganglionic blockade.³⁹

The specific sites of action of L-NAME mediating the sympathetic neural component to this hypertension are unknown, but afferent, central, and efferent mechanisms all could be involved. Neuronal NO synthase is expressed in the carotid sinus,⁴⁰ and neurophysiological data suggest that NO inhibition leads to decreased activation and/or resetting of the sinoaortic baroreceptors.¹⁹ In addition, NO synthase is expressed in the dorsal root^{41 42 43} and nodosal ganglia⁴¹ as well as in the nucleus tractus solitarius^{44 45} and rostral ventrolateral medulla.¹² Neurophysiological data suggest that endogenous NO synthesis modulates the central integration of baroreceptor and other visceral afferent input. For example, injection of L-NMMA into either the nucleus tractus solitarius¹¹ or rostral ventrolateral medulla⁸ results in a marked increase in efferent SNA and BP. NO synthase also is present in sympathetic preganglionic neurons,^{46 47} but it remains to be determined whether NO plays a physiological role in modulating ganglionic transmission. Studies using isolated canine blood vessels have provided some evidence to suggest that endothelial production of NO attenuates norepinephrine release from peripheral sympathetic nerve terminals, at least during field stimulation⁴⁸ ; however, it is unknown whether this effect of NO plays an important physiological role in the neural control of BP in intact animals.

The ease in detecting a large sympathetic component to sustained hypertension with chronic pharmacological inhibition of NO in rats contrasts with the difficulty in detecting a sympathetic component to the transient increase in BP with acute pharmacological inhibition of NO in humans.¹⁷ The difference may be related to species or more likely to long-term alterations in the central neural control of BP induced by chronic inhibition of neuronal NO synthase.

	Selected Abbreviations and Acronyms

 

BP = blood pressure L-NAME = N-nitro-L-arginine methyl ester L-NMMA = NG-monomethyl-L-arginine MAP = mean arterial pressure NO = nitric oxide SNA = sympathetic nerve activity

	Acknowledgments

 
This research was supported by a grant to Dr Victor from the Baxter Healthcare Corp. We are indebted to Dr Robert Star for critical evaluation of the manuscript.

Received March 10, 1995; first decision May 31, 1995; accepted June 26, 1995.

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