CLINICAL STUDIES: CARDIAC PHYSIOLOGY
Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans
Lukas E. Spieker, MDa,
Roberto Corti, MDa,
Christian Binggeli, MDa,
Thomas F. Lüscher, MD, FACC, FRCP, FESCa and
Georg Noll, MD, FESCa
a Department of Cardiology, University Hospital, Zürich, Switzerland
Manuscript received August 5, 1999;
revised manuscript received December 30, 1999,
accepted February 28, 2000.
Reprint requests and correspondence: Dr. Georg Noll, Cardiology, University Hospital, CH-8091 Zürich, Switzerland
karnog{at}usz.unizh.ch
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Abstract
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OBJECTIVES
We sought to investigate baroreceptor regulation of sympathetic nerve activity and hemodynamics after inhibition of nitric oxide (NO) synthesis.
BACKGROUND
Both the sympathetic nervous system and endothelium-derived substances play essential roles in cardiovascular homeostasis and diseases. Little is known about their interactions.
METHODS
In healthy volunteers, we recorded muscle sympathetic nerve activity (MSA) with microneurography and central hemodynamics measured at different levels of central venous pressure induced by lower body negative pressure.
RESULTS
After administration of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 1 mg/kg/min), systolic blood pressure increased by 24 mm Hg (p = 0.01) and diastolic blood pressure by 12 mm Hg (p = 0.009), while stroke volume index (measured by thermodilution) fell from 53 to 38 mL/min/m2 (p < 0.002). Administration of L-NMMA prevented the compensatory increase of heart rate, but not MSA, to orthostatic stress. The altered response of heart rate was not due to higher blood pressure, because heart rate responses were not altered during infusion of the alpha-1-adrenoceptor agonist phenylephrine (titrated to an equal increase of systolic blood pressure). In the presence of equal systolic blood pressure and central venous pressure, we found no difference in MSA during phenylephrine and L-NMMA infusion.
CONCLUSIONS
This study demonstrates a highly specific alteration of baroreceptor regulation of heart rate but not muscle sympathetic activity after inhibition of NO synthesis in healthy volunteers. This suggests an important role of NO in reflex-mediated heart rate regulation in humans.
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Abbreviations and Acronyms
| | LBNP | = lower body negative pressure | | L-NMMA | = NG-monomethyl-L-arginine | | MSA | = muscle sympathetic nerve activity | | NO | = nitric oxide |
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The vascular endothelium synthesizes and releases nitric oxide (NO) and plays a fundamental role in the basal and dynamic regulation of the circulation (1–4). Apart from the tone of peripheral resistance vessels, NO also regulates myocardial contractility and is synthesized in neuronal cells (5–8). However, little is known about the interactions of NO and other cardiovascular regulating systems, especially with the sympathetic nervous system. These interactions are of particular interest in congestive heart failure, arterial hypertension, atherosclerosis and septic shock, where sympathetic nerves innervating and constricting blood vessels act as important counterpart of the endothelium-derived vasodilator NO (5,9–11).
Sympathetic activity is mainly regulated by baroreceptors located in the cardiopulmonary and carotid vessel walls, which centrally inhibit sympathetic outflow. These stretch-activated mechanoreceptors not only regulate short-term changes of blood pressure but also react to chronic elevation of blood pressure by resetting sensitivity to a lower level (12,13). In hypertension, altered baroreflex-mediated regulation of muscle sympathetic nerve activity (MSA) has been described (14). Similarly, in congestive heart failure, an abnormal baroreflex contributes to sympathetic activation, which is an unfavorable prognostic factor (15–19). Alterations in endothelial function, with a resulting imbalance of endothelium-derived relaxing and contracting factors, may affect baroreceptor function because endothelial factors may act on baroreceptor nerve endings in the vessel wall. Various endogenous substances (e.g., NO, endothelin-1, prostacyclin, norepinephrine) have been shown to influence baroreceptor function in animals (12,20–24). It is not clear if these mediators also affect human baroreceptor function.
The aim of our study was to investigate the effects of NO synthase inhibition and alpha-1-adrenergic stimulation on baroreceptor-mediated regulation of sympathetic nerve activity, heart rate and hemodynamics in healthy humans.
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Methods
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Subjects.
Nine healthy normotensive volunteers (118 ± 2/65 ± 2 mm Hg, seven men and two women) with a mean age of 26 years (range 21 to 35 years) participated in this study. Right heart catheterization was performed in seven subjects (five men and two women), of whom three (one man and two women) were simultaneously studied by microneurography. Microneurographic measurements of sympathetic activity and noninvasive hemodynamic measurements were additionally performed in two male volunteers (without right heart catheterization). Each volunteer gave written, informed consent. This study was approved by the local ethical committee. Smokers and offspring of hypertensive parents were excluded (25). None of the subjects was taking any medications.
Microneurographic measurements.
Microneurography was performed as described previously (25–27). Subjects were studied in standardized fashion, that is, at 2 PM in a quiet, temperature-controlled room, after micturition to avoid any increase of sympathetic nerve activity through bladder distension (10). Multifiber recordings of MSA were obtained from the peroneal nerve. A reference electrode was inserted subcutaneously 1 to 2 cm from the recording electrode. Signals were amplified, filtered (700 to 2,000 Hz), integrated (time constant, 0.1 s) and digitized using an analog-digital board (MIO-16L; National Instruments, Austin, TX) and a modified commercial software (LabView; National Instruments). Data recorded on a computer (Macintosh Power PC 7100; Apple) were analyzed offline (MatLab; MathWorks, Natick, Massachusetts). The results were expressed as bursts per minute and cumulative sum of the amplitude in volts per minute.
Lower body negative pressure.
Lower body negative pressure (LBNP) decreases central venous pressure by restricting venous return of blood from the lower extremities to the heart (28). We used an air-tight plexiglass chamber in which the subjects were enclosed up to the waist. Negative pressure was applied with a commercial vacuum cleaner (15 and 30 mm Hg, each for 2 min), monitored with a manometer connected to the interior of the chamber.
Hemodynamic measurements.
Cardiac output (average of three measurements) was determined by thermodilution (Vigilance Monitor Model VGS1; Baxter Healthcare Corporation, Irvine, California) with a Swan-Ganz catheter (Model 746H-8F; Baxter Healthcare Corporation) inserted through a sheath introducer system (Cordis, Langenthal, Switzerland) in a cubital vein and propagated to the pulmonary artery under fluoroscopic guidance. Arterial blood pressure was measured noninvasively (relative changes: Finapres; Ohmeda, Sweden; absolute baseline values: Dinamap; Critikon, Tampa, Florida) and a one-lead electrocardiogram was recorded and digitized for computation of heart rate (29).
Experimental protocol.
After recording stable baseline values for 15 min, phenylephrine was administered intravenously through the distal lumen of the Swan-Ganz catheter (or a peripheral intravenous line in three volunteers) at two dosages (75 and 100 µg/min, each over 3 min at 0.75 and 1 ml/min). Cardiac output was measured by thermodilution after each dose of the drugs. During the last dose, LBNP was performed. After reestablishing baseline conditions, NG-monomethyl-L-arginine (L-NMMA) (Clinalfa, Läufelfingen, Switzerland) was administered in two doses (0.3 and 1 mg/kg/min, each for 3 min at 1 to 3 ml/min) and cardiac output was determined after each dose. Lower body negative pressure was performed again. The drug infusion order was not alternated because of the long elimination half life of L-NMMA.
Statistical analysis.
Results are presented as means ± SEM. Differences between drugs were evaluated using paired Student t tests with Bonferroni adjusted p values for multiple comparisons. The effects of LBNP were evaluated by repeated-measures analysis of variance (StatView 4.5; Abacus Concepts, Berkeley, California) (30). Statistical significance was accepted at p < 0.05.
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Results
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Hemodynamic effects.
Changes in hemodynamic parameters and sympathetic nerve activity after administration of drugs are shown in Table 1. L-NMMA and phenylephrine caused dose-related increases in arterial blood pressure. After 0.3 mg/kg/min of L-NMMA, blood pressure increased by 16.3% (p < 0.01); and by 18.6% after 1 mg/kg/min (p < 0.01). Similar increases were achieved after 75 µg/min of phenylephrine (+18.6%, p < 0.05) and after 100 µg/min (+19.4%, p < 0.01; intergroup differences not significant). Systemic vascular resistance changed accordingly by +26.8% (p < 0.05) and +77.1% (p < 0.001) after L-NMMA and by +43.8% (p < 0.01) and +56.5% (p < 0.01) after phenylephrine (intergroup differences not significant). At the higher doses (1.0 mg/kg/min and 100 µg/min, respectively), increases in arterial blood pressure were equal.
Heart rate was not affected by L-NMMA infusion (+4.5% and –6.0%, NS), in contrast to phenylephrine where heart rate decreased (–14.9% and –22.4%, p < 0.001). Stroke volume index declined after the higher dose of L-NMMA (–28.3%, p = 0.01) but not after phenylephrine. After phenylephrine, the decreased cardiac index was related to a dose- and blood pressure-dependent fall in heart rate. Central venous pressure was increased by phenylephrine (+43.6% and +123%, p < 0.01), but was not changed by L-NMMA.
LBNP.
During administration of L-NMMA, heart rate, but not MSA, failed to show a compensatory increase in response to decreased central venous pressure induced by LBNP (Fig. 1). This was in contrast to control conditions and phenylephrine infusion.
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Figure 1 Relative changes of central venous pressure (CVP), systolic blood pressure, muscle sympathetic nerve activity (MSA, bursts per minute and volts per minute) and heart rate during lower body negative pressure. Central venous pressure similarly decreased in both drugs (*p < 0.05 vs. baseline, intergroup differences NS). Also, there was no difference in systolic blood pressure, which remained constant during lower body negative pressure in both drugs. During infusion of L-NMMA (1 mg/kg/min), heart rate failed to increase in response to decreased central venous pressure. This was in contrast to phenylephrine (100 µg/min), where heart rate increased ( p < 0.05 vs. phenylephrine; *p < 0.01 by repeated-measures analysis of variance). Open circles = control; black circles = L-NMMA; black boxes = phenylephrine.
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Comparison of L-NMMA and phenylephrine.
Muscle sympathetic nerve activity was not significantly different after L-NMMA and phenylephrine infusions, in the presence of equal systolic blood pressure and comparable central venous pressure (Fig. 2). Stroke volume index was significantly decreased by L-NMMA, and systemic peripheral resistance was significantly higher during inhibition of NO synthesis with L-NMMA than during infusion of phenylephrine (p < 0.05).
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Figure 2 Hemodynamics and muscle sympathetic nervous activity (MSA) at similar levels of systemic arterial (sBP) and central venous (CVP) blood pressure after infusion of L-NMMA (1 mg/kg/min), and phenylephrine (PE, 100 µg/min) in combination with lower body negative pressure (LBNP –30 mm Hg). Stroke volume index (SVI) was significantly lower during L-NMMA infusion than during phenylephrine, whereas systemic vascular resistance (SVR) was significantly higher. No significant difference in sympathetic nerve activity between L-NMMA and phenylephrine could be observed (*p < 0.05).
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There were no adverse events during the study. Specifically, no clinical or electrocardiographic signs of ischemia were observed.
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Discussion
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This study shows that baroreflex regulation of heart rate but not MSA in response to orthostatic stress is altered after inhibition of NO synthesis in healthy subjects. Furthermore, inhibition of NO synthesis caused a decrease in cardiac contractility.
Baroreceptor regulation in orthostatic stress.
After inhibition of NO synthesis, heart rate failed to increase as a counterregulatory mechanism to falling central venous pressure induced by LBNP. Lower body negative pressure simulates the cardiovascular effects of orthostatic stress or hemorrhage by venous pooling of blood in the legs and decreasing central venous pressure (31,32). Lower body negative pressure <20 mm Hg unloads the cardiopulmonary mechanoreceptors; suction  20 mm Hg additionally deactivates arterial baroreceptors and increases heart rate (33). Both maneuvers result in an increase in sympathetic nerve traffic to blood vessels of arm and leg muscles (28). The observed altered baroreceptor response to orthostatic stress is not due to an increased blood pressure level after inhibition of NO synthesis, because heart rate increased similarly during titrated infusions of phenylephrine. Additionally, it has been previously shown that different central venous pressure levels do not influence sinus node responses to arterial baroreceptor responses (34).
Potential explanations.
The paradoxical bradycardia during NO synthase inhibition in response to falling central venous pressure and decreased stroke volume suggests the requirement of some basal NO for baroreceptor regulation of heart rate. This may take place at various anatomical levels from alterations in: 1) baroreceptor sensitivity (20,21,35–41); 2) central nervous coupling (8,35,42,43); 3) pre- and postsynaptic autonomic nerve traffic (44,45); and 4) transmission of autonomic nerve activity to end-organ cells (41,46–48). Our experiments do not allow us to differentiate between these possibilities. It could be hypothesized that NO is required as a parasympathetic messenger for transmission of the effects of acetylcholine to cardiac pacemaker cells. It was reported that alkyl esters of arginine are muscarinic receptor antagonists; however, this is not the case for L-NMMA (49). Because the response of peripheral sympathetic nerve activity to orthostatic stress was not affected by L-NMMA, differential regulation of muscle and cardiac sympathetic activity could be postulated (50,51). In fact, a dissociation of MSA in arm and leg has been described (52).
Endothelial and baroreceptor dysfunction.
Our findings partly reproduce the known alterations in baroreceptor regulation in disease states with endothelial dysfunction. Indeed, our results are in line with studies investigating baroreflex control in hypertensive patients. Grassi et al. (14) reported altered regulation of heart rate but not sympathetic nerve activity in hypertension. In heart failure, abnormal baroreceptor responses of heart rate and MSA to falling central venous pressure, related in part to the severity of hemodynamic abnormalities, have been demonstrated (15,17,53,54). Alterations of baroreflex function may contribute to elevated sympathetic nerve activity in heart failure (18), which is an unfavorable prognostic factor (17,19,54,55). Cardiopulmonary baroreflex control of sympathetic nerve activity is also deranged in hypertension and atherosclerosis (12,56,57), adding further evidence to the concept of endothelium dependency of baroreflex.
Previous studies.
Small doses of L-NMMA (50 µg/kg/min) were reported to have stimulating effects on MSA, whereas high doses decreased MSA (58). Combined infusion of L-NMMA and nitroprusside increased MSA, whereas mean arterial blood pressure was held constant. However, the effects of nitroprusside on central venous pressure must not be neglected. Additionally, when comparing sympathetic outflow during L-NMMA and phenylephrine infusions, it must be taken into account that phenylephrine increases central venous pressure (58,59). Elevated central venous pressure activates cardiopulmonary baroreceptors and therefore reduces sympathetic outflow. We found no differences in MSA during L-NMMA and phenylephrine when LBNP was used to achieve similar central venous pressure.
Further effects of no synthase inhibition.
Our results show that cardiac output is dependent on the availability of some basal NO. This is in line with other studies in humans (4). Constitutive and inducible forms of NO synthase are present in human myocardium (60). Further, our findings illustrate in vivo that venotonus is not determined by tonic release of NO, in contrast to arterial tonus. In vitro experiments comparing arterial and venous vessels showed only weak endothelium-dependent relaxation in veins in contrast to pronounced relaxation in arterial vessels (61).
Potential limitations.
Unfortunately, it is not possible to microneurographically measure cardiac sympathetic activity or parasympathetic nerve traffic in humans. We used heart rate as an end organ response as a marker of autonomic nerve traffic to cardiac pacemaker cells.
Our findings are in contrast to reported experiments in animals where NO synthase inhibition led to higher levels of sympathetic activity (20,21,35,40), and had minimal (62) or no effects on baroreflex regulation of heart rate (63). Possibly, differences in the experimental setting (e.g., use of anesthetics [64], isolation of the carotid sinus, species differences) or other neurohumoral systems (e.g., the renin angiotensin system [65], atrial natriuretic factor [66], arginine vasopressin or nonadrenergic noncholinergic neurotransmitters [67]) prevent these effects to be revealed in vivo.
Phenylephrine may exert effects on MSA and/or baroreflex function by activation of alpha-1-adrenoceptors. Indeed, norepinephrine effects on baroreceptor activity were demonstrated in isolated carotid sinus preparations (22–24). Alpha-1-adrenergic stimulation of phospholipase A2 leads to the release of free arachidonate, which is then metabolized to bioactive prostaglandins and leukotrienes. In addition, norepinephrine released from postsynaptic sympathetic nerve endings acts as an autocrine negative feedback loop on alpha-2-adrenoceptors.
Conclusions.
This study demonstrates altered baroreceptor regulation of heart rate but not MSA after inhibition of NO synthesis in healthy volunteers. These findings reproduce altered baroreflex regulation of heart rate in diseased states with endothelial dysfunction, for example, arterial hypertension and chronic heart failure. NO is required for maintenance of cardiac output. Nitric oxide inhibition does not lead to vasoconstriction of veins at rest, indicating a small tonic effect of NO on venous vessels in vivo.
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Acknowledgments
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The authors thank Isabella Sudano for helping with the experiments and Rosy Hug for organizational assistance.
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Footnotes
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This study was supported by the Swiss National Foundation (Nos. 32-42560.94 and 32-5106997) and the Italian Society of Hypertension.
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N. C Shah, S. Pringle, and A. Struthers
Aldosterone Blockade Over and Above ACE-Inhibitors in Patients with Coronary Artery Disease but without Heart Failure
Journal of Renin-Angiotensin-Aldosterone System,
March 1, 2006;
7(1):
20 - 30.
[Abstract]
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I. Sudano, L. Spieker, C. Binggeli, F. Ruschitzka, T. F. Luscher, G. Noll, and R. Corti
Coffee Blunts Mental Stress-Induced Blood Pressure Increase in Habitual but Not in Nonhabitual Coffee Drinkers
Hypertension,
September 1, 2005;
46(3):
521 - 526.
[Abstract]
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A M A Shehab, R J MacFadyen, M McLaren, R Tavendale, J J F Belch, and A D Struthers
Sudden unexpected death in heart failure may be preceded by short term, intraindividual increases in inflammation and in autonomic dysfunction: a pilot study
Heart,
November 1, 2004;
90(11):
1263 - 1268.
[Abstract]
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J. S. Sim, J. B. Dick, and A. D Struthers
Statin therapy increases vascular sensitivity to angiotensin II in hypercholesterolaemic patients
Journal of Renin-Angiotensin-Aldosterone System,
September 1, 2004;
5(3):
109 - 113.
[Abstract]
[PDF]
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K. D. Monahan, I. Eskurza, and D. R. Seals
Ascorbic acid increases cardiovagal baroreflex sensitivity in healthy older men
Am J Physiol Heart Circ Physiol,
June 1, 2004;
286(6):
H2113 - H2117.
[Abstract]
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W S Waring, S H Adwani, O Breukels, D J Webb, and S R J Maxwell
Hyperuricaemia does not impair cardiovascular function in healthy adults
Heart,
February 1, 2004;
90(2):
155 - 159.
[Abstract]
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J. Cui, R. Zhang, T. E. Wilson, S. Witkowski, C. G. Crandall, and B. D. Levine
Nitric oxide synthase inhibition does not affect regulation of muscle sympathetic nerve activity during head-up tilt
Am J Physiol Heart Circ Physiol,
November 1, 2003;
285(5):
H2105 - H2110.
[Abstract]
[Full Text]
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P. A. Ortiz and J. L. Garvin
Cardiovascular and renal control in NOS-deficient mouse models
Am J Physiol Regulatory Integrative Comp Physiol,
March 1, 2003;
284(3):
R628 - R638.
[Abstract]
[Full Text]
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S. Andreas, C. Bingeli, P. Mohacsi, T. F. Luscher, and G. Noll
Nasal Oxygen and Muscle Sympathetic Nerve Activity in Heart Failure
Chest,
February 1, 2003;
123(2):
366 - 371.
[Abstract]
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R. Corti, C. Binggeli, I. Sudano, L. Spieker, E. Hanseler, F. Ruschitzka, W. F. Chaplin, T. F. Luscher, and G. Noll
Coffee Acutely Increases Sympathetic Nerve Activity and Blood Pressure Independently of Caffeine Content: Role of Habitual Versus Nonhabitual Drinking
Circulation,
December 3, 2002;
106(23):
2935 - 2940.
[Abstract]
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W. H. Cooke, R. Zhang, J. H. Zuckerman, J. Cui, T. E. Wilson, C. G. Crandall, and B. D. Levine
Does nitric oxide buffer arterial blood pressure variability in humans?
J Appl Physiol,
October 1, 2002;
93(4):
1466 - 1470.
[Abstract]
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D Patterson, J B C Dick, and A D Struthers
Intensive statin treatment improves baroreflex sensitivity: another cardioprotective mechanism for statins?
Heart,
October 1, 2002;
88(4):
415 - 416.
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A. D Struthers
Review: Aldosterone-induced vasculopathy: a new reversible cause of cardiac death
Journal of Renin-Angiotensin-Aldosterone System,
December 1, 2001;
2(4):
211 - 214.
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K. L. Ryan, M. R. Tehrany, and J. R. Jauchem
Nitric oxide does not contribute to the hypotension of heatstroke
J Appl Physiol,
March 1, 2001;
90(3):
961 - 970.
[Abstract]
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Abstract
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