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Reduced sympathoneural responses to the cold pressor test in individuals with essential hypertension and in those genetically predisposed to hypertension
AJH
2004; 17:863– 868
Original Contributions
Reduced Sympathoneural Responses to the Cold Pressor Test in Individuals With Essential Hypertension and in Those Genetically Predisposed to Hypertension No Support for the “Pressor Reactor” Hypothesis of Hypertension Development Elisabeth Annie Lambert and Markus Peter Schlaich Background: The aim of this study was to examine the influences of genetic predisposition to hypertension and of age on the sympathetic nervous system response to the cold pressor test (CPT). Methods: A total of 32 young subjects (aged 27 ⫾ 2 years) were studied: 11 normotensive subjects without a family history of hypertension (FH), 14 normotensive subjects with a strong family history of hypertension (FH⫹), and eight hypertensive subjects. In addition, 21 older subjects (aged 53 ⫾ 2 years) were studied: 13 hypertensive and eight normotensive subjects. Blood pressure (BP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were recorded at rest and during a 2-min period of a CPT. Results: Both young and older hypertensive subjects had higher resting MSNA than did the normotensive ones (47 ⫾ 7 v 29 ⫾ 4 bursts per 100 heartbeats (P ⬍ .05) and 66 ⫾ 4 v 40 ⫾ 7 bursts per 100 heartbeats (P ⬍ .01), respectively).
T
The CPT resulted in HR increases of similar magnitude in all groups of patients. The FH⫹ group displayed slightly less increase in systolic BP than that of the FH- group (P ⬍ .05). The MSNA increased to a far greater degree in FH- (103%) than in FH⫹ (32%) and in young hypertensive patients (12%) (P ⬍ .05). Similarly, MSNA change with the CPT was greater in older normotensive subjects than in older hypertensive patients (61% v 12%, P ⬍ .05). Conclusions: Our results show that a CPT induces sympathetic responses that are subnormal in hypertensive patients and those with a family history of hypertension, highlighting the importance of genetic factors in determining the sympathetic nervous reactivity to CPT. Am J Hypertens 2004;17:863– 868 © 2004 American Journal of Hypertension, Ltd. Key Words: Stress, microneurography, heredity.
he notion of an exaggerated cardiovascular response to stress as a marker or mechanism in the pathogenesis of essential hypertension and coronary heart disease is a matter of controversy and remains to be delineated. A number of reports have demonstrated a higher sympathetic reactivity to stress in hypertensive and borderline hypertensive subjects,1,2 whereas others3 have found that the cardiovascular and sympatho-adrenal response to mental stress was similar in hypertensive and control subjects. Previous studies have established that genetic factors are important in the pathogenesis of hypertension.4 The predic-
tive strength of family history as a risk factor is doubled with one hypertensive first degree relative and increases nearly fourfold with two such relatives.5 It follows, then, that normotensive young subjects with a family history of hypertension provide an opportunity to assess early dysfunction of cardiovascular regulation. At rest, the sympathetic nervous system of normotensive offspring of hypertensive parents does not seem to be activated, but a greater cardiovascular reactivity to mental stress has recently been documented in these subjects.6 In a large prospective study, Menkes et al found that subjects displaying larger BP response to a cold
Received December 22, 2003. First decision March 2, 2004. Accepted May 11, 2004. From the Human Neurotransmitter Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia. This work was supported by National Health and Medical Research Council project grants 225126 and 225121. Dr. Schlaich is the recipient
of a Research Fellowship of the Deutsche Forschungsgemeinschaft DFG.
© 2004 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
Address correspondence and reprint requests to Dr. Elisabeth Lambert, Human Neurotransmitter Laboratory, Baker Heart Research Institute, PO Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia; e-mail: [email protected] 0895-7061/04/$30.00 doi:10.1016/j.amjhyper.2004.05.008
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pressor test (CPT) were at higher risk of developing hypertension later in life than those displaying low or moderate BP rise to the test.7 These results suggest an association between blood pressure (BP) reactivity to the CPT and incidence of subsequent hypertension. However, such increased cardiovascular reactivity in hypertensive subjects and offspring of hypertensives has not been described consistently across studies.8 The use of different psychological or physical stressors along with the differing inclusion criteria for subjects with respect to family history of hypertension may account for some discrepancies. We therefore studied the sympathetic reactivity induced by the CPT, which is a potent stimulus to muscle sympathetic nerve activity (MSNA), in subjects chosen with the aim of isolating individual influences of BP level, family history of hypertension, and age.
Methods Study Population We studied a total of 53 subjects (47 of white ethnicity and six Asian) comprising 32 young and 21 older subjects. The young ones (18 to 42 years, 28 male and four female) were divided into three groups: healthy normotensive subjects with (FH⫹; n ⫽ 14) and without (FH-; n ⫽ 11) a family history of essential hypertension, and eight untreated hypertensive subjects (HT) who also had a family history of essential hypertension. The older subjects (aged 48 to 63 years, 13 male and eight female) comprised eight normotensive subjects and 13 hypertensive ones. A positive family history was defined as both parents and at least one other family member being diagnosed with essential hypertension. A negative family history was recorded only in the absence of any evidence for essential hypertension or history of cardiovascular disease in the family. The parental history of hypertension was confirmed by the parents or the parents’ physicians. Older normotensive subjects were recruited regardless of their family history of hypertension; here it was the influence of age rather than family history that was the issue. Hypertension was defined as an average BP ⬎140 mm Hg systolic or ⬎90 mm Hg diastolic on multiple sphygmomanometric measurements over repeated clinic visits. Participants were classified as normotensive if their BP was consistently ⬍140 mm Hg systolic and ⬍90 mm Hg diastolic. Exclusion criteria for all subjects included a history of major illness, cardiovascular disease other than hypertension, and current drug medication. None of the participating subjects were current smokers or had a history of smoking or alcohol abuse. Hypertensive patients were either newly diagnosed with or currently treated for hypertension, but were free of all antihypertensive therapy for at least 3 weeks before the study. The investigation conformed with the principles outlined in the Declaration of Helsinki. The study protocol was approved by the Alfred Hospital Ethics Review Committee. The research protocol conformed to the relevant guidelines of the National Health and Medical Research Council of Australia
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and was approved by the Alfred Hospital Human Research Ethics Committee. All participants gave written informed consent before participation. All studies were performed with subjects in the supine position. Blood pressure was measured using a Finapres BP monitor positioned on the middle finger (model Datex-Ohmeda 2300, Englewood, CO). Resting Finapress BP was verified during the experiment by brachial auscultation. Heart rate was determined from lead III on the electrocardiographic recording (ECG). Muscle Sympathetic Nerve Activity Multiunit postganglionic sympathetic activity was recorded using microneurography in a muscle fascicle of the peroneal nerve at the fibular head, as described previously.9,10 The needle was adjusted until satisfactory spontaneous muscle sympathetic nerve activity (MSNA) was observed in accordance with previously described criteria.9,11 The nerve signal was amplified (⫻50,000), filtered (bandpass, 700 to 2000 Hz), and integrated. The ECG, BP, and MSNA were digitized with a sampling frequency of 1000 Hz (PowerLab recording system, model ML785/8SP, ADI Instruments, Castle Hill, NSW, Australia). After an acceptable nerve recording site was obtained, resting measurements were performed over a 20-min period. Cold stimulation (ie, CPT) was induced by submerging the hand contralateral to the BP measurement in ice cold water for a 2-min period. Sympathetic bursts were counted manually. The MSNA was expressed as burst frequency (bursts/min) and burst incidence (bursts/100 heartbeats). In addition, the amplitude of each burst was determined, and the total MSNA was calculated by multiplying the mean burst amplitude per minute per burst rate and expressed as units per minute. The MSNA response to the CPT was expressed as percentage of change in the total MSNA as well as absolute and relative (%) changes in burst frequency and burst incidence. Basal levels of MSNA, BP, and HR were averaged during 3 to 5 min before the CPT. The entire 2-min recording of the CPT was used to determine average changes of MSNA and BP from control. Maximum values of BP and HR during the CPT were assessed. Statistical Analysis Results are expressed as means ⫾ SEM. The effect of the CPT on HR, BP, and MSNA was analyzed using the Student t test. A one-way analysis of variance followed by the Bonferroni correction was used to compare the basal values and differences in responses to the CPT of HR, BP, and MSNA. Statistical significance was defined as P ⬍ .05.
Results Basal Characteristics in Young Subjects Characteristics of the study population and their basal cardiovascular values are reported in Table 1. The majority of the participants were men. Among the young subjects, the
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Table 1. Subjects characteristics and resting systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) in young and older subjects Young n Age (y) Sex BMI (kg 䡠 m⫺2) HR (beats/min) SBP (mm Hg) DBP (mm Hg) MSNA (bursts/min) MSNA (bursts/100 heart beats)
Older
FHⴚ
FHⴙ
HT
NT
HT
11 27 ⫾ 2 1F/10M 23 ⫾ 1 69 ⫾ 2 118 ⫾ 4 63 ⫾ 3 20 ⫾ 3 29 ⫾ 4
14 25 ⫾ 2 2F/12M 25 ⫾ 1 67 ⫾ 2 129 ⫾ 4 67 ⫾ 3 23 ⫾ 2 35 ⫾ 3
8 28 ⫾ 3 1F/7M 25 ⫾ 2 68 ⫾ 4 154 ⫾ 9* 83 ⫾ 9 32 ⫾ 5* 47 ⫾ 7*
8 52 ⫾ 2 4F/4M 25 ⫾ 2 68 ⫾ 2 135 ⫾ 4 75 ⫾ 2 28 ⫾ 6 40 ⫾ 7
13 53 ⫾ 1 4F/9M 28 ⫾ 2 59 ⫾ 2 155 ⫾ 3# 82 ⫾ 4 39 ⫾ 2# 66 ⫾ 4#
FH⫺ ⫽ normotensive subjects without a family history of hypertension, FH⫹ ⫽ normotensive subjects with a family history of hypertension, HT ⫽ hypertensive subjects, NT ⫽ normotensive subjects. * P ⬍ .05 vs FH⫺, # P ⬍ .05 vs NT.
three groups did not differ by age, sex ratio, or BMI. Baseline SBP levels were higher in HT compared with FH- (P ⬍ .001), whereas DBP levels were not significantly higher. The HT group displayed higher MSNA when expressed in both burst incidence and burst frequency (P ⬍ .05). Subjects in the FH⫹ group had BP levels, HR, and MSNA that were similar to those in the FH- group. Effects of a Cold Pressor Test on BP and Heart Rate in Young Subjects The CPT resulted in gradual increases in BP throughout the test in all three groups, with the maximal being reached during min 2 of the test (P ⬍ .001 for each group) (Fig. 1). The maximal rises in SBP were 33 ⫾ 3 mm Hg, 17 ⫾ 2 mm Hg, and 22 ⫾ 5 mm Hg SBP in FH-, FH⫹, and HT, respectively, with the increase in the FH⫹ group being significantly less than that in the FH- (P ⬍ .01). The maximal increases in DBP were 22 ⫾ 3 mm Hg, 14 ⫾ 1 mm Hg, and 18 ⫾ 4 mm Hg in FH-, FH⫹, and HT respectively. Average rises in SBP and DBP were 24 ⫾ 4 mm Hg, 12 ⫾ 2 mm Hg, and 15 ⫾ 5 mm Hg for the SBP in FH-, FH⫹, and HT,
respectively, and were 16 ⫾ 3 mm Hg, 9 ⫾ 1 mm Hg, and 12 ⫾ 3 mm Hg for the DBP. There were no statistical differences in the average BP responses to CPT among the three groups. The CPT induced a slight gradual rise in HR in the three groups of patients with the peak rise being only significant in the normotensive groups (11 ⫾ 3 beats/min, P ⬍ .001 in FH- and 13 ⫾ 3 beats/min, P ⬍ .01 in FH⫹). Effects of a Cold Pressor Test on Muscle Sympathetic Nerve Activity in Young Subjects In FH-, the CPT resulted in a significant MSNA increase by 17 ⫾ 2 bursts/min (103%, P ⬍ .001) or by 21 ⫾ 2 bursts/100 heartbeats (94%, P ⬍ .001) and an increase in total MSNA activity by 139% (P ⬍ .01) (Fig. 2). In FH⫹, the MSNA elevation was 6 ⫾ 3 bursts/min (32%, P ⬍ .05) or 5 ⫾ 4 bursts/100 heartbeats (18%, NS) and the increase in total MSNA activity was 54% (P ⬍ .05). No significant MSNA changes occurred in HT during the CPT. The MSNA changes seen in FH⫹ and HT were both lower
FIG. 1. Changes in heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) induced by the cold pressor test in young, normotensive subjects with (FH⫹) and without (FH-) a family history of hypertension and in young hypertensive subjects (HT). For the HR, only the maximal change is displayed. For the BP, both maximal and average values over the 2-min are displayed. *P ⬍ .05 versus FH-.
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sive subjects, respectively. No significant differences in BP and HR response were found between NT and HT groups. Effects of a Cold Pressor Test on Muscle Sympathetic Nerve Activity in Older Subjects
FIG. 2. Changes in muscle sympathetic nerve activity (MSNA) induced by the cold pressor test in young, normotensive subjects with (FH⫹) and without (FH-) a family history of hypertension and in young hypertensive subjects (HT). Average values are displayed and expressed as bursts per minute, bursts per 100 heartbeats and total activity. *P ⬍ .05 versus FH-.
compared with that seen in FH- for both burst frequency and incidence and total MSNA activity (P ⬍ .05).
The MSNA significantly increased in responses to the CPT in normotensive subjects: 11 ⫾ 3 bursts/min (61%, P ⬍ .05) or 12 ⫾ 3 bursts per 100 heartbeats (51%, P ⬍ .05) and by 132% in total activity (P ⬍ .05) (Fig. 4). In older hypertensive subjects, a slight increase in MSNA in response to the CPT was observed when MSNA was expressed as total activity (33%, P ⬍ .01). The changes in MSNA observed in older normotensive subjects were significantly higher than those seen in the older hypertensive subjects when expressed in burst frequency and total activity (P ⬍ .05).
Basal Characteristics in Older Subjects
Discussion
In the older group of subjects, patients were also well matched for age, sex ratio, and BMI. Hypertensive subjects were characterized by a higher SBP (P ⬍ .01) along with a high level of MSNA when expressed as burst incidence (P ⬍ .05) and burst frequency (P ⬍ .01) (Table 1).
This study demonstrates that hypertensive patients present a markedly reduced sympatho-excitatory response to a CPT and, more interestingly, that the same impairment can be observed in young subjects genetically predisposed to hypertension. These findings are of interest because they provide further new insight in the complex field of the development of hypertension and are in some ways in contradiction with previous theories on hypertension development. In fact, exaggerated BP reactions in response to acute exposure to stress has been hypothesized to be a marker for one’s predisposition to develop neurogenic hypertension later in life.12–14 Unequivocal support for this hypothesis has been difficult to obtain, given the heterogeneity of observations that seem to be dependent on factors such as the type of stress examined and the genetic predisposition of the subjects. Numerous reports have documented the importance of family history as a significant risk factor for the development of hypertension.4,5,7 The proposal by
Effects of a Cold Pressor Test on BP and Heart Rate in Older Subjects The CPT induced significant increases in BP in both groups. Maximum SBP increases were 27 ⫾ 7 mm Hg and 34 ⫾ 5 mm Hg, and maximal DBP were 15 ⫾ 4 mm Hg and 26 ⫾ 3 mm Hg in older NT and HT (Fig. 3). Average rises were 21 ⫾ 7 mm Hg and 25 ⫾ 4 mm Hg for SBP and 12 ⫾ 3 mm Hg and 17 ⫾ 2 mm Hg for DBP in older NT and HT, respectively (P ⬍ .05 for all variables). The maximal response in HR to the CPT was observed within min 1 of the test (9 ⫾ 3 beats/min, P ⬍ .05 and 15 ⫾ 3 beats/min, P ⬍ .01 in older normotensive and hyperten-
FIG. 3. Changes in heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) induced by the cold pressor test in older normotensive and hypertensive subjects. For the HR, only the maximal change is displayed. For the BP, both maximal and average values over the 2-min period are displayed.
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FIG. 4. Changes in muscle sympathetic nerve activity (MSNA) induced by the cold pressor test in older normotensive and hypertensive subjects. Average values are displayed and expressed as bursts per minute, bursts per 100 heartbeats and total activity. *P ⬍ .05 versus NT.
Hines and Brown12 that a period of exaggerated vascular reactivity is antecedent to the development of hypertension forms the basis of the stress reactivity hypothesis of hypertension. Recent results from Noll et al6 support this hypothesis, as these investigators reported more pronounced MSNA and BP response to a psychological challenge in offspring of hypertensive parents than in normotensive ones. Contrary to this concept, our results show that subjects with a strong family history of hypertension (that is, both parents hypertensive) displayed a lesser response of BP to the CPT. Moreover, muscle sympathetic nervous activity during the CPT was markedly attenuated in subjects with established hypertension as well as in young normotensive subjects with a positive family history of hypertension. Cold pressor stimulation involves both central neural and peripheral reflex mechanisms and has recently been shown to evoke an increase in norepinephrine spillover in the legs.15 In response to a CPT, BP changes have been documented to be either exaggerated or unchanged in hypertensive patients and in normotensive subjects with a parental history of hypertension.8 In the present study, although, young HT subjects exhibited less BP increase in response to CPT compared with the normotensive subjects without a parental history of hypertension, no statistical differences between these two groups were found. Similarly, no statistical significance in BP and HR rise in response to the CPT could be seen in older subjects. In the present study, the family history of hypertension of the older normotensive subjects was not taken into account, as accurate records were not always available and the death of some parents prevented corroboration of normal BP in some subjects. Nevertheless, these subjects displayed a significant rise in MSNA in response to the CPT, indicating that the sympathetic response to the CPT was not altered with aging.16 In agreement with previous studies, we found the BP, HR, and resting MSNA to be similar in the FH- and FH⫹ subjects6,17–19 and MSNA to be elevated in young HT patients.18 Our results of a small MSNA response to the CPT in hypertensive patients are consistent with previous studies.20,21 It could be argued that an augmented basal MSNA in our patients with hypertension may limit the capacity for any
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further increases in nerve activity. This is unlikely, given observations in patients with obstructive sleep apnea who displayed a high resting level of MSNA compared with controls (47 v 26 bursts/min) and yet showed normal response in MSNA to a CPT.22 Moreover, the impaired MSNA response to CPT observed in young FH⫹ occurred despite normal resting sympathetic tone. Calhoun et al17 found that sympathetic reactivity to CPT was unrelated to family history of hypertension in subjects of white ethnicity. The discrepancy between their results and ours may reflect a difference in the criteria used to indicate a genetic predisposition of hypertension. In our study, we applied more stringent requirements, in that FH⫹ subjects were recruited on the basis of having both parents hypertensive plus at least one other family member being diagnosed with essential hypertension; in contrast, Calhoun et al based their observation on the presence of hypertension in only one parent.17 Our findings indicate that the presence of a strong parental history of hypertension is likely to be an important determinant on the sympathetic reactivity to the CPT. This is relevant, as these subjects are at high risk for developing hypertension5 and already tend to display the same MSNA response to the CPT as their HT counterparts despite their normal resting sympathetic tone. Our finding of a diminished sympatho-excitation in response to a CPT in young subjects with a strong family of hypertension may reflect dysregulation at the level of the central nervous system involved in pain control. The observation that sympatho-excitation associated with the CPT occurs when skin temperature falls to a level that produces sensation of intense pain23 suggests that the MSNA elevation is principally driven by activation of high-threshold nociceptive fibers in the hand. Interestingly, painful stimuli induced by several methods is capable of elevating MSNA with a concomitant elevation in BP.24,25 Pain threshold and tolerance have been demonstrated to be higher in hypertensive and borderline hypertensive subjects than in normotensive ones.25,26 Furthermore, normotensive subjects with a parental history of hypertension have reported lower pain ratings in responses to several painful electrical27 and nonelectrical stimuli including the CPT.28,29 Mechanisms such as exaggerated endogenous opioid, enkephalins, and -endorphin increases may account for the hypoalgesia in hypertensive-prone individuals,30 whereas differences in baroreceptor activation associated with pain perception seems not to be of importance.25 Dysfunction in peripheral or central mechanisms of cardiovascular regulation may be involved in the reduced sympatho-excitatory response to the CPT observed in both hypertensive subjects and in those genetically predisposed to hypertension. Our results indicate that any dysfunction operates before any evidence of BP elevation. Possible mechanisms may involve activation of other systems (for instance, the renin-angiotensin system) affecting arterial baroreflex control during the CPT in hypertensive subjects and in those genetically
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predisposed to hypertension. This hypothesis remains to be elucidated. In light of previous studies linking exaggerated cardiovascular reactivity to stress and development of high BP, our results using CPT seem at odds. It should be emphasized that different stressors may induce different cardiovascular responses. The sympatho-excitation induced by the CPT does not seem to be caused by a defense reaction,24 whereas such a reaction elicited during mental stress induces only a small rise in MSNA.11 It has been reported that MSNA elevation is influenced by the perception of the stress and the level of task difficulty during mental stress testing.31 Also, mental stress produces a differentiated pattern of sympathetic activation, with a preferential stimulation of the cardiac sympathetic outflow, as indicated by a large increase in the spillover of noradrenaline to plasma from the heart.32 In summary, we report a strong impairment in MSNA in response to the CPT in hypertensive subjects and in normotensive offspring of hypertensive subjects. This observation highlights the importance of genetic factors in determining the sympathetic nervous reactivity to the CPT.
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Horikoshi Y, Tajima I, Igarashi H, Inui M, Kasahara K, Noguchi T: The adreno-sympathetic system, the genetic predisposition to hypertension, and stress. Am J Med Sci 1985;289:186 –191. 2. Ditto B, France C: Carotid baroreflex sensitivity at rest and during psychological stress in offspring of hypertensives and non-twin sibling pairs. Psychosom Med 1990;52:610 – 620. 3. Lindqvist M, Kahan T, Melcher A, Hjemdahl P: Cardiovascular and sympatho-adrenal responses to mental stress in primary hypertension. Clin Sci (Lond) 1993;85:401– 409. 4. Watt GC, Foy CJ, Holton DW, Edwards HE: Prediction of high blood pressure in young people: the limited usefulness of parental blood pressure data. J Hypertens 1991;9:55–58. 5. Hunt SC, Williams RR, Barlow GK: A comparison of positive family history definitions for defining risk of future disease. J Chron Dis 1986;39:809 – 821. 6. Noll G, Wenzel RR, Schneider M, Oesch V, Binggeli C, Shaw S, Weidmann P, Luscher TF: Increased activation of sympathetic nervous system and endothelin by mental stress in normotensive offspring of hypertensive parents. Circulation 1996;93:866 – 869. 7. Menkes MS, Matthews KA, Krantz DS, Lundberg U, Mead LA, Qaqish B, Liang KY, Thomas CB, Pearson TA: Cardiovascular reactivity to the cold pressor test as a predictor of hypertension. Hypertension 1989;14:524 –530. 8. Muldoon MF, Terrell DF, Bunker CH, Manuck SB: Family history studies in hypertension research. Review of the literature. Am J Hypertens 1993;6:76 – 88. 9. Sundlof G, Wallin BG: Human muscle nerve sympathetic activity at rest. Relationship to blood pressure and age. J Physiol 1978;274: 621– 637. 10. Lambert EA, Thompson J, Schlaich M, Laude D, Elghozi JL, Esler MD, Lambert GW: Sympathetic and cardiac baroreflex function in panic disorder. J Hypertens 2002;20:2445–2451. 11. Thompson JM, Jennings GL, Chin JP, Esler MD: Measurement of human sympathetic nervous responses to stressors by microneurography. J Auton Nerv Syst 1994;49:277–281. 12. Hines E, Brown G: The cold pressor test for measuring the react-
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ibility of the blood pressure: data concerning 571 normal and hypertensive subjects. Am Heart J 1936;11:1–9. Light KC: Cardiovascular responses to effortful active coping: implications for the role of stress in hypertension development. Psychophysiology 1981;18:216 –225. Manuck SB, Proietti JM, Rader SJ, Polefrone JM: Parental hypertension, affect, and cardiovascular response to cognitive challenge. Psychosom Med 1985;47:189 –200. Jacob G, Costa F, Shannon J, Robertson D, Biaggioni I: Dissociation between neural and vascular responses to sympathetic stimulation: contribution of local adrenergic receptor function. Hypertension 2000;35:76 – 81. Ng AV, Callister R, Johnson DG, Seals DR: Sympathetic neural reactivity to stress does not increase with age in healthy humans. Am J Physiol 1994;267:H344 –H353. Calhoun DA, Mutinga ML: Race, family history of hypertension, and sympathetic response to cold pressor testing. Blood Press 1997; 6:209 –213. Floras JS, Hara K: Sympathoneural and haemodynamic characteristics of young subjects with mild essential hypertension. J Hypertens 1993;11:647– 655. Hausberg M, Sinkey CA, Mark AL, Hoffman RP, Anderson EA: Sympathetic nerve activity and insulin sensitivity in normotensive offspring of hypertensive parents. Am J Hypertens 1998;11:1312– 1320. Schobel HP, Heusser K, Schmieder RE, Veelken R, Fischer T, Luft FC: Evidence against elevated sympathetic vasoconstrictor activity in borderline hypertension. J Am Soc Nephrol 1998;9:1581–1587. Schobel HP, Frank H, Naraghi R, Geiger H, Titz E, Heusser K: Hypertension in patients with neurovascular compression is associated with increased central sympathetic outflow. J Am Soc Nephrol 2002;13:35– 41. Narkiewicz K, Pesek CA, Kato M, Phillips BG, Davison DE, Somers VK: Baroreflex control of sympathetic nerve activity and heart rate in obstructive sleep apnea. Hypertension 1998;32:1039 – 1043. Kregel KC, Seals DR, Callister R: Sympathetic nervous system activity during skin cooling in humans: relationship to stimulus intensity and pain sensation. J Physiol 1992;454:359 –371. Nordin M, Fagius J: Effect of noxious stimulation on sympathetic vasoconstrictor outflow to human muscles. J Physiol 1995;489:885– 894. Schobel HP, Ringkamp M, Behrmann A, Forster C, Schmieder RE, Handwerker HO: Hemodynamic and sympathetic nerve responses to painful stimuli in normotensive and borderline hypertensive subjects. Pain 1996;66:117–124. Guasti L, Gaudio G, Zanotta D, Grimoldi P, Petrozzino MR, Tanzi F, Bertolini A, Grandi AM, Venco A: Relationship between a genetic predisposition to hypertension, blood pressure levels and pain sensitivity. Pain 1999;82:311–37. Page GD, France CR: Objective evidence of decreased pain perception in normotensives at risk for hypertension. Pain 1997;73:173– 180. France CR, Stewart KM: Parental history of hypertension and enhanced cardiovascular reactivity are associated with decreased pain ratings. Psychophysiology 1995;32:571–578. Stewart KM, France CR: Resting systolic blood pressure, parental history of hypertension, and sensitivity to noxious stimuli. Pain 1996;68:369 –374. France C, Ditto B: Risk for high blood pressure and decreased pain perception. Curr Dir Psychol Sci 1996;5:120 –125. Callister R, Suwarno NO, Seals DR: Sympathetic activity is influenced by task difficulty and stress perception during mental challenge in humans. J Physiol 1992;454:373–387. Esler M, Jennings G, Lambert G: Measurement of overall and cardiac norepinephrine release into plasma during cognitive challenge. Psychoneuroendocrinology 1989;14:477– 481.
2004; 17:863– 868
Original Contributions
Reduced Sympathoneural Responses to the Cold Pressor Test in Individuals With Essential Hypertension and in Those Genetically Predisposed to Hypertension No Support for the “Pressor Reactor” Hypothesis of Hypertension Development Elisabeth Annie Lambert and Markus Peter Schlaich Background: The aim of this study was to examine the influences of genetic predisposition to hypertension and of age on the sympathetic nervous system response to the cold pressor test (CPT). Methods: A total of 32 young subjects (aged 27 ⫾ 2 years) were studied: 11 normotensive subjects without a family history of hypertension (FH), 14 normotensive subjects with a strong family history of hypertension (FH⫹), and eight hypertensive subjects. In addition, 21 older subjects (aged 53 ⫾ 2 years) were studied: 13 hypertensive and eight normotensive subjects. Blood pressure (BP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were recorded at rest and during a 2-min period of a CPT. Results: Both young and older hypertensive subjects had higher resting MSNA than did the normotensive ones (47 ⫾ 7 v 29 ⫾ 4 bursts per 100 heartbeats (P ⬍ .05) and 66 ⫾ 4 v 40 ⫾ 7 bursts per 100 heartbeats (P ⬍ .01), respectively).
T
The CPT resulted in HR increases of similar magnitude in all groups of patients. The FH⫹ group displayed slightly less increase in systolic BP than that of the FH- group (P ⬍ .05). The MSNA increased to a far greater degree in FH- (103%) than in FH⫹ (32%) and in young hypertensive patients (12%) (P ⬍ .05). Similarly, MSNA change with the CPT was greater in older normotensive subjects than in older hypertensive patients (61% v 12%, P ⬍ .05). Conclusions: Our results show that a CPT induces sympathetic responses that are subnormal in hypertensive patients and those with a family history of hypertension, highlighting the importance of genetic factors in determining the sympathetic nervous reactivity to CPT. Am J Hypertens 2004;17:863– 868 © 2004 American Journal of Hypertension, Ltd. Key Words: Stress, microneurography, heredity.
he notion of an exaggerated cardiovascular response to stress as a marker or mechanism in the pathogenesis of essential hypertension and coronary heart disease is a matter of controversy and remains to be delineated. A number of reports have demonstrated a higher sympathetic reactivity to stress in hypertensive and borderline hypertensive subjects,1,2 whereas others3 have found that the cardiovascular and sympatho-adrenal response to mental stress was similar in hypertensive and control subjects. Previous studies have established that genetic factors are important in the pathogenesis of hypertension.4 The predic-
tive strength of family history as a risk factor is doubled with one hypertensive first degree relative and increases nearly fourfold with two such relatives.5 It follows, then, that normotensive young subjects with a family history of hypertension provide an opportunity to assess early dysfunction of cardiovascular regulation. At rest, the sympathetic nervous system of normotensive offspring of hypertensive parents does not seem to be activated, but a greater cardiovascular reactivity to mental stress has recently been documented in these subjects.6 In a large prospective study, Menkes et al found that subjects displaying larger BP response to a cold
Received December 22, 2003. First decision March 2, 2004. Accepted May 11, 2004. From the Human Neurotransmitter Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia. This work was supported by National Health and Medical Research Council project grants 225126 and 225121. Dr. Schlaich is the recipient
of a Research Fellowship of the Deutsche Forschungsgemeinschaft DFG.
© 2004 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
Address correspondence and reprint requests to Dr. Elisabeth Lambert, Human Neurotransmitter Laboratory, Baker Heart Research Institute, PO Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia; e-mail: [email protected] 0895-7061/04/$30.00 doi:10.1016/j.amjhyper.2004.05.008
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pressor test (CPT) were at higher risk of developing hypertension later in life than those displaying low or moderate BP rise to the test.7 These results suggest an association between blood pressure (BP) reactivity to the CPT and incidence of subsequent hypertension. However, such increased cardiovascular reactivity in hypertensive subjects and offspring of hypertensives has not been described consistently across studies.8 The use of different psychological or physical stressors along with the differing inclusion criteria for subjects with respect to family history of hypertension may account for some discrepancies. We therefore studied the sympathetic reactivity induced by the CPT, which is a potent stimulus to muscle sympathetic nerve activity (MSNA), in subjects chosen with the aim of isolating individual influences of BP level, family history of hypertension, and age.
Methods Study Population We studied a total of 53 subjects (47 of white ethnicity and six Asian) comprising 32 young and 21 older subjects. The young ones (18 to 42 years, 28 male and four female) were divided into three groups: healthy normotensive subjects with (FH⫹; n ⫽ 14) and without (FH-; n ⫽ 11) a family history of essential hypertension, and eight untreated hypertensive subjects (HT) who also had a family history of essential hypertension. The older subjects (aged 48 to 63 years, 13 male and eight female) comprised eight normotensive subjects and 13 hypertensive ones. A positive family history was defined as both parents and at least one other family member being diagnosed with essential hypertension. A negative family history was recorded only in the absence of any evidence for essential hypertension or history of cardiovascular disease in the family. The parental history of hypertension was confirmed by the parents or the parents’ physicians. Older normotensive subjects were recruited regardless of their family history of hypertension; here it was the influence of age rather than family history that was the issue. Hypertension was defined as an average BP ⬎140 mm Hg systolic or ⬎90 mm Hg diastolic on multiple sphygmomanometric measurements over repeated clinic visits. Participants were classified as normotensive if their BP was consistently ⬍140 mm Hg systolic and ⬍90 mm Hg diastolic. Exclusion criteria for all subjects included a history of major illness, cardiovascular disease other than hypertension, and current drug medication. None of the participating subjects were current smokers or had a history of smoking or alcohol abuse. Hypertensive patients were either newly diagnosed with or currently treated for hypertension, but were free of all antihypertensive therapy for at least 3 weeks before the study. The investigation conformed with the principles outlined in the Declaration of Helsinki. The study protocol was approved by the Alfred Hospital Ethics Review Committee. The research protocol conformed to the relevant guidelines of the National Health and Medical Research Council of Australia
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and was approved by the Alfred Hospital Human Research Ethics Committee. All participants gave written informed consent before participation. All studies were performed with subjects in the supine position. Blood pressure was measured using a Finapres BP monitor positioned on the middle finger (model Datex-Ohmeda 2300, Englewood, CO). Resting Finapress BP was verified during the experiment by brachial auscultation. Heart rate was determined from lead III on the electrocardiographic recording (ECG). Muscle Sympathetic Nerve Activity Multiunit postganglionic sympathetic activity was recorded using microneurography in a muscle fascicle of the peroneal nerve at the fibular head, as described previously.9,10 The needle was adjusted until satisfactory spontaneous muscle sympathetic nerve activity (MSNA) was observed in accordance with previously described criteria.9,11 The nerve signal was amplified (⫻50,000), filtered (bandpass, 700 to 2000 Hz), and integrated. The ECG, BP, and MSNA were digitized with a sampling frequency of 1000 Hz (PowerLab recording system, model ML785/8SP, ADI Instruments, Castle Hill, NSW, Australia). After an acceptable nerve recording site was obtained, resting measurements were performed over a 20-min period. Cold stimulation (ie, CPT) was induced by submerging the hand contralateral to the BP measurement in ice cold water for a 2-min period. Sympathetic bursts were counted manually. The MSNA was expressed as burst frequency (bursts/min) and burst incidence (bursts/100 heartbeats). In addition, the amplitude of each burst was determined, and the total MSNA was calculated by multiplying the mean burst amplitude per minute per burst rate and expressed as units per minute. The MSNA response to the CPT was expressed as percentage of change in the total MSNA as well as absolute and relative (%) changes in burst frequency and burst incidence. Basal levels of MSNA, BP, and HR were averaged during 3 to 5 min before the CPT. The entire 2-min recording of the CPT was used to determine average changes of MSNA and BP from control. Maximum values of BP and HR during the CPT were assessed. Statistical Analysis Results are expressed as means ⫾ SEM. The effect of the CPT on HR, BP, and MSNA was analyzed using the Student t test. A one-way analysis of variance followed by the Bonferroni correction was used to compare the basal values and differences in responses to the CPT of HR, BP, and MSNA. Statistical significance was defined as P ⬍ .05.
Results Basal Characteristics in Young Subjects Characteristics of the study population and their basal cardiovascular values are reported in Table 1. The majority of the participants were men. Among the young subjects, the
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Table 1. Subjects characteristics and resting systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) in young and older subjects Young n Age (y) Sex BMI (kg 䡠 m⫺2) HR (beats/min) SBP (mm Hg) DBP (mm Hg) MSNA (bursts/min) MSNA (bursts/100 heart beats)
Older
FHⴚ
FHⴙ
HT
NT
HT
11 27 ⫾ 2 1F/10M 23 ⫾ 1 69 ⫾ 2 118 ⫾ 4 63 ⫾ 3 20 ⫾ 3 29 ⫾ 4
14 25 ⫾ 2 2F/12M 25 ⫾ 1 67 ⫾ 2 129 ⫾ 4 67 ⫾ 3 23 ⫾ 2 35 ⫾ 3
8 28 ⫾ 3 1F/7M 25 ⫾ 2 68 ⫾ 4 154 ⫾ 9* 83 ⫾ 9 32 ⫾ 5* 47 ⫾ 7*
8 52 ⫾ 2 4F/4M 25 ⫾ 2 68 ⫾ 2 135 ⫾ 4 75 ⫾ 2 28 ⫾ 6 40 ⫾ 7
13 53 ⫾ 1 4F/9M 28 ⫾ 2 59 ⫾ 2 155 ⫾ 3# 82 ⫾ 4 39 ⫾ 2# 66 ⫾ 4#
FH⫺ ⫽ normotensive subjects without a family history of hypertension, FH⫹ ⫽ normotensive subjects with a family history of hypertension, HT ⫽ hypertensive subjects, NT ⫽ normotensive subjects. * P ⬍ .05 vs FH⫺, # P ⬍ .05 vs NT.
three groups did not differ by age, sex ratio, or BMI. Baseline SBP levels were higher in HT compared with FH- (P ⬍ .001), whereas DBP levels were not significantly higher. The HT group displayed higher MSNA when expressed in both burst incidence and burst frequency (P ⬍ .05). Subjects in the FH⫹ group had BP levels, HR, and MSNA that were similar to those in the FH- group. Effects of a Cold Pressor Test on BP and Heart Rate in Young Subjects The CPT resulted in gradual increases in BP throughout the test in all three groups, with the maximal being reached during min 2 of the test (P ⬍ .001 for each group) (Fig. 1). The maximal rises in SBP were 33 ⫾ 3 mm Hg, 17 ⫾ 2 mm Hg, and 22 ⫾ 5 mm Hg SBP in FH-, FH⫹, and HT, respectively, with the increase in the FH⫹ group being significantly less than that in the FH- (P ⬍ .01). The maximal increases in DBP were 22 ⫾ 3 mm Hg, 14 ⫾ 1 mm Hg, and 18 ⫾ 4 mm Hg in FH-, FH⫹, and HT respectively. Average rises in SBP and DBP were 24 ⫾ 4 mm Hg, 12 ⫾ 2 mm Hg, and 15 ⫾ 5 mm Hg for the SBP in FH-, FH⫹, and HT,
respectively, and were 16 ⫾ 3 mm Hg, 9 ⫾ 1 mm Hg, and 12 ⫾ 3 mm Hg for the DBP. There were no statistical differences in the average BP responses to CPT among the three groups. The CPT induced a slight gradual rise in HR in the three groups of patients with the peak rise being only significant in the normotensive groups (11 ⫾ 3 beats/min, P ⬍ .001 in FH- and 13 ⫾ 3 beats/min, P ⬍ .01 in FH⫹). Effects of a Cold Pressor Test on Muscle Sympathetic Nerve Activity in Young Subjects In FH-, the CPT resulted in a significant MSNA increase by 17 ⫾ 2 bursts/min (103%, P ⬍ .001) or by 21 ⫾ 2 bursts/100 heartbeats (94%, P ⬍ .001) and an increase in total MSNA activity by 139% (P ⬍ .01) (Fig. 2). In FH⫹, the MSNA elevation was 6 ⫾ 3 bursts/min (32%, P ⬍ .05) or 5 ⫾ 4 bursts/100 heartbeats (18%, NS) and the increase in total MSNA activity was 54% (P ⬍ .05). No significant MSNA changes occurred in HT during the CPT. The MSNA changes seen in FH⫹ and HT were both lower
FIG. 1. Changes in heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) induced by the cold pressor test in young, normotensive subjects with (FH⫹) and without (FH-) a family history of hypertension and in young hypertensive subjects (HT). For the HR, only the maximal change is displayed. For the BP, both maximal and average values over the 2-min are displayed. *P ⬍ .05 versus FH-.
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sive subjects, respectively. No significant differences in BP and HR response were found between NT and HT groups. Effects of a Cold Pressor Test on Muscle Sympathetic Nerve Activity in Older Subjects
FIG. 2. Changes in muscle sympathetic nerve activity (MSNA) induced by the cold pressor test in young, normotensive subjects with (FH⫹) and without (FH-) a family history of hypertension and in young hypertensive subjects (HT). Average values are displayed and expressed as bursts per minute, bursts per 100 heartbeats and total activity. *P ⬍ .05 versus FH-.
compared with that seen in FH- for both burst frequency and incidence and total MSNA activity (P ⬍ .05).
The MSNA significantly increased in responses to the CPT in normotensive subjects: 11 ⫾ 3 bursts/min (61%, P ⬍ .05) or 12 ⫾ 3 bursts per 100 heartbeats (51%, P ⬍ .05) and by 132% in total activity (P ⬍ .05) (Fig. 4). In older hypertensive subjects, a slight increase in MSNA in response to the CPT was observed when MSNA was expressed as total activity (33%, P ⬍ .01). The changes in MSNA observed in older normotensive subjects were significantly higher than those seen in the older hypertensive subjects when expressed in burst frequency and total activity (P ⬍ .05).
Basal Characteristics in Older Subjects
Discussion
In the older group of subjects, patients were also well matched for age, sex ratio, and BMI. Hypertensive subjects were characterized by a higher SBP (P ⬍ .01) along with a high level of MSNA when expressed as burst incidence (P ⬍ .05) and burst frequency (P ⬍ .01) (Table 1).
This study demonstrates that hypertensive patients present a markedly reduced sympatho-excitatory response to a CPT and, more interestingly, that the same impairment can be observed in young subjects genetically predisposed to hypertension. These findings are of interest because they provide further new insight in the complex field of the development of hypertension and are in some ways in contradiction with previous theories on hypertension development. In fact, exaggerated BP reactions in response to acute exposure to stress has been hypothesized to be a marker for one’s predisposition to develop neurogenic hypertension later in life.12–14 Unequivocal support for this hypothesis has been difficult to obtain, given the heterogeneity of observations that seem to be dependent on factors such as the type of stress examined and the genetic predisposition of the subjects. Numerous reports have documented the importance of family history as a significant risk factor for the development of hypertension.4,5,7 The proposal by
Effects of a Cold Pressor Test on BP and Heart Rate in Older Subjects The CPT induced significant increases in BP in both groups. Maximum SBP increases were 27 ⫾ 7 mm Hg and 34 ⫾ 5 mm Hg, and maximal DBP were 15 ⫾ 4 mm Hg and 26 ⫾ 3 mm Hg in older NT and HT (Fig. 3). Average rises were 21 ⫾ 7 mm Hg and 25 ⫾ 4 mm Hg for SBP and 12 ⫾ 3 mm Hg and 17 ⫾ 2 mm Hg for DBP in older NT and HT, respectively (P ⬍ .05 for all variables). The maximal response in HR to the CPT was observed within min 1 of the test (9 ⫾ 3 beats/min, P ⬍ .05 and 15 ⫾ 3 beats/min, P ⬍ .01 in older normotensive and hyperten-
FIG. 3. Changes in heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) induced by the cold pressor test in older normotensive and hypertensive subjects. For the HR, only the maximal change is displayed. For the BP, both maximal and average values over the 2-min period are displayed.
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FIG. 4. Changes in muscle sympathetic nerve activity (MSNA) induced by the cold pressor test in older normotensive and hypertensive subjects. Average values are displayed and expressed as bursts per minute, bursts per 100 heartbeats and total activity. *P ⬍ .05 versus NT.
Hines and Brown12 that a period of exaggerated vascular reactivity is antecedent to the development of hypertension forms the basis of the stress reactivity hypothesis of hypertension. Recent results from Noll et al6 support this hypothesis, as these investigators reported more pronounced MSNA and BP response to a psychological challenge in offspring of hypertensive parents than in normotensive ones. Contrary to this concept, our results show that subjects with a strong family history of hypertension (that is, both parents hypertensive) displayed a lesser response of BP to the CPT. Moreover, muscle sympathetic nervous activity during the CPT was markedly attenuated in subjects with established hypertension as well as in young normotensive subjects with a positive family history of hypertension. Cold pressor stimulation involves both central neural and peripheral reflex mechanisms and has recently been shown to evoke an increase in norepinephrine spillover in the legs.15 In response to a CPT, BP changes have been documented to be either exaggerated or unchanged in hypertensive patients and in normotensive subjects with a parental history of hypertension.8 In the present study, although, young HT subjects exhibited less BP increase in response to CPT compared with the normotensive subjects without a parental history of hypertension, no statistical differences between these two groups were found. Similarly, no statistical significance in BP and HR rise in response to the CPT could be seen in older subjects. In the present study, the family history of hypertension of the older normotensive subjects was not taken into account, as accurate records were not always available and the death of some parents prevented corroboration of normal BP in some subjects. Nevertheless, these subjects displayed a significant rise in MSNA in response to the CPT, indicating that the sympathetic response to the CPT was not altered with aging.16 In agreement with previous studies, we found the BP, HR, and resting MSNA to be similar in the FH- and FH⫹ subjects6,17–19 and MSNA to be elevated in young HT patients.18 Our results of a small MSNA response to the CPT in hypertensive patients are consistent with previous studies.20,21 It could be argued that an augmented basal MSNA in our patients with hypertension may limit the capacity for any
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further increases in nerve activity. This is unlikely, given observations in patients with obstructive sleep apnea who displayed a high resting level of MSNA compared with controls (47 v 26 bursts/min) and yet showed normal response in MSNA to a CPT.22 Moreover, the impaired MSNA response to CPT observed in young FH⫹ occurred despite normal resting sympathetic tone. Calhoun et al17 found that sympathetic reactivity to CPT was unrelated to family history of hypertension in subjects of white ethnicity. The discrepancy between their results and ours may reflect a difference in the criteria used to indicate a genetic predisposition of hypertension. In our study, we applied more stringent requirements, in that FH⫹ subjects were recruited on the basis of having both parents hypertensive plus at least one other family member being diagnosed with essential hypertension; in contrast, Calhoun et al based their observation on the presence of hypertension in only one parent.17 Our findings indicate that the presence of a strong parental history of hypertension is likely to be an important determinant on the sympathetic reactivity to the CPT. This is relevant, as these subjects are at high risk for developing hypertension5 and already tend to display the same MSNA response to the CPT as their HT counterparts despite their normal resting sympathetic tone. Our finding of a diminished sympatho-excitation in response to a CPT in young subjects with a strong family of hypertension may reflect dysregulation at the level of the central nervous system involved in pain control. The observation that sympatho-excitation associated with the CPT occurs when skin temperature falls to a level that produces sensation of intense pain23 suggests that the MSNA elevation is principally driven by activation of high-threshold nociceptive fibers in the hand. Interestingly, painful stimuli induced by several methods is capable of elevating MSNA with a concomitant elevation in BP.24,25 Pain threshold and tolerance have been demonstrated to be higher in hypertensive and borderline hypertensive subjects than in normotensive ones.25,26 Furthermore, normotensive subjects with a parental history of hypertension have reported lower pain ratings in responses to several painful electrical27 and nonelectrical stimuli including the CPT.28,29 Mechanisms such as exaggerated endogenous opioid, enkephalins, and -endorphin increases may account for the hypoalgesia in hypertensive-prone individuals,30 whereas differences in baroreceptor activation associated with pain perception seems not to be of importance.25 Dysfunction in peripheral or central mechanisms of cardiovascular regulation may be involved in the reduced sympatho-excitatory response to the CPT observed in both hypertensive subjects and in those genetically predisposed to hypertension. Our results indicate that any dysfunction operates before any evidence of BP elevation. Possible mechanisms may involve activation of other systems (for instance, the renin-angiotensin system) affecting arterial baroreflex control during the CPT in hypertensive subjects and in those genetically
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predisposed to hypertension. This hypothesis remains to be elucidated. In light of previous studies linking exaggerated cardiovascular reactivity to stress and development of high BP, our results using CPT seem at odds. It should be emphasized that different stressors may induce different cardiovascular responses. The sympatho-excitation induced by the CPT does not seem to be caused by a defense reaction,24 whereas such a reaction elicited during mental stress induces only a small rise in MSNA.11 It has been reported that MSNA elevation is influenced by the perception of the stress and the level of task difficulty during mental stress testing.31 Also, mental stress produces a differentiated pattern of sympathetic activation, with a preferential stimulation of the cardiac sympathetic outflow, as indicated by a large increase in the spillover of noradrenaline to plasma from the heart.32 In summary, we report a strong impairment in MSNA in response to the CPT in hypertensive subjects and in normotensive offspring of hypertensive subjects. This observation highlights the importance of genetic factors in determining the sympathetic nervous reactivity to the CPT.
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