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Hypertension-related hypoalgesia, autonomic function and spontaneous baroreflex sensitivity
Autonomic Neuroscience: Basic and Clinical 99 (2002) 127 – 133 www.elsevier.com/locate/autneu
Hypertension-related hypoalgesia, autonomic function and spontaneous baroreflex sensitivity Luigina Guasti a,*, Danilo Zanotta a, Luca T. Mainardi b, Maria R. Petrozzino a, Paola Grimoldi a, Deborah Garganico a, Alessio Diolisi a, Giovanni Gaudio a, Catherine Klersy c, Anna M. Grandi a, Cinzia Simoni a, Sergio Cerutti b a
Internal Medicine, Department of Clinical and Biological Sciences, University of Insubria, Ospedale di Circolo, Varese, Italy b Department of Biomedical Engineering, Polytechnic University, Milan, Italy c Department of Biometry and Clinical Epidemiology, IRCCS Policlinico S. Matteo, Pavia, Italy Accepted 27 November 2001
Abstract Objective: The mechanisms involved in the relationship between pain perception and hypertension are poorly understood. This study has sought to investigate whether the spontaneous baroreflex sensitivity and the autonomic nervous system balance are related to hypertensionassociated hypoalgesia. Methods: In the morning, 73 untreated male subjects (45 hypertensives, 28 normotensives) were submitted to a simultaneous recording of electrocardiographic and blood pressure signals in resting condition. The tracings were analysed off-line to evaluate the spectral components of the low frequency (LF) and high frequency (HF) powers (autoregressive algorithm; LF/HF ratio used in subsequent analysis as an index of sympathovagal balance), and the alphaLF (aLF), an index of baroreflex sensitivity. After the rest period, the subjects underwent dental pain perception evaluation (pulpar tester: test current increasing from 0 to 0.03 mA, expressed in relative Units) to determine the dental pain threshold and tolerance. Afterwards, a 24-h ambulatory blood pressure monitoring was performed. Results: A significant relationship was observed between aLF and pain threshold (r = 0.34; p = 0.003). When a multivariate analysis was computed to control for age, 24-h systolic pressure and LF/HF ratio, aLF was a predictive independent factor associated with pain threshold (model p = 0.019; r = 0.31; p = 0.025). Moreover, the 24-h systolic pressure was independently associated with pain threshold (model p = 0.019; r = 0.30, p = 0.031). The relationship between aLF and relative tolerance was not statistically significant. When the association between the LF/HF ratio and pain sensitivity was assessed as a secondary endpoint, no significant relationship was observed. Since no significant interaction was found, the effect of aLF and LF/HF ratio on pain perception was assumed to be similar in normotensive and hypertensive subjects. Conclusions: The relationship found between unstimulated baroreflex sensitivity and pain threshold suggests a modulation of pain perception by baroreflex pathways in hypertension-associated hypoalgesia. In a baseline condition, the autonomic nervous system balance does not seem to influence pain sensitivity. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Pain threshold; Spectral analysis; Baroreflex sensitivity; Hypertension, essential
1. Introduction Although a relationship between hypertension and hypoalgesia has been reproducibly found in numerous studies on man, the factors linking blood pressure levels with pain sensitivity are still poorly understood (Zamir and Segal, 1979; Zamir and Shuber, 1980; Ghione et al., 1988; Guasti et al., 1995, 1999a; Ghione, 1996).
*
Corresponding author. Tel.: +39-332-278-111; fax: +39-332-278-595. E-mail address: [email protected] (L. Guasti).
Ever since the first studies were carried out, it has been suggested that the baroreceptor arc function may be involved in the possible interactions between pain and cardiovascular control systems and a rewarding mechanism following baroreceptor-mediated antinociception has been proposed as a pathophysiological factor in hypertension (Dworkin et al., 1979). However, this association has not been experimentally investigated yet. The baroreceptors modulate blood pressure and heart rate and help buffer rapid changes in blood pressure. In addition to the known effects of baroreceptor stimulation on cardiovascular control, there are complex behavioural
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implications following baroreceptor activation, indicating baroreceptor-mediated central nervous system inhibition (Dworkin et al., 1994). Among these, changes in arousal and vigilance have been studied after baroreflex stimulation by following EEG changes and by studies on sensorimotor performances (Vaitl and Gruppe, 1991). As regards the pain perception, baroreflex stimulation in normal subjects and in patients with cardiovascular disease has been associated with a reduced perception of a noxious stimulus (Elbert et al., 1988; Dworkin et al., 1994; Kardos et al., 1994; Droste et al., 1994). Central anatomic areas, such as the nuclei of the solitary tract, are sites of relevance in the pathways of pain perception and are loci of primary interest in the neural network, which relay the afferent stimuli from the mechanoreceptors in the carotid sinus and aorta. Various structures such as anatomical projections from the hypothalamus, the amygdala, the ventrolateral medulla, together with reciprocal connection from these areas to the nuclei of tracti solitarii and interconnection between these areas participate in forming the central portion of the baroreflex arc (Loewy and McKellar, 1980; Seller, 1991). Most of these neural regions are also involved in the pain modulatory system (Fields, 1984). However, only a few studies have investigated the role of baroreceptors on pain sensitivity in man and there are no reports on the correlation between pain threshold and spontaneous baroreflex sensitivity in hypertensive patients. The investigation of spontaneous baroreflex sensitivity allows baroreflex functioning to be determined in a normal range of blood pressure and without the use of drugs. Although prospective studies on baroreflex sensitivity have been performed with the phenylephrine method (La Rovere et al., 1988), a fair correlation was reported between the results obtained by this method and the results found using the aLF index (Robbe et al., 1987). Unstimulated conditions may be particularly useful when studies on pain are focused upon. This study sought to investigate in normotensive and hypertensive subjects whether baroreflex sensitivity is associated with the pain perception pattern in a resting condition. As a secondary endpoint, we evaluated the potential influence of the autonomic balance measured at rest on pain sensitivity.
2. Materials and methods Eighty subjects were studied: 50 consecutive hypertensive subjects together with a control group of 30 normotensives. In all the subjects, baroreflex sensitivity and dental pain perception were investigated, and ambulatory blood pressure was obtained by a 24-h period monitoring. As for inclusion criteria, all the subjects were male, aged 30 – 50 years, not taking any medication (or after a wash-out period of antihypertensive treatment for at least 3 weeks), with a dental formula suitable for the pulpar test (see below). Moreover, they were included in the study if no disease
(apart from essential hypertension) was found after a clinical examination and routine laboratory tests. In particular, we rejected subjects with obesity, cardiac or pulmonary diseases, stroke or neuro-psychiatric disturbances, fibromyalgia, irritable bowel disease and diabetes from the study. No subjects had a secondary form of hypertension and none was involved in competitive sport activities. The hypertensive subjects were recruited among our out-patients, whereas the normotensives were studied during a general clinical check-up. All the subjects were asked not to smoke or to eat chocolates or drink teas, coffees, cola-containing substances or alcoholic beverages during the previous 12 h. Of the 80 subjects initially studied, the following data reported the results obtained in 73 subjects, 45 hypertensive patients and 28 normotensives: because the recording of the tachogram and/or the systogram was unsatisfactory in 5 hypertensive patients and 2 normotensives, these subjects were excluded from the study. The mean age was 40 F 3 and 41 F 3 years in normotensive and hypertensive subjects, respectively, and the body-mass index was 24.5 F 1.7 and 25.1 F 1.9 kg/m2, respectively. The study was approved by the Ethical Committee of our Department and all the subjects gave informed consent to the study.
3. RR interval and blood pressure analysis All the subjects were kept between 9:00 and 10:00 AM in a supine and comfortable position. During the rest period, they were submitted to a continuous electrocardiographic recording by means of a polygraph (Cardioline WS2000, Remco Italia) connected with a microcomputer. Standard electrocardiographic leads were sampled at 250 Hz, 12 bits precision and stored on hard disk for off-line processing, together with a continuous blood pressure signal. Blood pressure was obtained non-invasively by a plethysmographic method (Finapres, Ohmeda). The device was mounted on the middle finger of the right hand and was positioned at the level of the right atrium. The blood pressure signal was digitalized by a 12-bit analog/digital converter at a rate of 250 Hz. Continuous Finapres systolic blood pressure was used for subsequent analysis. The duration time of the simultaneous recording of electrocardiographic and blood pressure signals was 25 min. As previously described, QRS detection and RR interval measurement were automatically performed by the Cardioline WS2000 equipment (Guasti et al., 1999b). This algorithm looked for the R wave peak as a reference point. Afterwards, each QRS complex was interpolated by a parabolic curve. The R point was chosen to correspond with the maximum of the interpolating parabola to improve the accuracy of detection of the peak R wave (Baselli and Cerutti, 1985). The systolic blood pressure value was automatically identified as the maximum of the parabolic curve fitting the pressure tracing.
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The use of an interactive graphic interface allowed the operator to visually identify and correct premature beats, missed beats and artefacts both on the RR and the blood pressure tracings. Corrections made on RR intervals determined automatic corrections in blood pressure series. In this way, a series of successive RR intervals (RR tachogram) and a series of corresponding successive systolic blood pressure values (systogram) were obtained. The power spectrum analysis was performed by an autoregressive algorithm on a 3- to 5-min recording, after a visual identification of the tachogram. The order was automatically selected (AIC criterion) (Baselli and Cerutti, 1985) in a range between 8 and 15, 8 being the most frequently used. For each spectrum, two frequency bands were selected: 0.04– 0.15 and 0.15 – 0.40 Hz for the low frequency (LF) and high frequency (HF) components, respectively (Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). The following variables were calculated: mean RR intervals (ms), standard deviation of RR intervals (ms), LF power (ms2), HF power (ms2), LF power (normalized units, nu), HF power (nu) and LF/HF ratio. The LF component calculated on the RR series in normalized units is the percentage value of RR power in respect to the total power minus the VLF component. This parameter and the LF/HF ratio have an immediate interpretation in terms of sympathovagal balance in the control of the heart. A cross-spectral analysis of the RR tachogram and the systogram was performed to verify the coherence (see below) in LF band between the two signals. The continuously monitored systolic blood pressure registered in the time interval, which was used subsequently in cross-spectral analysis, is indicated as ‘‘Finapres systolic blood pressure’’. A non-invasive measure of the baroreceptive gain can be extracted by the ratio between power spectral densities of RR interval and systolic blood pressure (SBP) series. The magnitude of the systolic arterial pressure – RR transfer function can be calculated by sampling at LF and HF bands detected on the systolic – arterial-pressure series, thus obtaining two indexes of baroreflex gain that are referred to as aLF and aHF. aLF and aHF are closely related. However, since the influences of the feedback and feed-forward relationships cannot be separated, these traditional indexes obtained by transfer function analysis are closer to the baroreflex gain if the RR interval is mainly driven by systolic pressure changes. This condition is more fulfilled at LF band than HF (Askelrod et al., 1985; De Boer et al., 1985; Taylor and Eckberg, 1996; Porta et al., 2000), thus rendering the alpha index in LF more reliable. To quantify baroreceptor gain, aLF was considered (Robbe et al., 1987; Pagani et al., 1988; Malliani et al., 1991). The gain in the LF band can be expressed as aLF (ms/mm Hg): pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi aLF ¼ PRRLF =PSBPLF where PRR-LF is the power (ms2) in the LF band obtained by the tachogram and PSBP-LF is the power (mm Hg2) in the LF
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band obtained by the systogram. The amount of linear coupling between two signals in the frequency domain can be expressed by means of the coherence function. We used the k2 value, i.e. the squared coherence values. For all the considered spectra, the coherence in LF band was > 0.5.
4. Dental pain perception evaluation As previously described (Guasti et al., 1995, 1999a), the experimental pain was induced by means of a pulpar tester (MEDI-tester, MEDIC-AL) which delivers automatic intermittent bursts of test current of linearly increasing intensity (from 0 to 0.03 mA; voltage: 6500 mV; frequency: 5 Hz). As test current intensity increases, a number from 0 to 80 (relative Units, rU) appears on a display not visible to the subjects under examination. The stimulator was applied on the enamel surface of the tooth through a metal cylinder (inner diameter: 0.9 mm) with an electrode paste to improve contact. The operator’s hand was placed on the lips of the subject to close the circuit. All the measures were carried out blind (i.e., without the operator knowing the subject’s blood pressure). Three healthy teeth were evaluated in each subject (two upper incisors and one inferior incisor) and the data reported refer to the mean value of the three. Subjects with caries, abrasions or marked parodontal disease were excluded from the study (see above). Since only Adelta and C fibers are thought to be contained in the pulp, superficial sensations cannot interact with the stimulation of the pain perception pathway (Andersson et al., 1973; Azerad and Woda, 1977). Dental pain threshold was defined as the minimal intensity of test current that elicited a pulp sensation. The subjects were previously instructed to raise their right hand as the pain threshold occurred. The stimulation was then interrupted and reapplied immediately afterwards to determine pain tolerance (intensity of test current at the time when the subject asked for the test to be stopped) (Guasti et al., 1995; 1999a). Moreover, the value of: (pain threshold pain tolerance)/pain threshold 100 (%) was analysed and defined as ‘‘relative tolerance’’. The values of pain threshold and relative tolerance were used in subsequent analysis.
5. Ambulatory blood pressure monitoring All the subjects underwent a non-invasive blood pressure monitoring after pain perception evaluation. As described previously (Guasti et al., 1995), a TAKEDA TM2421 (A and D) set to take one measure every 15 min for a 24-h period was used. This instrument has a combined auscultatory and oscillometric method to minimize errors. The test quality was good (>80% valid measurements) in 70 subjects, whereas 3 subjects repeated the test successfully the day after. A computerized program did the reading and editing of the data (Guasti et al., 1995). All the hypertensive
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patients showed a daytime (7:00 AM –10:00 PM) blood pressure z 140 and/or 90 mm Hg, whereas normotensives had daytime blood pressure < 140/90 mm Hg. The 24-h systolic blood pressure was 140.09 F 11.35 and 125.82 F 5.86 mm Hg, in hypertensive and normotensive subjects, respectively, whereas the 24-h diastolic blood pressure was 91.45 F 9.50 in hypertensives and 78.36 F 5.89 mm Hg in normotensives.
6. Statistical analysis Descriptive statistics have been computed as mean and standard deviation (S.D.). In order to assess the association of aLF with pain perception (expressed as pain threshold and relative tolerance), a series of linear models have been fitted, both univariate and multivariate (in order to control for age, LF/HF ratio and 24-h systolic pressure). Correlation coefficients have been computed. Similarly, the association between LF/HF ratio with pain sensitivity has been assessed. Finally, in order to verify whether the effect of aLF and LF/HF ratio on pain perception was different in normotensive and hypertensive subjects, linear models including both the main effects (aLF or LF/HF ratio and hypertensive status) and the interactions were fitted. A p value < 0.05 was retained for statistical significance. All tests were two-tailed. Stata7 (StataCorp, College Station, TX) was used for computation.
Fig. 1. Scatterplot showing the negative significant correlation between the baroreflex sensitivity (aLF index, expressed in ms/mm Hg) and the dental pain threshold (expressed in relative Units, rU) (univariate regression analysis: r = 0.34, p = 0.003).
and 70.13 F 44.19%, respectively. aLF was 8.58 F 4.67 ms/ mm Hg and LF/HF ratio was 3.37 F 3.30 in the global population. In hypertensive patients, pain sensitivity variables were 23.63 F 7.11 rU for pain threshold, 38.86 F 14.28 rU for pain tolerance and 67.43 F 42.54% for relative tolerance, whereas in normotensives, the values were 20.57 F 5.01, 36.08 F 14.61 rU and 75.88 F 47.47%, respectively for threshold, tolerance and relative tolerance. The aLF and LF/HF ratio in the hypertensive patients were 8.47 F 4.96 ms/mm Hg and 3.60 F 3.33, respectively; in normotensives, the aLF was 8.76 F 4.24 ms/mm Hg and LF/HF ratio was 3.07 F 3.14.
7. Results Table 1 reports the descriptive statistics of the variables studied. The mean value of pain threshold, pain tolerance and relative tolerance was 22.46 F 6.50, 37.70 F 14.30 rU Table 1 Descriptive statistics of the population study
Pain threshold (rU) Pain tolerance (rU) Relative tolerance (%) Age (years) RR interval (ms) SDNN (ms) aLF (ms/mm Hg) LF/HF ratio LF power (ms2) HF power (ms2) LF power (nu) HF power (nu) 24-h SBP (mm Hg) 24-h DBP (mm Hg) Finapres SBP (mm Hg)
Mean
S.D.
22.46 37.70 70.13 41.04 899.14 38.73 8.58 3.37 673.46 369.24 62.65 31.00 134.54 86.36 126.87
6.50 14.30 44.19 7.63 121.35 17.33 4.67 3.30 1032.92 733.09 17.77 17.35 11.84 10.45 16.61
RR indicates RR interval at electrocardiographic tracing, S.D. indicates standard deviation, LF indicates low frequency power, HF indicates high frequency power, nu indicates normalized units, SBP indicates systolic blood pressure and DBP indicates diastolic blood pressure.
8. Pain perception, baroreflex sensitivity and autonomic balance A significant relationship was observed in a univariate linear regression analysis between aLF and pain threshold (Fig. 1, Table 2). When a multivariate analysis was computed to control for age, 24-h systolic pressure and LF/HF ratio, aLF was a predictive independent factor associated with pain threshold. Moreover, the 24-h systolic pressure was independently associated with pain threshold (Table 2).
Table 2 Univariate and multivariate regression analysis Outcome = pain threshold Univariate model aLF Multivariate model aLF LF/HF ratio Age 24-h systolic blood pressure
Beta
95% CI
r
p
0.54
0.89; 0.18
0.34 0.003
0.46 0.21 0.07 0.14
0.86; 0.67; 0.29; 0.01;
0.31 0.07 0.04 0.30
Model p 0.003 0.019
0.06 0.24 0.14 0.27
0.025 0.352 0.502 0.031
LF indicates low frequency power, HF indicates high frequency power and 24-h indicates 24 hours.
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The relationship between aLF and relative tolerance was not statistically significant (univariate analysis: r = 0.08, p = 0.51; multivariate analysis: model p = 0.58, r for aLF = 0.07, p for aLF = 0.87). When the association between the autonomic balance index LF/HF ratio and pain sensitivity was assessed as a secondary endpoint, no significant association was observed between the LF/HF ratio and pain threshold or relative tolerance (r = 0.07, p = 0.56; r = 0.02, p = 0.87, respectively). In order to investigate whether the effect of the aLF and LF/HF ratio variables on pain perception was different in the two subgroups of subjects with or without hypertension, we studied the interaction between the presence or absence of hypertensive status and both the aLF and the LF/HF ratio. Since the interaction was not significant, the influence of the aLF and LF/HF ratio on pain perception (pain threshold or relative tolerance) was considered to be similar in hypertensive and normotensive subjects (Table 2).
9. Discussion The elusive link between hypertension and hypoalgesia has been poorly investigated. Although a relationship between an impaired baroreflex function and hypoalgesia has been hypothesized, no previous study has been aimed at investigating the possible correlation between baroreflex sensitivity and pain perception in hypertension. The major result of the present study is the finding of a correlation between the unstimulated baroreflex sensitivity and pain threshold suggesting that spontaneous baroreflex function may account, at least in part, for the pain perception pattern. Moreover, hypertension-related hypoalgesia studies have reported an association between pain perception and blood pressure levels. In this study, in a multivariate regression analysis, the aLF index was independently associated with pain threshold after controlling for 24-h systolic pressure, age and LF/HF ratio. Moreover, the 24-h systolic pressure was another factor which predicts pain threshold independently. The more the baroreceptor gain is reduced, the higher the level of hypertension-related hypoalgesia is. As expected, the higher the blood pressure is, the lower the sensitivity is. As indicated by the similar correlation coefficients obtained, the aLF index and the 24h systolic pressure influence the pain sensitivity to a similar extent. Moreover, we report the lack of a relationship between the autonomic nervous system balance and pain sensitivity in normotensive and hypertensive subjects when they are studied in a baseline condition.
10. Autonomic tone and sensitivity to pain Power spectrum analysis has been proved a useful tool to investigate the autonomic balance, particularly when the LF/
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HF ratio and the normalized units are considered (Askelrod et al., 1981; Pomeranz et al., 1985; Malliani et al., 1991; Kamath and Fallen, 1993; Montano et al., 1994; Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996; Pagani et al., 1997). Interactions between the sympathetic nervous system activation and the antinociceptive system have been established (Berkenbosch et al., 1981; Van Loon et al., 1981; Fields, 1984; Alfoldi et al., 1991; Jin and Rockhold, 1991; Martin et al., 1999). The descending noradrenergic pathways may partly affect the nociceptive processing (Martin et al., 1999). Circulating catecholamines can stimulate beta-endorphin secretion via beta-adrenergic receptor mechanisms and may influence the opiate response to stress (Berkenbosch et al., 1981). A reduced central sympathetic tone induced by clonidine, a central a2-adrenergic receptor agonist, induced a significant increase in betaendorphin-like immunoreactivity (Alfoldi et al., 1991). In humans, isometric muscle contraction elicited a sympathetic neural response that could be modified by endogenous opiate antagonists and a different autonomic response to exercise has been reported in patients with silent or symptomatic myocardial ischemia (Norwell et al., 1989; Farrell et al., 1991; Krittayaphong et al., 1994). Moreover, since naloxone, an opioid antagonist, was found to potentiate cardiopulmonary baroreflex, a tonic inhibitory effect on sympathetic responses to orthostatic stress was thought to operate in normal humans (Schobel et al., 1992). In this study, no significant association was obtained between the LF/HF ratio, an index of the sympathovagal balance and pain sensitivity in a state of rest. In some of the previous studies, however, the relationship between the autonomic system and pain sensitivity was obtained involving autonomic stimuli, and consequently, analysing changes in baroreflex function. It has to be acknowledged that we did not perform functional tests in order to stimulate the autonomic nervous system, so the results reported here only apply to a resting condition.
11. Baroreflex sensitivity and pain perception In hypertension, an impaired baroreflex sensitivity was reported and a correlation between non-invasive ambulatory 24-h systolic blood pressure and baroreflex function measures was described (Gribbin et al., 1971; Takeshita et al., 1975; Eckberg, 1979; Sleight, 1979; Floras et al., 1988; Mancia and Grassi, 1995; Siche´ et al., 1995). Moreover, this alteration does not seem to be reversed by the antihypertensive treatment (Ylitalo et al., 1997). In this study, the baroreflex sensitivity for heart rate was investigated during an unstimulated state by computing the aLF index. A cross-spectral analysis of the tachogram of RR interval and the systogram (obtained at rest and in baseline condition) was performed to obtain the coherence between the two signals and then to compute the baroreceptor gain (Guasti et al., 1999b) which was calculated by analysing in
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the frequency domain the RR-interval changes which occur in response to spontaneous variations of beat-to-beat systolic blood pressure values (Robbe et al., 1987; Pagani et al., 1988; Malliani et al., 1991). A recent study comparing a new method with traditional ones for computing indexes of spontaneous baroreflex sensitivity showed that the aLF index was similar to the newly calculated indexes in control condition, where the latter were computed by a model approach which fixes the temporal direction of the influences of systolic pressure on RR interval, thus avoiding feedforward relationships between systolic pressure and RR interval and exploring the baroreflex pathway directly (Porta et al., 2000). Previous experimental manipulation of baroreflex function revealed significant effects on the rating of painful stimuli in normotensive subjects and patients with myocardial ischemia (Elbert et al., 1988; Dworkin et al., 1994; Kardos et al., 1994; Droste et al., 1994). Moreover, differences in response to baroreceptor stimulation have been observed at different tonic blood pressure levels, possibly indicating different behaviours of the mechanisms underlying the interaction between blood pressure and pain regulatory mechanisms (Elbert et al., 1988). However, experimental protocols using a painful stimulation associated with a disturbing stimulus such as neck suction may have an impact on the verbal report on pain rating (Vaitl and Gruppe, 1991). A fair reproducibility has been reported as regards the dental pain sensitivity parameters when pulp stimulation was used to test experimental pain in hypertensives (Ghione, 1996). In this study, the spontaneous baroreflex sensitivity was correlated with pain threshold (r = 0.34, p = 0.003), suggesting a modulation of pain sensitivity by baroreflex pathways. Possibly, pain tolerance is more dependent on central influences than pain threshold (Fields, 1984). The lack of correlation between relative pain tolerance and the cardiovascular control of circulation may be accounted by a more relevant influence from the central nervous system on pain tolerance. Among the factors which may modify the pain sensitivity pattern, the degree of blood pressure elevation seems of relevance in determining the modulation of pain perception towards hypoalgesic behaviours (Guasti et al., 1999a). In patients with coronary artery disease, hypertensive subjects showed both a higher experimental dental pain threshold and higher prevalence of silent ischemia during exercise stress tests (Falcone et al., 1997). Moreover, the occurrence of pain during exercise-induced ischemia was associated with blood pressure at the time of the onset of ischemia (Go et al., 1997). In this study, in a multivariate model, the pain threshold was independently predicted by both the baroreceptor gain expressed by aLF index and the 24-h systolic pressure. Therefore, hypertension-dependent hypoalgesia may also be mediated through a reduced resting baroreflex sensitivity. Both opioid and non-opioid influences have been described in studies on blood pressure-associated changes in pain sensitivity (Sheps et al., 1992; McCubbin and Bruehl, 1994; Guasti et al., 1996; Schobel et al., 1998).
An involvement of modulating factors which affect baroreceptor function through opioid or non-opioid operating mechanisms may account, at least in part, for the association between a reduced perception to pain and hypertension.
References Alfoldi, A., Simko, K., Fekete, M.I., Farsang, C., 1991. Adrenergic and dopaminergic regulation of circulating beta-endorphin-like immunoreactivity in hypertension. Acta Physiol. Hung. 78, 99 – 106. Andersson, S.A., Ericson, T., Holmgren, E., Linquist, G., 1973. Electroacupuncture: effect on pain threshold measured with electrical stimulation of tooth. Brain Res. 63, 393 – 396. Askelrod, S., Gordon, D., Ubel, P.A., Shannon, D.C., Harger, A.C., Cohen, R.J., 1981. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat to beat cardiovascular control. Science 213, 220 – 222. Askelrod, S., Gordon, D., Mawed, J.B., Snidman, N.C., Shannon, D.C., Cohen, R.J., 1985. Hemodynamic regulation: investigation by spectral analysis. Am. J. Physiol. Heart Circ. Physiol. 249, H867 – H875. Azerad, J., Woda, A., 1977. Sensation evoked by bipolar intrapulpar stimulation in man. Pain 4, 145 – 152. Baselli, G., Cerutti, S., 1985. Identification techniques applied to processing of signals from cardiovascular system. Med. Infant. (London) 10, 223 – 235. Berkenbosch, F., Vermes, I., Tilders, F.J.H., 1981. Epinephrine as a potent releaser of immunoreactive beta-endorphin in rats. Eur. J. Pharmacol. 72, 97 – 100. De Boer, R.W., Karemaker, J.M., Strackee, J., 1985. Relationships between short-term blood pressure fluctuations and heart rate variability in resting subjects. A spectral analysis approach. Med. Biol. Eng. Comput. 23, 352 – 358. Droste, C., Kardos, A., Brody, S., Greenlee, M.W., Roskamm, H., Rau, H., 1994. Baroreceptor stimulation: pain perception and sensory thresholds. Biol. Psychol. 37, 101 – 113. Dworkin, B., Filewich, R., Miller, N., Craigmyle, N., Pickering, T., 1979. Baroreceptor activation reduces reactivity to noxious stimulation: implications in hypertension. Science 205, 1299 – 1301. Dworkin, B.R., Elbert, T., Rau, H., Birbaumer, N., Pauli, P., Droste, C., 1994. Central effects of baroreceptor activation in humans: attenuation of skeletal reflexes and pain perception. Proc. Natl. Acad. Sci. U. S. A. 91, 6329 – 6333. Eckberg, D.L., 1979. Carotid baroreflex function in young men with borderline blood pressure elevation. Circulation 59, 632 – 636. Elbert, T., Rockstroh, B., Lutzenberger, W., Kessler, M., Pietrowsky, R., 1988. Baroreceptor stimulation alters pain sensation depending on tonic blood pressure. Psychophysiology 25, 25 – 29. Falcone, C., Auguadro, C., Sconocchia, R., Angoli, L., 1997. Susceptibility to pain in hypertensive and normotensive patients with coronary artery diseases. Response to dental pulp stimulation. Hypertension 30, 1279 – 1283. Farrell, P.A., Ebert, T.J., Kampine, J.P., 1991. Naloxone augments muscle sympathetic nerve activity during isometric exercise in humans. Am. J. Physiol. 260, E379 – E388. Fields, H.L., 1984. Neurophysiology of pain and pain modulation. Am. J. Med. 77, 2 – 8. Floras, J.S., Hassan, M.O., Jones, J.V., Osikowska, B.A., Sever, P.S., Sleight, P., 1988. Consequences of impaired arterial baroreflex in essential hypertension: effects on pressor responses, plasma noradrenaline and blood pressure variability. J. Hypertens. 6, 525 – 535. Ghione, S., 1996. Hypertension-associated hypalgesia. Evidence in experimental animals and humans, pathophysiological mechanisms, and potential clinical consequences. Hypertension 28, 494 – 504. Ghione, S., Rosa, S., Mezzasalma, L., Panattoni, E., 1988. Arterial hyper-
L. Guasti et al. / Autonomic Neuroscience: Basic and Clinical 99 (2002) 127–133 tension is associated with hypalgesia in humans. Hypertension 12, 491 – 497. Go, B.M., Sheffield, D., Krittayaphong, R., Maixner, W., Sheps, D.S., 1997. Association of systolic blood pressure at time of myocardial ischemia with angina pectoris during exercise testing. Am. J. Cardiol. 79, 954 – 956. Gribbin, B., Pikering, T.G., Sleight, P., Peto, R., 1971. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ. Res. 29, 424 – 431. Guasti, L., Cattaneo, R., Rinaldi, O., Rossi, M.G., Bianchi, L., Gaudio, G., Grandi, A.M., Gorini, G., Venco, A., 1995. Twenty-four hour noninvasive blood pressure monitoring and pain perception. Hypertension 25, 1301 – 1305. Guasti, L., Cattaneo, R., Daneri, A., Bianchi, L., Gaudio, G., Regazzi, M.B., Grandi, A.M., Bertolini, A., Restelli, E., Venco, A., 1996. Endogenous beta-endorphins in hypertension: correlation with 24-hour ambulatory blood pressure. J. Am. Coll. Cardiol. 28, 1243 – 1248. Guasti, L., Gaudio, G., Zanotta, D., Grimoldi, P., Petrozzino, M.R., Tanzi, F., Bertolini, A., Grandi, A.M., Venco, A., 1999a. Relationship between a genetic predisposition to hypertension, blood pressure levels and pain sensitivity. Pain 82, 311 – 317. Guasti, L., Grimoldi, P., Mainardi, L.T., Petrozzino, M.R., Piantanida, E., Garganico, D., Diolisi, A., Zanotta, D., Bertolini, A., Ageno, W., Grandi, A.M., Cerutti, S., Venco, A., 1999b. Autonomic function and baroreflex sensitivity during a normal ovulatory cycle in humans. Acta Cardiol. 54, 209 – 213. Jin, C.B., Rockhold, R.W., 1991. Sympathoadrenal control by paraventricular hypothalamic beta-endorphin in hypertension. Hypertension 18, 503 – 515. Kamath, M.V., Fallen, E.L., 1993. Power spectral analysis of heart rate variability: a noninvasive signature of cardiac autonomic function. Crit. Rev. Biomed. Eng. 21, 245 – 311. Kardos, A., Rau, H., Greenlee, M.W., Droste, C., Brody, S., Roskamm, H., 1994. Reduced pain during baroreceptor stimulation in patients with symptomatic and silent myocardial ischemia. Cardiovasc. Res. 28, 515 – 518. Krittayaphong, R., Cascio, W.E., Ballenger, M.N., Glekas, G., De Gent, G.E., Sheps, D.S., 1994. Heart rate variability during exercise: difference in patients with painful and painless ischemia. Circulation 90, I162 (abstract). La Rovere, M.T., Specchia, G., Mortara, A., Schwartz, P.J., 1988. Baroreflex sensitivity, clinical correlates and cardiovascular mortality among patients with a first myocardial infarction. A prospective study. Circulation 78, 816 – 824. Loewy, A.D., McKellar, S., 1980. The neuroanatomical basis of central cardiovascular control. Fed. Proc. 39, 2495 – 2503. Malliani, A., Pagani, M., Lombardi, F., Cerutti, S., 1991. Cardiovascular neural regulation explored in the frequency domain. Circulation 84, 482 – 492. Mancia, G., Grassi, G., 1995. Baroreceptor control of the circulation in man. An update. Clin. Exp. Hypertens. 17 (1 and 2), 387 – 397. Martin, W.J., Gupta, N.K., Loo, M.C., Rohde, D.S., Basbaum, A.L., 1999. Differential effects of neurotoxic destruction of descending noradrenergic pathways on acute and persistent nociceptive processing. Pain 80, 57 – 65. McCubbin, J.A., Bruehl, S., 1994. Do endogenous opioids mediate the relationship between blood pressure and pain sensitivity in normotensives? Pain 57, 63 – 67. Montano, N., Ruscone, T.G., Porta, A., Lombardi, F., Pagani, M., Malliani, A., 1994. Power spectrum analysis of heart rate variability to assess changes in sympathovagal balance during graded orthostatic tilt. Circulation 90, 1826 – 1831. Norwell, N., Roth, D.L., Franco, E., Pepine, C.J., 1989. Cardiovascular reactivity and silent ischemia in response to mental stress in symptomatic and asymptomatic coronary artery disease patients: results of a pilot study. Clin. Cardiol. 12, 634 – 638.
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Pagani, M., Somers, V., Furlan, R., Dell’Orto, S., Conway, J., Baselli, G., Cerutti, S., Sleight, P., Malliani, A., 1988. Changes in autonomic regulation induced by physical training in mild hypertension. Hypertension 12, 600 – 610. Pagani, M., Montano, N., Porta, A., Malliani, A., Abboud, F., Birkett, C., Somers, V., 1997. Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans. Circulation 95, 1441 – 1448. Pomeranz, M., Macaulay, R.J.B., Caudill, M.A., Kutz, I., Adam, D., Gordon, D., Kilborn, K.M., Barger, A.C., Shannon, D.C., Cohen, R.J., Benson, H., 1985. Assessment of autonomic function in humans by heart rate spectral analysis. Am. J. Physiol. 248, H151 – H153. Porta, A., Baselli, G., Rimoldi, O., Malliani, A., Pagani, M., 2000. Assessing baroreflex gain from spontaneous variability in conscious dogs: role of causality and respiration. Am. J. Physiol. Heart Circ. Physiol. 279, H2558 – H2567. Robbe, H.W.J., Mulder, L.J.M., Ruddel, H., Langewitz, W.A., Veldman, J.B.P., Mulder, G., 1987. Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 10, 538 – 543. Schobel, H.P., Oren, R.M., Mark, A.L., Ferguson, D.W., 1992. Naloxone potentiates cardiopulmonary baroreflex sympathetic control in normal humans. Circ. Res. 70, 172 – 183. Schobel, H.P., Handwerker, H.O., Schmieder, R.E., Heusser, K., Dominiak, P., Luft, F.C., 1998. Effects of naloxone on haemodynamic and sympathetic nerve responses to pain in normotensive vs. hypertensive men. J. Auton. Nerv. Syst. 69, 49 – 55. Seller, H., 1991. Central baroreflex pathways. In: Persson, P.B., Kirchheim, H.R. (Eds.), Baroreceptor Reflexes. Integrative Functions and Clinical Aspects. Springer-Verlag, Germany, pp. 45 – 74. Sheps, D.S., Bragdon, E.E., Flint Gray III, T., Ballenger, M., Usedom, J.E., Maixner, W., 1992. Relation between systemic hypertension and pain perception. Am. J. Cardiol. 70, 3F – 5F. Siche´, J.P., Herpin, D., Asmar, R.G., Poncelet, P., Chamontin, B., Comparat, V., Gressin, V., Boutelant, S., Mallion, J.M., 1995. Non-invasive ambulatory blood pressure variability and cardiac baroreflex sensitivity. J. Hypertens. 13, 1654 – 1659. Sleight, P., 1979. Reflex control of the heart. Am. J. Cardiol. 44, 889 – 894. Takeshita, A., Tanaka, S., Kuroiwa, A., Nakamura, M., 1975. Reduced baroreceptor sensitivity in borderline hypertension. Circulation 51, 738 – 741. Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996. Heart rate variability. Standards of measurements, physiological interpretation, and clinical use. Circulation 93, 1043 – 1065. Taylor, J.A., Eckberg, D.L., 1996. Fundamental relations between shortterm RR interval and arterial pressure oscillations in humans. Circulation 93, 1527 – 1532. Vaitl, D., Gruppe, H., 1991. Baroreceptor stimulation and changes in EEG and vigilance. In: Persson, P.B., Kirchheim, H.R. (Eds.), Baroreceptor Reflexes. Integrative Functions and Clinical Aspects. Springer-Verlag, Germany, pp. 293 – 313. Van Loon, G.R., Appel, N.M., Ho, D., 1981. Beta-endorphin induced increases in plasma epinephrine, norepinephrine and dopamine in rats: inhibition of adrenomedullary response by intracerebral somatostatin. Brain Res. 212, 207 – 214. Ylitalo, A., Airaksinen, K.E.J., Tahvanainen, K.U.O., Kuusela, T.A., Ikaheimo, M.J., Rantala, A., Lilja, M., Huikuri, H.V., 1997. Baroreflex sensitivity in drug-treated systemic hypertension. Am. J. Cardiol. 80, 1369 – 1372. Zamir, N., Segal, M., 1979. Hypertension-induced analgesia: changes in pain sensitivity in experimental hypertensive rats. Brain Res. 160, 170 – 173. Zamir, N., Shuber, E., 1980. Altered pain perception in hypertensive humans. Brain Res. 201, 471 – 474.
Hypertension-related hypoalgesia, autonomic function and spontaneous baroreflex sensitivity Luigina Guasti a,*, Danilo Zanotta a, Luca T. Mainardi b, Maria R. Petrozzino a, Paola Grimoldi a, Deborah Garganico a, Alessio Diolisi a, Giovanni Gaudio a, Catherine Klersy c, Anna M. Grandi a, Cinzia Simoni a, Sergio Cerutti b a
Internal Medicine, Department of Clinical and Biological Sciences, University of Insubria, Ospedale di Circolo, Varese, Italy b Department of Biomedical Engineering, Polytechnic University, Milan, Italy c Department of Biometry and Clinical Epidemiology, IRCCS Policlinico S. Matteo, Pavia, Italy Accepted 27 November 2001
Abstract Objective: The mechanisms involved in the relationship between pain perception and hypertension are poorly understood. This study has sought to investigate whether the spontaneous baroreflex sensitivity and the autonomic nervous system balance are related to hypertensionassociated hypoalgesia. Methods: In the morning, 73 untreated male subjects (45 hypertensives, 28 normotensives) were submitted to a simultaneous recording of electrocardiographic and blood pressure signals in resting condition. The tracings were analysed off-line to evaluate the spectral components of the low frequency (LF) and high frequency (HF) powers (autoregressive algorithm; LF/HF ratio used in subsequent analysis as an index of sympathovagal balance), and the alphaLF (aLF), an index of baroreflex sensitivity. After the rest period, the subjects underwent dental pain perception evaluation (pulpar tester: test current increasing from 0 to 0.03 mA, expressed in relative Units) to determine the dental pain threshold and tolerance. Afterwards, a 24-h ambulatory blood pressure monitoring was performed. Results: A significant relationship was observed between aLF and pain threshold (r = 0.34; p = 0.003). When a multivariate analysis was computed to control for age, 24-h systolic pressure and LF/HF ratio, aLF was a predictive independent factor associated with pain threshold (model p = 0.019; r = 0.31; p = 0.025). Moreover, the 24-h systolic pressure was independently associated with pain threshold (model p = 0.019; r = 0.30, p = 0.031). The relationship between aLF and relative tolerance was not statistically significant. When the association between the LF/HF ratio and pain sensitivity was assessed as a secondary endpoint, no significant relationship was observed. Since no significant interaction was found, the effect of aLF and LF/HF ratio on pain perception was assumed to be similar in normotensive and hypertensive subjects. Conclusions: The relationship found between unstimulated baroreflex sensitivity and pain threshold suggests a modulation of pain perception by baroreflex pathways in hypertension-associated hypoalgesia. In a baseline condition, the autonomic nervous system balance does not seem to influence pain sensitivity. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Pain threshold; Spectral analysis; Baroreflex sensitivity; Hypertension, essential
1. Introduction Although a relationship between hypertension and hypoalgesia has been reproducibly found in numerous studies on man, the factors linking blood pressure levels with pain sensitivity are still poorly understood (Zamir and Segal, 1979; Zamir and Shuber, 1980; Ghione et al., 1988; Guasti et al., 1995, 1999a; Ghione, 1996).
*
Corresponding author. Tel.: +39-332-278-111; fax: +39-332-278-595. E-mail address: [email protected] (L. Guasti).
Ever since the first studies were carried out, it has been suggested that the baroreceptor arc function may be involved in the possible interactions between pain and cardiovascular control systems and a rewarding mechanism following baroreceptor-mediated antinociception has been proposed as a pathophysiological factor in hypertension (Dworkin et al., 1979). However, this association has not been experimentally investigated yet. The baroreceptors modulate blood pressure and heart rate and help buffer rapid changes in blood pressure. In addition to the known effects of baroreceptor stimulation on cardiovascular control, there are complex behavioural
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implications following baroreceptor activation, indicating baroreceptor-mediated central nervous system inhibition (Dworkin et al., 1994). Among these, changes in arousal and vigilance have been studied after baroreflex stimulation by following EEG changes and by studies on sensorimotor performances (Vaitl and Gruppe, 1991). As regards the pain perception, baroreflex stimulation in normal subjects and in patients with cardiovascular disease has been associated with a reduced perception of a noxious stimulus (Elbert et al., 1988; Dworkin et al., 1994; Kardos et al., 1994; Droste et al., 1994). Central anatomic areas, such as the nuclei of the solitary tract, are sites of relevance in the pathways of pain perception and are loci of primary interest in the neural network, which relay the afferent stimuli from the mechanoreceptors in the carotid sinus and aorta. Various structures such as anatomical projections from the hypothalamus, the amygdala, the ventrolateral medulla, together with reciprocal connection from these areas to the nuclei of tracti solitarii and interconnection between these areas participate in forming the central portion of the baroreflex arc (Loewy and McKellar, 1980; Seller, 1991). Most of these neural regions are also involved in the pain modulatory system (Fields, 1984). However, only a few studies have investigated the role of baroreceptors on pain sensitivity in man and there are no reports on the correlation between pain threshold and spontaneous baroreflex sensitivity in hypertensive patients. The investigation of spontaneous baroreflex sensitivity allows baroreflex functioning to be determined in a normal range of blood pressure and without the use of drugs. Although prospective studies on baroreflex sensitivity have been performed with the phenylephrine method (La Rovere et al., 1988), a fair correlation was reported between the results obtained by this method and the results found using the aLF index (Robbe et al., 1987). Unstimulated conditions may be particularly useful when studies on pain are focused upon. This study sought to investigate in normotensive and hypertensive subjects whether baroreflex sensitivity is associated with the pain perception pattern in a resting condition. As a secondary endpoint, we evaluated the potential influence of the autonomic balance measured at rest on pain sensitivity.
2. Materials and methods Eighty subjects were studied: 50 consecutive hypertensive subjects together with a control group of 30 normotensives. In all the subjects, baroreflex sensitivity and dental pain perception were investigated, and ambulatory blood pressure was obtained by a 24-h period monitoring. As for inclusion criteria, all the subjects were male, aged 30 – 50 years, not taking any medication (or after a wash-out period of antihypertensive treatment for at least 3 weeks), with a dental formula suitable for the pulpar test (see below). Moreover, they were included in the study if no disease
(apart from essential hypertension) was found after a clinical examination and routine laboratory tests. In particular, we rejected subjects with obesity, cardiac or pulmonary diseases, stroke or neuro-psychiatric disturbances, fibromyalgia, irritable bowel disease and diabetes from the study. No subjects had a secondary form of hypertension and none was involved in competitive sport activities. The hypertensive subjects were recruited among our out-patients, whereas the normotensives were studied during a general clinical check-up. All the subjects were asked not to smoke or to eat chocolates or drink teas, coffees, cola-containing substances or alcoholic beverages during the previous 12 h. Of the 80 subjects initially studied, the following data reported the results obtained in 73 subjects, 45 hypertensive patients and 28 normotensives: because the recording of the tachogram and/or the systogram was unsatisfactory in 5 hypertensive patients and 2 normotensives, these subjects were excluded from the study. The mean age was 40 F 3 and 41 F 3 years in normotensive and hypertensive subjects, respectively, and the body-mass index was 24.5 F 1.7 and 25.1 F 1.9 kg/m2, respectively. The study was approved by the Ethical Committee of our Department and all the subjects gave informed consent to the study.
3. RR interval and blood pressure analysis All the subjects were kept between 9:00 and 10:00 AM in a supine and comfortable position. During the rest period, they were submitted to a continuous electrocardiographic recording by means of a polygraph (Cardioline WS2000, Remco Italia) connected with a microcomputer. Standard electrocardiographic leads were sampled at 250 Hz, 12 bits precision and stored on hard disk for off-line processing, together with a continuous blood pressure signal. Blood pressure was obtained non-invasively by a plethysmographic method (Finapres, Ohmeda). The device was mounted on the middle finger of the right hand and was positioned at the level of the right atrium. The blood pressure signal was digitalized by a 12-bit analog/digital converter at a rate of 250 Hz. Continuous Finapres systolic blood pressure was used for subsequent analysis. The duration time of the simultaneous recording of electrocardiographic and blood pressure signals was 25 min. As previously described, QRS detection and RR interval measurement were automatically performed by the Cardioline WS2000 equipment (Guasti et al., 1999b). This algorithm looked for the R wave peak as a reference point. Afterwards, each QRS complex was interpolated by a parabolic curve. The R point was chosen to correspond with the maximum of the interpolating parabola to improve the accuracy of detection of the peak R wave (Baselli and Cerutti, 1985). The systolic blood pressure value was automatically identified as the maximum of the parabolic curve fitting the pressure tracing.
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The use of an interactive graphic interface allowed the operator to visually identify and correct premature beats, missed beats and artefacts both on the RR and the blood pressure tracings. Corrections made on RR intervals determined automatic corrections in blood pressure series. In this way, a series of successive RR intervals (RR tachogram) and a series of corresponding successive systolic blood pressure values (systogram) were obtained. The power spectrum analysis was performed by an autoregressive algorithm on a 3- to 5-min recording, after a visual identification of the tachogram. The order was automatically selected (AIC criterion) (Baselli and Cerutti, 1985) in a range between 8 and 15, 8 being the most frequently used. For each spectrum, two frequency bands were selected: 0.04– 0.15 and 0.15 – 0.40 Hz for the low frequency (LF) and high frequency (HF) components, respectively (Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). The following variables were calculated: mean RR intervals (ms), standard deviation of RR intervals (ms), LF power (ms2), HF power (ms2), LF power (normalized units, nu), HF power (nu) and LF/HF ratio. The LF component calculated on the RR series in normalized units is the percentage value of RR power in respect to the total power minus the VLF component. This parameter and the LF/HF ratio have an immediate interpretation in terms of sympathovagal balance in the control of the heart. A cross-spectral analysis of the RR tachogram and the systogram was performed to verify the coherence (see below) in LF band between the two signals. The continuously monitored systolic blood pressure registered in the time interval, which was used subsequently in cross-spectral analysis, is indicated as ‘‘Finapres systolic blood pressure’’. A non-invasive measure of the baroreceptive gain can be extracted by the ratio between power spectral densities of RR interval and systolic blood pressure (SBP) series. The magnitude of the systolic arterial pressure – RR transfer function can be calculated by sampling at LF and HF bands detected on the systolic – arterial-pressure series, thus obtaining two indexes of baroreflex gain that are referred to as aLF and aHF. aLF and aHF are closely related. However, since the influences of the feedback and feed-forward relationships cannot be separated, these traditional indexes obtained by transfer function analysis are closer to the baroreflex gain if the RR interval is mainly driven by systolic pressure changes. This condition is more fulfilled at LF band than HF (Askelrod et al., 1985; De Boer et al., 1985; Taylor and Eckberg, 1996; Porta et al., 2000), thus rendering the alpha index in LF more reliable. To quantify baroreceptor gain, aLF was considered (Robbe et al., 1987; Pagani et al., 1988; Malliani et al., 1991). The gain in the LF band can be expressed as aLF (ms/mm Hg): pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi aLF ¼ PRRLF =PSBPLF where PRR-LF is the power (ms2) in the LF band obtained by the tachogram and PSBP-LF is the power (mm Hg2) in the LF
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band obtained by the systogram. The amount of linear coupling between two signals in the frequency domain can be expressed by means of the coherence function. We used the k2 value, i.e. the squared coherence values. For all the considered spectra, the coherence in LF band was > 0.5.
4. Dental pain perception evaluation As previously described (Guasti et al., 1995, 1999a), the experimental pain was induced by means of a pulpar tester (MEDI-tester, MEDIC-AL) which delivers automatic intermittent bursts of test current of linearly increasing intensity (from 0 to 0.03 mA; voltage: 6500 mV; frequency: 5 Hz). As test current intensity increases, a number from 0 to 80 (relative Units, rU) appears on a display not visible to the subjects under examination. The stimulator was applied on the enamel surface of the tooth through a metal cylinder (inner diameter: 0.9 mm) with an electrode paste to improve contact. The operator’s hand was placed on the lips of the subject to close the circuit. All the measures were carried out blind (i.e., without the operator knowing the subject’s blood pressure). Three healthy teeth were evaluated in each subject (two upper incisors and one inferior incisor) and the data reported refer to the mean value of the three. Subjects with caries, abrasions or marked parodontal disease were excluded from the study (see above). Since only Adelta and C fibers are thought to be contained in the pulp, superficial sensations cannot interact with the stimulation of the pain perception pathway (Andersson et al., 1973; Azerad and Woda, 1977). Dental pain threshold was defined as the minimal intensity of test current that elicited a pulp sensation. The subjects were previously instructed to raise their right hand as the pain threshold occurred. The stimulation was then interrupted and reapplied immediately afterwards to determine pain tolerance (intensity of test current at the time when the subject asked for the test to be stopped) (Guasti et al., 1995; 1999a). Moreover, the value of: (pain threshold pain tolerance)/pain threshold 100 (%) was analysed and defined as ‘‘relative tolerance’’. The values of pain threshold and relative tolerance were used in subsequent analysis.
5. Ambulatory blood pressure monitoring All the subjects underwent a non-invasive blood pressure monitoring after pain perception evaluation. As described previously (Guasti et al., 1995), a TAKEDA TM2421 (A and D) set to take one measure every 15 min for a 24-h period was used. This instrument has a combined auscultatory and oscillometric method to minimize errors. The test quality was good (>80% valid measurements) in 70 subjects, whereas 3 subjects repeated the test successfully the day after. A computerized program did the reading and editing of the data (Guasti et al., 1995). All the hypertensive
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patients showed a daytime (7:00 AM –10:00 PM) blood pressure z 140 and/or 90 mm Hg, whereas normotensives had daytime blood pressure < 140/90 mm Hg. The 24-h systolic blood pressure was 140.09 F 11.35 and 125.82 F 5.86 mm Hg, in hypertensive and normotensive subjects, respectively, whereas the 24-h diastolic blood pressure was 91.45 F 9.50 in hypertensives and 78.36 F 5.89 mm Hg in normotensives.
6. Statistical analysis Descriptive statistics have been computed as mean and standard deviation (S.D.). In order to assess the association of aLF with pain perception (expressed as pain threshold and relative tolerance), a series of linear models have been fitted, both univariate and multivariate (in order to control for age, LF/HF ratio and 24-h systolic pressure). Correlation coefficients have been computed. Similarly, the association between LF/HF ratio with pain sensitivity has been assessed. Finally, in order to verify whether the effect of aLF and LF/HF ratio on pain perception was different in normotensive and hypertensive subjects, linear models including both the main effects (aLF or LF/HF ratio and hypertensive status) and the interactions were fitted. A p value < 0.05 was retained for statistical significance. All tests were two-tailed. Stata7 (StataCorp, College Station, TX) was used for computation.
Fig. 1. Scatterplot showing the negative significant correlation between the baroreflex sensitivity (aLF index, expressed in ms/mm Hg) and the dental pain threshold (expressed in relative Units, rU) (univariate regression analysis: r = 0.34, p = 0.003).
and 70.13 F 44.19%, respectively. aLF was 8.58 F 4.67 ms/ mm Hg and LF/HF ratio was 3.37 F 3.30 in the global population. In hypertensive patients, pain sensitivity variables were 23.63 F 7.11 rU for pain threshold, 38.86 F 14.28 rU for pain tolerance and 67.43 F 42.54% for relative tolerance, whereas in normotensives, the values were 20.57 F 5.01, 36.08 F 14.61 rU and 75.88 F 47.47%, respectively for threshold, tolerance and relative tolerance. The aLF and LF/HF ratio in the hypertensive patients were 8.47 F 4.96 ms/mm Hg and 3.60 F 3.33, respectively; in normotensives, the aLF was 8.76 F 4.24 ms/mm Hg and LF/HF ratio was 3.07 F 3.14.
7. Results Table 1 reports the descriptive statistics of the variables studied. The mean value of pain threshold, pain tolerance and relative tolerance was 22.46 F 6.50, 37.70 F 14.30 rU Table 1 Descriptive statistics of the population study
Pain threshold (rU) Pain tolerance (rU) Relative tolerance (%) Age (years) RR interval (ms) SDNN (ms) aLF (ms/mm Hg) LF/HF ratio LF power (ms2) HF power (ms2) LF power (nu) HF power (nu) 24-h SBP (mm Hg) 24-h DBP (mm Hg) Finapres SBP (mm Hg)
Mean
S.D.
22.46 37.70 70.13 41.04 899.14 38.73 8.58 3.37 673.46 369.24 62.65 31.00 134.54 86.36 126.87
6.50 14.30 44.19 7.63 121.35 17.33 4.67 3.30 1032.92 733.09 17.77 17.35 11.84 10.45 16.61
RR indicates RR interval at electrocardiographic tracing, S.D. indicates standard deviation, LF indicates low frequency power, HF indicates high frequency power, nu indicates normalized units, SBP indicates systolic blood pressure and DBP indicates diastolic blood pressure.
8. Pain perception, baroreflex sensitivity and autonomic balance A significant relationship was observed in a univariate linear regression analysis between aLF and pain threshold (Fig. 1, Table 2). When a multivariate analysis was computed to control for age, 24-h systolic pressure and LF/HF ratio, aLF was a predictive independent factor associated with pain threshold. Moreover, the 24-h systolic pressure was independently associated with pain threshold (Table 2).
Table 2 Univariate and multivariate regression analysis Outcome = pain threshold Univariate model aLF Multivariate model aLF LF/HF ratio Age 24-h systolic blood pressure
Beta
95% CI
r
p
0.54
0.89; 0.18
0.34 0.003
0.46 0.21 0.07 0.14
0.86; 0.67; 0.29; 0.01;
0.31 0.07 0.04 0.30
Model p 0.003 0.019
0.06 0.24 0.14 0.27
0.025 0.352 0.502 0.031
LF indicates low frequency power, HF indicates high frequency power and 24-h indicates 24 hours.
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The relationship between aLF and relative tolerance was not statistically significant (univariate analysis: r = 0.08, p = 0.51; multivariate analysis: model p = 0.58, r for aLF = 0.07, p for aLF = 0.87). When the association between the autonomic balance index LF/HF ratio and pain sensitivity was assessed as a secondary endpoint, no significant association was observed between the LF/HF ratio and pain threshold or relative tolerance (r = 0.07, p = 0.56; r = 0.02, p = 0.87, respectively). In order to investigate whether the effect of the aLF and LF/HF ratio variables on pain perception was different in the two subgroups of subjects with or without hypertension, we studied the interaction between the presence or absence of hypertensive status and both the aLF and the LF/HF ratio. Since the interaction was not significant, the influence of the aLF and LF/HF ratio on pain perception (pain threshold or relative tolerance) was considered to be similar in hypertensive and normotensive subjects (Table 2).
9. Discussion The elusive link between hypertension and hypoalgesia has been poorly investigated. Although a relationship between an impaired baroreflex function and hypoalgesia has been hypothesized, no previous study has been aimed at investigating the possible correlation between baroreflex sensitivity and pain perception in hypertension. The major result of the present study is the finding of a correlation between the unstimulated baroreflex sensitivity and pain threshold suggesting that spontaneous baroreflex function may account, at least in part, for the pain perception pattern. Moreover, hypertension-related hypoalgesia studies have reported an association between pain perception and blood pressure levels. In this study, in a multivariate regression analysis, the aLF index was independently associated with pain threshold after controlling for 24-h systolic pressure, age and LF/HF ratio. Moreover, the 24-h systolic pressure was another factor which predicts pain threshold independently. The more the baroreceptor gain is reduced, the higher the level of hypertension-related hypoalgesia is. As expected, the higher the blood pressure is, the lower the sensitivity is. As indicated by the similar correlation coefficients obtained, the aLF index and the 24h systolic pressure influence the pain sensitivity to a similar extent. Moreover, we report the lack of a relationship between the autonomic nervous system balance and pain sensitivity in normotensive and hypertensive subjects when they are studied in a baseline condition.
10. Autonomic tone and sensitivity to pain Power spectrum analysis has been proved a useful tool to investigate the autonomic balance, particularly when the LF/
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HF ratio and the normalized units are considered (Askelrod et al., 1981; Pomeranz et al., 1985; Malliani et al., 1991; Kamath and Fallen, 1993; Montano et al., 1994; Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996; Pagani et al., 1997). Interactions between the sympathetic nervous system activation and the antinociceptive system have been established (Berkenbosch et al., 1981; Van Loon et al., 1981; Fields, 1984; Alfoldi et al., 1991; Jin and Rockhold, 1991; Martin et al., 1999). The descending noradrenergic pathways may partly affect the nociceptive processing (Martin et al., 1999). Circulating catecholamines can stimulate beta-endorphin secretion via beta-adrenergic receptor mechanisms and may influence the opiate response to stress (Berkenbosch et al., 1981). A reduced central sympathetic tone induced by clonidine, a central a2-adrenergic receptor agonist, induced a significant increase in betaendorphin-like immunoreactivity (Alfoldi et al., 1991). In humans, isometric muscle contraction elicited a sympathetic neural response that could be modified by endogenous opiate antagonists and a different autonomic response to exercise has been reported in patients with silent or symptomatic myocardial ischemia (Norwell et al., 1989; Farrell et al., 1991; Krittayaphong et al., 1994). Moreover, since naloxone, an opioid antagonist, was found to potentiate cardiopulmonary baroreflex, a tonic inhibitory effect on sympathetic responses to orthostatic stress was thought to operate in normal humans (Schobel et al., 1992). In this study, no significant association was obtained between the LF/HF ratio, an index of the sympathovagal balance and pain sensitivity in a state of rest. In some of the previous studies, however, the relationship between the autonomic system and pain sensitivity was obtained involving autonomic stimuli, and consequently, analysing changes in baroreflex function. It has to be acknowledged that we did not perform functional tests in order to stimulate the autonomic nervous system, so the results reported here only apply to a resting condition.
11. Baroreflex sensitivity and pain perception In hypertension, an impaired baroreflex sensitivity was reported and a correlation between non-invasive ambulatory 24-h systolic blood pressure and baroreflex function measures was described (Gribbin et al., 1971; Takeshita et al., 1975; Eckberg, 1979; Sleight, 1979; Floras et al., 1988; Mancia and Grassi, 1995; Siche´ et al., 1995). Moreover, this alteration does not seem to be reversed by the antihypertensive treatment (Ylitalo et al., 1997). In this study, the baroreflex sensitivity for heart rate was investigated during an unstimulated state by computing the aLF index. A cross-spectral analysis of the tachogram of RR interval and the systogram (obtained at rest and in baseline condition) was performed to obtain the coherence between the two signals and then to compute the baroreceptor gain (Guasti et al., 1999b) which was calculated by analysing in
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the frequency domain the RR-interval changes which occur in response to spontaneous variations of beat-to-beat systolic blood pressure values (Robbe et al., 1987; Pagani et al., 1988; Malliani et al., 1991). A recent study comparing a new method with traditional ones for computing indexes of spontaneous baroreflex sensitivity showed that the aLF index was similar to the newly calculated indexes in control condition, where the latter were computed by a model approach which fixes the temporal direction of the influences of systolic pressure on RR interval, thus avoiding feedforward relationships between systolic pressure and RR interval and exploring the baroreflex pathway directly (Porta et al., 2000). Previous experimental manipulation of baroreflex function revealed significant effects on the rating of painful stimuli in normotensive subjects and patients with myocardial ischemia (Elbert et al., 1988; Dworkin et al., 1994; Kardos et al., 1994; Droste et al., 1994). Moreover, differences in response to baroreceptor stimulation have been observed at different tonic blood pressure levels, possibly indicating different behaviours of the mechanisms underlying the interaction between blood pressure and pain regulatory mechanisms (Elbert et al., 1988). However, experimental protocols using a painful stimulation associated with a disturbing stimulus such as neck suction may have an impact on the verbal report on pain rating (Vaitl and Gruppe, 1991). A fair reproducibility has been reported as regards the dental pain sensitivity parameters when pulp stimulation was used to test experimental pain in hypertensives (Ghione, 1996). In this study, the spontaneous baroreflex sensitivity was correlated with pain threshold (r = 0.34, p = 0.003), suggesting a modulation of pain sensitivity by baroreflex pathways. Possibly, pain tolerance is more dependent on central influences than pain threshold (Fields, 1984). The lack of correlation between relative pain tolerance and the cardiovascular control of circulation may be accounted by a more relevant influence from the central nervous system on pain tolerance. Among the factors which may modify the pain sensitivity pattern, the degree of blood pressure elevation seems of relevance in determining the modulation of pain perception towards hypoalgesic behaviours (Guasti et al., 1999a). In patients with coronary artery disease, hypertensive subjects showed both a higher experimental dental pain threshold and higher prevalence of silent ischemia during exercise stress tests (Falcone et al., 1997). Moreover, the occurrence of pain during exercise-induced ischemia was associated with blood pressure at the time of the onset of ischemia (Go et al., 1997). In this study, in a multivariate model, the pain threshold was independently predicted by both the baroreceptor gain expressed by aLF index and the 24-h systolic pressure. Therefore, hypertension-dependent hypoalgesia may also be mediated through a reduced resting baroreflex sensitivity. Both opioid and non-opioid influences have been described in studies on blood pressure-associated changes in pain sensitivity (Sheps et al., 1992; McCubbin and Bruehl, 1994; Guasti et al., 1996; Schobel et al., 1998).
An involvement of modulating factors which affect baroreceptor function through opioid or non-opioid operating mechanisms may account, at least in part, for the association between a reduced perception to pain and hypertension.
References Alfoldi, A., Simko, K., Fekete, M.I., Farsang, C., 1991. Adrenergic and dopaminergic regulation of circulating beta-endorphin-like immunoreactivity in hypertension. Acta Physiol. Hung. 78, 99 – 106. Andersson, S.A., Ericson, T., Holmgren, E., Linquist, G., 1973. Electroacupuncture: effect on pain threshold measured with electrical stimulation of tooth. Brain Res. 63, 393 – 396. Askelrod, S., Gordon, D., Ubel, P.A., Shannon, D.C., Harger, A.C., Cohen, R.J., 1981. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat to beat cardiovascular control. Science 213, 220 – 222. Askelrod, S., Gordon, D., Mawed, J.B., Snidman, N.C., Shannon, D.C., Cohen, R.J., 1985. Hemodynamic regulation: investigation by spectral analysis. Am. J. Physiol. Heart Circ. Physiol. 249, H867 – H875. Azerad, J., Woda, A., 1977. Sensation evoked by bipolar intrapulpar stimulation in man. Pain 4, 145 – 152. Baselli, G., Cerutti, S., 1985. Identification techniques applied to processing of signals from cardiovascular system. Med. Infant. (London) 10, 223 – 235. Berkenbosch, F., Vermes, I., Tilders, F.J.H., 1981. Epinephrine as a potent releaser of immunoreactive beta-endorphin in rats. Eur. J. Pharmacol. 72, 97 – 100. De Boer, R.W., Karemaker, J.M., Strackee, J., 1985. Relationships between short-term blood pressure fluctuations and heart rate variability in resting subjects. A spectral analysis approach. Med. Biol. Eng. Comput. 23, 352 – 358. Droste, C., Kardos, A., Brody, S., Greenlee, M.W., Roskamm, H., Rau, H., 1994. Baroreceptor stimulation: pain perception and sensory thresholds. Biol. Psychol. 37, 101 – 113. Dworkin, B., Filewich, R., Miller, N., Craigmyle, N., Pickering, T., 1979. Baroreceptor activation reduces reactivity to noxious stimulation: implications in hypertension. Science 205, 1299 – 1301. Dworkin, B.R., Elbert, T., Rau, H., Birbaumer, N., Pauli, P., Droste, C., 1994. Central effects of baroreceptor activation in humans: attenuation of skeletal reflexes and pain perception. Proc. Natl. Acad. Sci. U. S. A. 91, 6329 – 6333. Eckberg, D.L., 1979. Carotid baroreflex function in young men with borderline blood pressure elevation. Circulation 59, 632 – 636. Elbert, T., Rockstroh, B., Lutzenberger, W., Kessler, M., Pietrowsky, R., 1988. Baroreceptor stimulation alters pain sensation depending on tonic blood pressure. Psychophysiology 25, 25 – 29. Falcone, C., Auguadro, C., Sconocchia, R., Angoli, L., 1997. Susceptibility to pain in hypertensive and normotensive patients with coronary artery diseases. Response to dental pulp stimulation. Hypertension 30, 1279 – 1283. Farrell, P.A., Ebert, T.J., Kampine, J.P., 1991. Naloxone augments muscle sympathetic nerve activity during isometric exercise in humans. Am. J. Physiol. 260, E379 – E388. Fields, H.L., 1984. Neurophysiology of pain and pain modulation. Am. J. Med. 77, 2 – 8. Floras, J.S., Hassan, M.O., Jones, J.V., Osikowska, B.A., Sever, P.S., Sleight, P., 1988. Consequences of impaired arterial baroreflex in essential hypertension: effects on pressor responses, plasma noradrenaline and blood pressure variability. J. Hypertens. 6, 525 – 535. Ghione, S., 1996. Hypertension-associated hypalgesia. Evidence in experimental animals and humans, pathophysiological mechanisms, and potential clinical consequences. Hypertension 28, 494 – 504. Ghione, S., Rosa, S., Mezzasalma, L., Panattoni, E., 1988. Arterial hyper-
L. Guasti et al. / Autonomic Neuroscience: Basic and Clinical 99 (2002) 127–133 tension is associated with hypalgesia in humans. Hypertension 12, 491 – 497. Go, B.M., Sheffield, D., Krittayaphong, R., Maixner, W., Sheps, D.S., 1997. Association of systolic blood pressure at time of myocardial ischemia with angina pectoris during exercise testing. Am. J. Cardiol. 79, 954 – 956. Gribbin, B., Pikering, T.G., Sleight, P., Peto, R., 1971. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ. Res. 29, 424 – 431. Guasti, L., Cattaneo, R., Rinaldi, O., Rossi, M.G., Bianchi, L., Gaudio, G., Grandi, A.M., Gorini, G., Venco, A., 1995. Twenty-four hour noninvasive blood pressure monitoring and pain perception. Hypertension 25, 1301 – 1305. Guasti, L., Cattaneo, R., Daneri, A., Bianchi, L., Gaudio, G., Regazzi, M.B., Grandi, A.M., Bertolini, A., Restelli, E., Venco, A., 1996. Endogenous beta-endorphins in hypertension: correlation with 24-hour ambulatory blood pressure. J. Am. Coll. Cardiol. 28, 1243 – 1248. Guasti, L., Gaudio, G., Zanotta, D., Grimoldi, P., Petrozzino, M.R., Tanzi, F., Bertolini, A., Grandi, A.M., Venco, A., 1999a. Relationship between a genetic predisposition to hypertension, blood pressure levels and pain sensitivity. Pain 82, 311 – 317. Guasti, L., Grimoldi, P., Mainardi, L.T., Petrozzino, M.R., Piantanida, E., Garganico, D., Diolisi, A., Zanotta, D., Bertolini, A., Ageno, W., Grandi, A.M., Cerutti, S., Venco, A., 1999b. Autonomic function and baroreflex sensitivity during a normal ovulatory cycle in humans. Acta Cardiol. 54, 209 – 213. Jin, C.B., Rockhold, R.W., 1991. Sympathoadrenal control by paraventricular hypothalamic beta-endorphin in hypertension. Hypertension 18, 503 – 515. Kamath, M.V., Fallen, E.L., 1993. Power spectral analysis of heart rate variability: a noninvasive signature of cardiac autonomic function. Crit. Rev. Biomed. Eng. 21, 245 – 311. Kardos, A., Rau, H., Greenlee, M.W., Droste, C., Brody, S., Roskamm, H., 1994. Reduced pain during baroreceptor stimulation in patients with symptomatic and silent myocardial ischemia. Cardiovasc. Res. 28, 515 – 518. Krittayaphong, R., Cascio, W.E., Ballenger, M.N., Glekas, G., De Gent, G.E., Sheps, D.S., 1994. Heart rate variability during exercise: difference in patients with painful and painless ischemia. Circulation 90, I162 (abstract). La Rovere, M.T., Specchia, G., Mortara, A., Schwartz, P.J., 1988. Baroreflex sensitivity, clinical correlates and cardiovascular mortality among patients with a first myocardial infarction. A prospective study. Circulation 78, 816 – 824. Loewy, A.D., McKellar, S., 1980. The neuroanatomical basis of central cardiovascular control. Fed. Proc. 39, 2495 – 2503. Malliani, A., Pagani, M., Lombardi, F., Cerutti, S., 1991. Cardiovascular neural regulation explored in the frequency domain. Circulation 84, 482 – 492. Mancia, G., Grassi, G., 1995. Baroreceptor control of the circulation in man. An update. Clin. Exp. Hypertens. 17 (1 and 2), 387 – 397. Martin, W.J., Gupta, N.K., Loo, M.C., Rohde, D.S., Basbaum, A.L., 1999. Differential effects of neurotoxic destruction of descending noradrenergic pathways on acute and persistent nociceptive processing. Pain 80, 57 – 65. McCubbin, J.A., Bruehl, S., 1994. Do endogenous opioids mediate the relationship between blood pressure and pain sensitivity in normotensives? Pain 57, 63 – 67. Montano, N., Ruscone, T.G., Porta, A., Lombardi, F., Pagani, M., Malliani, A., 1994. Power spectrum analysis of heart rate variability to assess changes in sympathovagal balance during graded orthostatic tilt. Circulation 90, 1826 – 1831. Norwell, N., Roth, D.L., Franco, E., Pepine, C.J., 1989. Cardiovascular reactivity and silent ischemia in response to mental stress in symptomatic and asymptomatic coronary artery disease patients: results of a pilot study. Clin. Cardiol. 12, 634 – 638.
133
Pagani, M., Somers, V., Furlan, R., Dell’Orto, S., Conway, J., Baselli, G., Cerutti, S., Sleight, P., Malliani, A., 1988. Changes in autonomic regulation induced by physical training in mild hypertension. Hypertension 12, 600 – 610. Pagani, M., Montano, N., Porta, A., Malliani, A., Abboud, F., Birkett, C., Somers, V., 1997. Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans. Circulation 95, 1441 – 1448. Pomeranz, M., Macaulay, R.J.B., Caudill, M.A., Kutz, I., Adam, D., Gordon, D., Kilborn, K.M., Barger, A.C., Shannon, D.C., Cohen, R.J., Benson, H., 1985. Assessment of autonomic function in humans by heart rate spectral analysis. Am. J. Physiol. 248, H151 – H153. Porta, A., Baselli, G., Rimoldi, O., Malliani, A., Pagani, M., 2000. Assessing baroreflex gain from spontaneous variability in conscious dogs: role of causality and respiration. Am. J. Physiol. Heart Circ. Physiol. 279, H2558 – H2567. Robbe, H.W.J., Mulder, L.J.M., Ruddel, H., Langewitz, W.A., Veldman, J.B.P., Mulder, G., 1987. Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 10, 538 – 543. Schobel, H.P., Oren, R.M., Mark, A.L., Ferguson, D.W., 1992. Naloxone potentiates cardiopulmonary baroreflex sympathetic control in normal humans. Circ. Res. 70, 172 – 183. Schobel, H.P., Handwerker, H.O., Schmieder, R.E., Heusser, K., Dominiak, P., Luft, F.C., 1998. Effects of naloxone on haemodynamic and sympathetic nerve responses to pain in normotensive vs. hypertensive men. J. Auton. Nerv. Syst. 69, 49 – 55. Seller, H., 1991. Central baroreflex pathways. In: Persson, P.B., Kirchheim, H.R. (Eds.), Baroreceptor Reflexes. Integrative Functions and Clinical Aspects. Springer-Verlag, Germany, pp. 45 – 74. Sheps, D.S., Bragdon, E.E., Flint Gray III, T., Ballenger, M., Usedom, J.E., Maixner, W., 1992. Relation between systemic hypertension and pain perception. Am. J. Cardiol. 70, 3F – 5F. Siche´, J.P., Herpin, D., Asmar, R.G., Poncelet, P., Chamontin, B., Comparat, V., Gressin, V., Boutelant, S., Mallion, J.M., 1995. Non-invasive ambulatory blood pressure variability and cardiac baroreflex sensitivity. J. Hypertens. 13, 1654 – 1659. Sleight, P., 1979. Reflex control of the heart. Am. J. Cardiol. 44, 889 – 894. Takeshita, A., Tanaka, S., Kuroiwa, A., Nakamura, M., 1975. Reduced baroreceptor sensitivity in borderline hypertension. Circulation 51, 738 – 741. Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996. Heart rate variability. Standards of measurements, physiological interpretation, and clinical use. Circulation 93, 1043 – 1065. Taylor, J.A., Eckberg, D.L., 1996. Fundamental relations between shortterm RR interval and arterial pressure oscillations in humans. Circulation 93, 1527 – 1532. Vaitl, D., Gruppe, H., 1991. Baroreceptor stimulation and changes in EEG and vigilance. In: Persson, P.B., Kirchheim, H.R. (Eds.), Baroreceptor Reflexes. Integrative Functions and Clinical Aspects. Springer-Verlag, Germany, pp. 293 – 313. Van Loon, G.R., Appel, N.M., Ho, D., 1981. Beta-endorphin induced increases in plasma epinephrine, norepinephrine and dopamine in rats: inhibition of adrenomedullary response by intracerebral somatostatin. Brain Res. 212, 207 – 214. Ylitalo, A., Airaksinen, K.E.J., Tahvanainen, K.U.O., Kuusela, T.A., Ikaheimo, M.J., Rantala, A., Lilja, M., Huikuri, H.V., 1997. Baroreflex sensitivity in drug-treated systemic hypertension. Am. J. Cardiol. 80, 1369 – 1372. Zamir, N., Segal, M., 1979. Hypertension-induced analgesia: changes in pain sensitivity in experimental hypertensive rats. Brain Res. 160, 170 – 173. Zamir, N., Shuber, E., 1980. Altered pain perception in hypertensive humans. Brain Res. 201, 471 – 474.