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Normal sympathetic vasomotor and cardiac parasympathetic activities in patients with primary aldosteronism: assessment by spectral analysis
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ELSEVIER
Autonomic Nervous System Journal of the Autonomic Nervous System 52 (1995) 213-223
Normal sympathetic vasomotor and cardiac parasympathetic activities in patients with primary aldosteronism: assessment by spectral analysis Masanori Munakata a,,, Yutaka Imai a, Junichiro Hashimoto a, Ken Omata a, Mitsuyuki Nakao b, Mitsuaki Yamamoto b, Keishi Abe a a
Second Department oflnternal Medicine, Tohoku University School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai 980, Japan b Graduate School oflnformation Science, Tohoku University, Sendai, Japan Received 1 September 1994; revision received and accepted 20 September 1994
Abstract
The role of the autonomic nervous system in hypertension due to mineralocorticoid excess remains unclear. To address this issue, we performed power spectral analysis of blood pressure (BP) and RR interval oscillations in 20 patients with primary aldosteronism (PA), 54 patients with essential hypertension (EH) and 45 normotensive (NT) subjects. Blood pressure and the degree of organ damage were similar between PA and EH groups. Age did not differ between the three groups. The Mayer wave power spectrum (MWP) of BP (approx. 0.1 Hz), an index of sympathetic vasomotor tone, was smaller in patients with PA than in patients with EH either while subjects were supine (systolic/diastolic; 3.9 + 3.2 (SD)/1.5 + 1.3 vs. 5.5 + 4.2/2.1 + 1.6 mmHg 2, P < 0.05 for both) or standing (7.6 + 6.6/3.0 + 3.0 vs. 17.7 + 23.7/7.2 + 8.3 mmHg z, P < 0.05 for both). Supine respiratory-related power spectrum (RRP) of the RR interval (approx. 0.25 Hz), an index of cardiac parasympathetic tone, was greater in patients with PA than in patients with EH (545 + 574 vs. 302 + 464 ms 2, P < 0.01). The MWP of BP and the RRP of the RR interval were similar between patients with PA and NT subjects. Adrenalectomy reduced the 24-h mean BP ( - 18 mmHg for systolic BP, P < 0.001; - 12 mmHg for diastolic BP, P < 0.01) and increased the 24-h mean heart rate ( + 8 bpm, P < 0.001). Furthermore, the diastolic MWP increased mildly ( + 32%, P < 0.05) and the RRP of the RR interval decreased dramatically ( - 75%, P < 0.01) following adrenalectomy. These results suggest that both vascular sympathetic and cardiac parasympathetic regulatory systems have minor roles in the maintenance of hypertension in patients with PA. The autonomic nervous system contributes more to the maintenance of BP following than prior to adrenalectomy. This information may be useful for the management of hypertension still persists after removal of adrenal adenoma. Keywords: Sympathetic nervous system; Parasympathetic nervous system; Power spectral analysis; Primary aldosteronism
* Corresponding author. Tel.: (81-22) 274-1111, Ext. 2520; Fax: (81-22) 274-5332. 0165-1838/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0165-1838(94)00159-6
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M. Munakata et al. / Journal of the Autonomic Nervous System 52 (1995) 213-223
I. Introduction P r i m a r y a l d o s t e r o n i s m is c a u s e d by t h e excess s e c r e t i o n o f a l d o s t e r o n e f r o m an a d r e n a l a d e n o m a a n d is c h a r a c t e r i z e d by h y p e r t e n s i o n , hyp o k a l e m i a a n d m e t a b o l i c alkalosis. T h e h y p e r t e n sive state is h e m o d y n a m i c a l l y c h a r a c t e r i z e d by i n c r e a s e d p e r i p h e r a l resistance, slight e x p a n s i o n of p l a s m a v o l u m e [32] a n d i n c r e a s e d total b o d y a n d e x c h a n g e a b l e s o d i u m c o n t e n t [34]. S o d i u m r e a b s o r p t i o n in t h e distal t u b u l e o f t h e k i d n e y is i n c r e a s e d s e c o n d a r y to excess m i n e r a l o c o r t i c o i d s , causing v o l u m e expansion. A l d o s t e r o n e m a y inc r e a s e t h e total p e r i p h e r a l r e s i s t a n c e by d i r e c t effects on t h e c e n t r a l n e r v o u s system [17] a n d by i n c r e a s i n g s o d i u m influx into v a s c u l a r s m o o t h m u s c l e cells [18], t h e r e b y p o t e n t i a t i n g s m o o t h m u s c l e cell tone. Neurogenic mechanisms often are implicated in t h e p a t h o g e n e s i s o f h y p e r t e n s i o n . H o w e v e r , it r e m a i n s u n c l e a r how t h e a u t o n o m i c n e r v o u s syst e m is involved in the d e v e l o p m e n t a n d m a i n t e n a n c e o f h y p e r t e n s i o n d u e to p r i m a r y a l d o s t e r o nism. It has b e e n r e p o r t e d t h a t p l a s m a n o r e p i nephrine concentration and urinary excretion of
n o r e p i n e p h r i n e in p a t i e n t s with P A a r e lower t h a n in p a t i e n t s with e s s e n t i a l h y p e r t e n s i o n ( E H ) [7,11]. Bravo et al. have r e p o r t e d t h a t c o m b i n e d a - a n d / J - b l o c k a d e p r o d u c e s no d e t e c t a b l e c h a n g e s in BP in p a t i e n t s with P A a l t h o u g h p l a s m a n o r e p i n e p h r i n e c o n c e n t r a t i o n s a r e similar to p a t i e n t s with E H [3]. M i y a j i m a et al. have d e m o n s t r a t e d t h a t tibial nerve m u s c l e sympat h e t i c nerve activity is l o w e r in p a t i e n t s with P A t h a n in p a t i e n t s with E H [19]. A v a i l a b l e e v i d e n c e suggests t h a t the s y m p a t h e t i c n e r v o u s system cont r i b u t e s less to t h e m a i n t e n a n c e of h y p e r t e n s i o n in p a t i e n t s with P A t h a n in p a t i e n t s with E H . T h e effects of a d r e n e r g i c s t i m u l a t i o n on b l o o d p r e s s u r e , however, d e p e n d n o t only on s y m p a t h e t i c n e r v o u s system activity, b u t also on t h e n a t u r e o f t h e t a r g e t organs. Several r e p o r t s have d e m o n s t r a t e d e n h a n c e d sensitivity o f v a s c u l a r s m o o t h m u s c l e cells to v a s o c o n s t r i c t o r s u b s t a n c e s during administration of electrolyte-active s t e r o i d s [5,27]. T h e r e f o r e , t h e n e t s y m p a t h e t i c v a s c u l a r effect a p p e a r s to b e i m p o r t a n t in patients with PA. F u r t h e r m o r e , a l t h o u g h r e d u c e d p a r a s y m p a t h e t i c activity a n d i m p a i r e d b a r o r e f l e x f u n c t i o n have b e e n r e p o r t e d in p a t i e n t s with E H ,
Table 1 Clinical characteristics of 20 patients with primary aldosteronism No
Name
Sex
Age
Side of tumor
PAC (ng/dl)
PRA (ng/ml per 6 h)
Plasma K (mEq/l)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
M.N R.N M.S R.K T.K J.T H.T I.N K.S H.T K.E Y.D K.O K.S N.S S.S N.K N.K S.M Y.K
F F M F F F F F F M F F M F F F F F F F
36 34 30 43 32 30 58 36 34 52 44 35 35 61 46 38 32 51 49 25
right left left bilateral left right left right left right right right right bilateral right right right right right left
30.4 18.0 18.7 33.9 108.5 21.2 46.1 23.8 49.8 38.8 47.1 26.8 18.9 50.6 28.8 21.8 34.0 152.9 120.1 44.3
trace trace trace trace trace trace trace trace trace trace trace trace trace trace trace 3.2 trace 1.5 1.0 1.1
2.6 4.1 3.1 3.0 1.7 3.2 3.1 3.0 3.0 3.2 2.7 3.5 1.5 3.0 4.2 3.8 3.4 2.9 1.9 3.3
PAC, Plasma aldosterone concentration; PRA, Plasma renin activity, trace means the value below 1.0. Patients No. 4, 10, 16, 18 and 19 had been treated until 48 h prior to the study because of their severe hypretension.
M. Munakata et al. /Journal of the Autonomic Nervous System 52 (1995) 213-223
the pathogenic role of the depressor neural system in the maintenance of hypertension of PA is unknown. It is known that activities of the autonomic nervous system are linked to specific cardiovascular frequency oscillations. Respiratory-related oscillations of the heart rate are mediated purely by the vagus nerve. The amplitude of these oscillations reflects cardiac parasympathetic tone [2,25]. The 10-s oscillations of the BP, known as Mayer waves, are mediated by the a-adrenergic system. The amplitude of these waves has been reported to reflect sympathetic vasomotor activity [15,30]. Cross-spectral analysis between the oscillations of BP and RR interval provides an index of the baroreflex function [26,31]. Consequently, assessment of simultaneous spectral analysis of BP and RR interval oscillations may provide a non-invasive assessment of systemic neural cardiovascular regulations. In this study, we examined autonomic nervous functions in 20 patients with PA using this new technique. The results were compared relative to 54 patients with EH and 45 normotensive (NT) subjects. To further assess changes in autonomic nervous system functions following a normalization of plasma aldosterone concentration, the experiments were repeated in 18 patients with PA who underwent adrenalectomy.
215
assessment of electrocardiogram, chest roentgenogram, urinalysis, peripheral blood evaluation, urinary electrolyte excretion, 24-h creatinine clearance and ambulatory blood pressure monitoring. A stimulation test for renin release using captopril (50 mg p.o.) [14] a n d / o r furosemide (40 mg i.v.) [1] was performed in all hypertensive patients. The diagnosis of PA was based on the demonstration of increased production of aldosterone, suppressed plasma renin activity and evidence of unilateral or bilateral adrenal adenoma by computed tomography, magnetic resonance imaging and adrenal scintillation scanning with and without dexamethasone treatment. Adrenal venography and simultaneous assay of adrenal venous plasma aldosterone concentrations were performed to confirm the existence of an aldosterone-producing adenoma in certain patients. Patients with idiopathic hyperaldosteronism were excluded from the present study. Eighteen patients, including two patients with bilateral adenomas, underwent surgery. Total unilateral adrenalectomy and subtotal adrenalectomy on the opposite side were performed in the two patients with bilateral adenomas. The presence of an adrenal adenoma was confirmed by histological examination. Plasma aldosterone levels normalized in all patients following the surgical treatment.
2.2. Autonomic function test 2. Materials and methods
2.1. Subjects We evaluated 20 patients with aldosteroneproducing adrenal adenomas (18 unilateral and two bilateral) ranging in age from 30 to 61 years (mean age 40 years). Clinical characteristics of the PA patients are listed in Table 1.54 patients with EH (WHO stage I or II, ranging in age from 20 to 74 years (mean age 42 years), and 45 NT subjects aged 21 to 72 years (mean age 39 years) served as controls. The mean age did not differ between the three groups. All patients, except NT subjects, were hospitalized and placed on a diet containing approx. 10 g NaC1 per day. All patients underwent fundoscopic examination, and
The study protocol was approved by the Ethics Committee of the Tohoku University School of Medicine. All subjects gave informed consent prior to participation in the study. The autonomic function test was performed in an air-conditioned room. All hypertensive patients were advised to discontinue their cardiovascular medications at least 1 week prior to the study. It was, however, difficult to stop antihypertensive therapy in 5 patients with PA (see Table 1) because of their severe hypertension. All of them were treated with long-acting calcium antagonists until 48 h prior to the study. All subjects were instructed to avoid cigarettes and beverages containing caffeine on the day of the experiment. The experiments were performed between 2:00 p.m. and
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M. Munakata et aL / Journal of the Autonomic Nert~ous System 52 (1995) 213 -223
4:00 p.m. to minimize the effects of circadian rhythm on BP and heart rate [20], variables known to be significantly affected by autonomic nervous system activity. Each subject was placed supine on a bed. The electrocardiogram (ECG) was monitored using a standard lead II. Blood pressure was monitored on the right middle finger with a digital photoplethysmographic device (Finapres 2300; Ohmeda, Englewood, CO, USA). The procedure for signal recording and analysis has been described elsewhere [22-24]. In brief, the analog ECG and BP signals were fed into a signal processor (7T-18; NEC San-ei, Tokyo, Japan) with an R wave detector accurate to within 1 ms. The systolic (SBP) and diastolic (DBP) BP were measured at each R-wave. The R R interval was calculated during this period and then digitized on a floppy disk. Data were collected for 7 min after supine rest for 20 min. The subject was then moved to the standing position and, after 5 min for hemodynamic equilibration, data were recorded for another 7 min. Off-line analysis was later performed on a personal computer (PC 9801-RX; NEC). The trendgrams of R R interval, SBP and DBP, derived from 7-min recordings, were inspected visually on the computer display. A 256-s segment without movement artifacts or premature ventricular contractions was selected for the final analysis. We calculated the Mayer wave power spectrum for BP (0.07-0.14 Hz; mmHg2), and the respiratory-related power spectrum for the R R interval (0.15-0.40 Hz; ms2), as indicators of sympathetic vasomotor and cardiac parasympathetic activities, respectively [2,15,25,30]. To examine the baroreceptor-heart rate reflex, a transfer function analysis between the oscillations of SBP and the R R interval was p e r f o r m e d simultaneously [26,31]. We have shown that the baroreflex modulates R R interval oscillations over the entire frequency range from 0.02 to 0.40 Hz. The effects are exerted more frequently and markedly at frequencies above 0.07 Hz [24]. Thus, next, we calculated the modulus of the transfer function in the Mayer wave frequency (GMayer:0.07-0.14 Hz) and that in the respiratory-frequency (GRespiratory: 0.15-0.4(I Hz) for those frequency points with a
coherence > 0.5 as indicators of baroreflex function. This method of determining arterial baroreflex activity has been validated previously by the classic phenylephrine method [26,31].
2.3. Statistical analysis All data are expressed as mean + S.D. Comparison of data among the groups was performed by an unpaired t-test or by the KolmogorovSmirnov test. Within group comparison was done by the paired t-test or by the Wilcoxon test. All statistical analyses were performed with a commercially available statistical package (SYSTAT ver 5.0, Evanston, IL, USA). A P value less than 0.05 was considered significant.
3. Results
In the PA group, all data were similar between patients received antihypertensive treatment until 48 h prior to the study and those in which treatment was discontinued at least 1 week prior to study. Thus, they were treated alltogether in the subsequent analysis. Resting finger BP measurements were higher in patients with PA than in NT subjects (150 + 22 vs. l l0 + 13 mmHg for systolic BP, P < 0.001; 81 + 10 vs. 53 + 10 mmHg for diastolic BP, P < 0.001). Also, they were similar to those obtained in patients with E H (147 + 21 mmHg for systolic BP, 7 8 + 14 mmHg for diastolic BP). The R R interval in patients with E H (840 + 127 ms) was shorter than that in NT subjects (932 + 126 ms) or PA patients (938 + 141 ms)(P < 0.01 for both). There was no difference with respect to fundoscopic changes, cardiothoracic ratios, and 24-h creatinine clearance between PA and E H groups (Fig. 1), suggesting a similar degree of organ damage between the two hypertensive groups. The duration of hypertension, the body mass index and the total cholesterol concentration also were similar between patients with PA and EH. Supine MWPs of BP of patients with PA were smaller than those of patients with E H (systolic/diastolic; 3.9 + 3.2/1.5 + 1.3 vs. 5.5 + 4.2/2.1 + 1.6 mmHg 2, P < 0.05 for both) and were similar to those of NT subjects
M. Munakata et aL /Journal of the Autonomic Nervous System 52 (1995) 213-223
(4.3 + 4.2/1.2 + 1.0 mmHg2)(Figs. 2 and 3). Supine R R P of the R R interval of patients with PA was greater than that of patients with E H (545 ++_574 vs. 302 + 464 ms 2, P < 0.01; Fig. 4) and did not differ from that of N T subjects (653 + 625 ms2). Standing MWPs of BP of patients
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EH NT PA Fig.'2. Mayer wave power spectra of systolic blood pressure (MWP of SBP) of essentially hypertensive patients (EH), normotensive subjects (NT) and patients with primary aldosteronism (PA). Upper panel shows the data while subjects are supine and the lower the data while standing.
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Fig. 1. Brar graphs show a degree of fundoscopic changes (Kaith-Wagner classification), cardiothoracic ratios (CTR), 24-h creatinine clearance (Ccr), body mass index (BMI), total cholesterol and duration of hypertension of essential hypertension (EH) and primary aldosteronism (PA) groups.
with PA also were smaller than those of patients with E H (7.6 _+ 6.6/3.0 _+ 3.0 vs. 17.7 +_ 23.7/7.2 + 8.3 mmHg 2, P < 0.05 for both) and were similar to those of NT subjects (6.9 _+ 4.8/2.3 + 1.7 mmHg2). (Figs. 2 and 3). Standing RRPs of the R R interval of PA, E H and N T groups were 779 ___82, 735 _+ 129 and 775 _+ 125 ms 2, respectively (n.s. among each group). The GMayer and GRespiratory values were greater in patients with PA than in patients with E H (8.1 + 4.9 vs. 5.4 + 2.5 m s / m m H g , P < 0.01 f o r GMayer and 14.6 +_ 8.9 vs. 9.8 ___5.7 m s / m m H g , P < 0.05 f o r GRespiratory) and similar to N T subjects (7.1 +_ 4.6 m s / m m H g for GMayer and 17.7 + 9.2 m s / m m H g for GRespiratory) (Fig. 5).
218
M. Munakata et al. /Journal of the Autonomic Neruous System 52 (1995) 213-223
The 24-h mean BP decreased following adrenalectomy (141 + 13 vs. 123 + 18 mmHg for systolic BP, P < 0.001; 90 + 11 vs. 78 + 11 mmHg for diastolic BP, P < 0.01) while the 24-h mean heart rate increased following adrenalectomy (66 + 6 vs. 75 + 6 bpm, P < 0.001). The day-night difference (i.e., day-time mean - night-time mean) in systolic BP, diastolic BP and heart rate (11.3 + 9.7 mmHg, 9.5 + 6.8 mmHg, 12.1 + 3.9 bpm, respectively) were not affected by adrenalectomy (10.2 __+7.2 mmHg, 6.9 + 4.6 mmHg and 15.0 + 6.6 bpm, respectively), suggesting that the decrease in BP and the increase in heart rate occurred t h r o u g h o u t the day and night. Following adrenalectomy, the supine diastolic MWP in-
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creased ( + 32%, P < 0.05) while the RRP of the R R interval decreased ( - 75%, P < 0.01) (Fig. 6). The systolic MWP did not change significantly. Both the GMayer and the GRespiratory decreased following adrenalectomy ( - 4 2 % for GMayer, and - 3 9 % for GRespiratory , P < 0.05 for both)(Fig. 7).
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4. Discussion
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..a3... PA EH NT Fig. 3. Mayer wave power spectra of diastolic blood pressure (MWP of DBP) of essentially hypertensive patients (EH), normotensive subjects (NT) and patients with primary aldosteronism (PA). Upper panel shows the data while subjects are supine and the lower the data while standing.
Our study demonstrated that the features of both the Mayer wave power spectrum of BP and the respiratory-related power spectrum of the R R interval differ between patients with PA and patients with E H independent of the severity of the hypertension. The Mayer wave power spec-
M. Munakata et al. /Journal of the Autonomic Nervous System 52 (1995) 213-223
trum of BP and the respiratory-related power spectrum of the R R interval reflect sympathetic vasomotor and cardiac parasympathetic tone, respectively. Our data suggest that autonomic cardiovascular regulations in patients with PA differ from those of patients with EH. The sympathetic nervous activity of patients with PA has been studied with the measurements of plasma norepinephrine concentration [3,7], urinary excretion of norepinephrine [11] and tibial nerve muscle sympathetic activity [19]• The majority of the available evidence suggests a minor role of the sympathetic nervous system in the maintenance of hypertension in patients with PA. Sym-
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pathetic BP regulation, however, depends not only on sympathetic nerve activity but also on vascular responsiveness. Since hyperresponsiveness to several vasopressor substances has been demonstrated in mineralocorticoid excess hypertension [5,27], the net assessment of sympathetic vascular tone appears to be important. Thus, we used the Mayer wave spectrum of BP as an indicator of sympathetic vascular tone. The amplitude of this parameter is determined by both
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M. Munakata et al. /Journal of the Autonomic Nert,ous System 52 (1995) 213-223 P=0.017 10
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frequency (GMayer) and in the respiratory-frequency (GRespira~ory)before and after adrenalectomy in 18 patients with primary aldosteronism.
a-adrenergic activity and the responsiveness of blood vessels [22]. In our study, the Mayer wave spectrum of BP in patients with PA was smaller than in patients with E H and similar to N T subjects. These results suggest that the net sympathetic vascular effect in patients with PA was smaller than in patients with EH. Thus, as previously reported, the sympathetic nervous system contributes less to the maintenance of hypertension in patients with PA than in patients with EH. Since the amplitude of Mayer waves is affected considerably by age [21], we carefully matched both age and degree of organ damage between patients with PA and EH. To our knowledge, baroreflex functions in patients with PA have not been examined. We need careful attention to apply the traditional vasoactive methods to patients with PA, since they often demonstrate very severe hypertension [4] and possibly show a hyperresponsiveness to vasoactive
agents [27]. In this study, we have adopted a new method based on transfer function analysis between the oscillations of systolic BP and the R R interval [24] to assess baroreflex function. Based on previous reports, we calculated the modulus of the transfer function at the Mayer wave frequency (GMayer) and at the respiratory frequency (G Respiratory) [26,31]. Both the GMayer and the GRespiratory were greater in patients with PA than in patients with EH, and were similar to those of N T subjects. These data suggest that baroreceptor control of the sinus node is preserved in patients with PA. Normal cardiac parasympathetic tone is further supported by the fact that respiratory-related power of the RR, which is mediated primarily by efferent vagal nerve activity [2,25] and is affected by several afferent inputs including baroreflex [24], also was normal in patients with PA. It is well known that both vagal tone and baroreflex sensitivity decrease with age and with increases in BP. However, neither age nor BP differed among patients with PA and EH. Since both parameters decreased following adrenalectomy, it can be indicated that hyperaldosteronism and its associated conditions potentiate vasodepressor neural function against high BP. Our study did not provide an explanation for this observation. However, suppression of the renin-angiotensin system may be involved. It is well known that endogenous angiotensin 1I modulates the baroreflex property. Some investigators have reported that angiotensin II decreases baroreflex sensitivity [6,9] and that the blockade of the renin angiotensin system potentiates it in normal subjects [13]. It also has been shown that intravenous infusion of angiotensin II into the vertebral artery reduced vagal nerve activity in conscious dogs [28]. Thus, suppressed angiotensin II formation appears to augment both resting vagal tone and its reflex regulation. We were unable to exclude the possibility that other factors such as hyperaldosteronism, hypervolemia, hypokalemia and metabolic alkalosis modulated these neural functions. However, there is no evidence to suggest or support this possibility. Following adrenalectomy, the MWP of DBP increased by about 30% when compared to pre-
M. Munakata et al. /Journal of the Autonomic Nervous System 52 (1995) 213-223
operative value. These results suggest that the sympathetic nervous system contributes more to the maintenance of BP following adrenalectomy than before adrenalectomy. The explanation for the increase in sympathetic vascular tone following adrenalectomy remains unclear, however, two possibilities exist. First, this may be a compensatory adaptation of the cardiovascular system to a new body fluid status. It is well known that a dynamic balance exists between blood volume and vasoconstrictor properties. Vasoconstrictive mediators, including the renin-angiotensin and sympathetic nervous systems are suppressed physiologically when extracellular fluid volume is expanded sufficiently [16]. Under volume overload, vascular resistance increases to avoid hyperperfusion through autoregulatory mechanism. The increase in total peripheral resistance, then, elicits the reflex inhibition of the central outflow of the sympathetic nerve activity. Aldosterone can augment the sympathetic nerve activity through central mechanism [17] but this effect presumably is overcome by the reflex inhibitory effect due to volume overload in patients with primary aldosteronism. Consequently, the central outflow of the sympathetic nervous activity is suppressed [19]. Since body fluid decreases following adrenalectomy, the sympathetic nervous system will be activated to compensate for a loss in body fluid. Second, the sympathetic nervous activity may be augmented by the recovery of the reninangiotensin system activity. It is known that angiotensin II is a strong modulator of sympathetic nervous system function [29]. Angiotensin II facilitates cardiovascular responses to sympathetic stimulation and depletion of endogenous angiotensin II attenuates it. Sympathetic nervous system seems to be difficult to get excited in patients with PA because of low angiotensin II levels. Recovery of the renin-angiotensin system activity following adrenalectomy, thus, may lead to activation of sympathetic activity. The MWP of SBP did not increase after adrenalectomy as that of DBP did. This means that MWP of DBP and that of SBP are mediated at least in part by different mechanisms. Possibly the MWP of DBP depends more on the sympathetic mechanism than that of SBP, since admin-
221
istration of a-adrenoceptor blocker predominantly reduced the former MWP [10]. Finally we will discuss the clinical importance of the post-operative changes in the autonomic nervous activities in adrenalectomized PA patients. Primary aldosteronism can be cured by surgical removal of adrenal adenoma. However hypertension still exists in 23-30% of the adrenalectomized patients irrespective of normalization of plasma aldosterone levels [8,12]. In our long-term follow-up study of 90 cases of surgically treated aldosterone producing adenomas, hypertension persisted in 38 patients (42%) [33]. Duration of hypertension, age and renal function were important predictors of the post-operative BP. In the present study, we found that the sympathetic vascular tone increased following adrenalectomy. The vasopressor system may be involved in the maintenance of post-operative hypertension especially in case that it potentially possesses a pathogenic predisposition. This information may justify the use of adrenergic blockers for the treatment of post-operative hypertension [4]. In conclusion, our data demonstrate that vascular sympathetic and cardiac parasympathetic regulatory systems have minor roles in the maintenance of hypertension in patients with PA. Following adrenalectomy, however, sympathetic vascular tone is increased mildly and cardiac parasympathetic tone is decreased dramatically. Thus, the autonomic nervous system is more important in the maintenance of BP following rather than prior to adrenalectomy. This information may be useful for the management of hypertension still persists after removal of adrenal adenoma.
References [1] Abe, K., lrokawa, N., Aoyagi, H., Memezawa, H., Yasujima, M., Otsuka, Y., Saito, T. and Yoshinaga, K., Circulating renin in essential hypertension: an evaluation of its significance in the Japanese population, Am. Heart J., 89 (1975) 723-730. [2] Akselrod, D., Gordon, J.B., Madwed, J.B., Snidman, N.C., Shannon, C. and Cohen, R.J., Hemodynamic regulation: Investigation by spectral analysis, Am. J. Physiol., 249 (1985) H867-H875.
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[3] Bravo, E.L., Tarazi, R.C., Dustan, H.P. and Fouad, F.M., The sympathetic nervous system and hypertension in primary aldosteronism, Hypertension, 7 (1985) 90-96. [4] Bravo, E.L., Fouad-Tarazi, F.M., Tarazi, R.C., Pohl, M., Gifford, R.W. and Vidt, D.G., Clinical implications of primary aldosteronism with resistant hypertension, Hypertension, 11 (1988) 1-207-I-211 (Suppl. I). [51 Chobanian, A.V., Volicer, L., Tifft, C.P., Gavras, H., Liang, C. and Faxon, D., Mineralocorticoid-induced hypertension in patients with orthostatic hypotension, New Engl. J. Med., 301 (1979) 68-73. [6] Garner, M.G., Phippard, A.F., Fletcher, P.J., Maclean, J.M., Duggin, G.G., Horvath, J.S. and Tiller, D.J., Effect of angiotensin II on baroreceptor reflex control of heart rate in conscious baboons. Hypertension, 10 (1987) 628634. [7] Gordon, R.D., Bachmann A.W., Jackson, R.V. and Saar, N., Increased sympathetic activity in renovascular hypertension in man, Clin. Exp. Pharmacol. Physiol., 9 (1982) 277-281. [81 Granberg, P.O., Adamsson, U., Hamberger, B. and Lins, P.E., Surgical treatment of primary aldosteronism, Ann. Chir. Gynaecol., 72 (1983) 171-176. 191 Guo, G.B. and Abboud, F.M., Angiotensin II attenuates baroreflex control of heart rate and sympathetic activity. Am. J. Physiol., 246 (1984) H80-H89. [lll] Hashimoto, J., Imai, Y., Munakata, M. and Abe, K., Assessment of autonomic control of the short-term oscillations in R-R interval and blood pressure in conscious rats by power spectral analysis. High Blood Pressure, 3 (1994) 89-96. [11] Horky, K., Kopecka, J. and Widimsky Jr., J., Urinary excretion of catecholamines in patients with primary aldosteronism before and after unilateral adrenalectomy, Coron. Vasoact., 25 (1983) 401-412. [12] Horky, K., Widimsky Jr., J., Hradec, E., Gregorova, I. and Hradec, M., Long-term results of surgical and conservative treatment of patients with primary aldosteronism, Exp. Clin. Endocrinol. 90 (1987) 337-346. [13] Ibsen, H., Egan, B., Osterziel, K., Vander, A.J. and Julius, S., Reflex-hemodynamic adjustments and baroreflex sensitivity during converting enzyme inhibition with MK-421 in normal humans, Hypertension, 5 (1983) 1184-I-191. [14] Imai, Y., Abe, K., Otsuka, Y., Sakurai, Y., Ito, T., Sato, M., Haruyama, T., Omata, K., Hiwatari, M. and Yoshinaga, K., Exaggerated response of renin secretion to captopril (SQ 14225) in renovascular hypertension. Jpn. Heart J., 21 (1980) 303-314. [15] Inoue, K., Miyake, S., Kunashiro, M., Ogata, H., Ueta, T. and Akatsu, T., Power spectral analysis of blood pressure variability in traumatic quadriplegic humans, Am. J. Physiol., 260 (1991) H842-H847. [16] lzzo Jr., J.L., Horwitz, D., Lawton, W.J. and Keiser, H.R., Fludrocortisone suppression of sympathetic nervous activity, Clin. Pharmacol. Ther., 33 (1983) 102-106. 1171 Kageyama, Y. and Bravo, E.L., Hypertensive mechanisms
associated with centrally administered aldosterone in dogs, Hypertension, 11 (1988) 750-753. [18] Menard, M.R. and Friedman, S.M., Direct measurement of sodium influx in vascular smooth muscle, Hypertension, 7 (1985) 873-878. [19] Miyajima, E., Yamada, Y., Yoshida, Y., Matsukawa, T., Shionoiri, H., Tochikubo, O. and Ishii, M., Muscle sympathetic nerve activity in renovascular hypertension and primary aldosteronism, Hypertension, 17 (1991) 10571062. [20] Munakata, M., Imai, Y., Abe, K., Sasaki, S., Minami, N., Hashimoto, J., Sakuma, H., Ichijyo, T., Yoshizawa, M., Sekino, H. and Yoshinaga, K., Assessment of age-dependent changes in circadian blood pressure rhythm in patients with essential hypertension, J. Hypertens., 9 (1991) 407-415. [21] Munakata, M., Imai, Y., Hashimoto, J., Sasaki, S., Sakuma, H., Watanabe, N., Nishiyama, A. and Abe, K., Altered Mayer wave characteristics in young patients with essential hypertension. Ther. Res., 13 (1992) 99-102. [22] Munakata, M., Imai, Y., Sekino, H. and Abe, K., Rhythmic oscillations of blood pressure and RR interval in patients with chronic renal failure, Med. Biol. Eng. Comput., 31 (1993) sl15-s122. [23] Munakata, M., Imai, Y., Mizunashi, K., Sekino, H. and Abe, K., The role of calcium ions in the regulation of rhythmic oscillations in blood pressure. J. Hypertens., 11 (1993) s172-s173 (Suppl. 5). [24] Munakata, M., Imai, Y., Takagi, H., Nakao, M, Yamamoto, M. and Abe, K., Altered frequency-dependent characteristics of the cardiac baroreflex in essential hypertension. J. Auton. Nerv. Syst., 49 (1994) 33-45. [25] Pagani, M., Lombardi, F., Guzzeti, S., Rimoldi, O., Furlan, R., Pizzinelli, P., Sandrone, G., Malfatto, G., Dell'Orto, S., Piccaluga, E., Turiel, M., Baselli, G., Cerutti, S. and Malliani, A., Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympathovagal interaction in man and conscious dog. Circ. Res., 59 (1986) 178-193. [261 Pagani, M., Somers, V., Furlan, R., Dell'Orto, S., Conway, J., Baselli, G., Cerutti, S., Sleight, P. and Malliani, A., Changes in autonomic regulation induced by physical training in mild hypertension, Hypertension, 12 (1988) 600-610. [27] Philipp, T., Luth, B., Wucherer, G. and Distler, A., Mechanism of mineralocorticoid-induced hypertension in man. In: W. Kaufmann, G. Wambach, A. Helber, and K.A. Meurer (Eds.), Mineralocorticoids and Hypertension. Springer, New York, NY, 1983, pp. 129-139. [28] Potter, E.K. and Reid, I.A., Intravertebral angiotensin II inhibits cardiac vagal efferent activity in dogs, Neuroendocrinology, 40 (1985) 493-496. [29] Reid, I.A., Interaction between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am. J. Physiol., 262 (1992) E763-E778. [30] Rimoldi, O., Pierini, S., Ferrari, A., Cerutti, S., Pagani, M. and Malliani, A., Analysis of short-term oscillations of
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R-R and arterial pressure in conscious dogs, Am. J. Physiol., 258 (1990) H967-H976. [31] Robbe, H.W.J., Mulder, L.J.M., Ruddel, H., Langewitz, W.A., Veldman, J.B.P. and Mulder, G., Assessment of baroreflex sensitivity by means of spectral analysis, Hypertension, 10 (1987) 538-543. [32] Tarazi, R.C., Ibrahim, M.M., Bravo, E.L. and Dustan, H.P., Hemodynamic characteristics of primary aldosteronism, New Engl. J. Med., 289 (1973) 1330-1335. [33] Tsunoda, K., Imai, Y., Omata, K., Watanabe, N., Mis-
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awa, S., Munakata, M., Sakuma, H., Mimami, N., Kohzuki, M. and Abe, K., Long-term follow-up study of 90 cases of surgically treated aldosterone-producing adenoma, Jpn. J. Coll. Angiol., 33 (1993) 153 (Japanese with English abstract). [34] Williams, E.D., Boddy, K. and Brown, J.J., Body elemental composition, with particular reference to total and exchangeable sodium and potassium and total chlorine, in untreated and treated primary hyperaldosteronism, J. Hypertens., 2 (1984) 171-176.
ELSEVIER
Autonomic Nervous System Journal of the Autonomic Nervous System 52 (1995) 213-223
Normal sympathetic vasomotor and cardiac parasympathetic activities in patients with primary aldosteronism: assessment by spectral analysis Masanori Munakata a,,, Yutaka Imai a, Junichiro Hashimoto a, Ken Omata a, Mitsuyuki Nakao b, Mitsuaki Yamamoto b, Keishi Abe a a
Second Department oflnternal Medicine, Tohoku University School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai 980, Japan b Graduate School oflnformation Science, Tohoku University, Sendai, Japan Received 1 September 1994; revision received and accepted 20 September 1994
Abstract
The role of the autonomic nervous system in hypertension due to mineralocorticoid excess remains unclear. To address this issue, we performed power spectral analysis of blood pressure (BP) and RR interval oscillations in 20 patients with primary aldosteronism (PA), 54 patients with essential hypertension (EH) and 45 normotensive (NT) subjects. Blood pressure and the degree of organ damage were similar between PA and EH groups. Age did not differ between the three groups. The Mayer wave power spectrum (MWP) of BP (approx. 0.1 Hz), an index of sympathetic vasomotor tone, was smaller in patients with PA than in patients with EH either while subjects were supine (systolic/diastolic; 3.9 + 3.2 (SD)/1.5 + 1.3 vs. 5.5 + 4.2/2.1 + 1.6 mmHg 2, P < 0.05 for both) or standing (7.6 + 6.6/3.0 + 3.0 vs. 17.7 + 23.7/7.2 + 8.3 mmHg z, P < 0.05 for both). Supine respiratory-related power spectrum (RRP) of the RR interval (approx. 0.25 Hz), an index of cardiac parasympathetic tone, was greater in patients with PA than in patients with EH (545 + 574 vs. 302 + 464 ms 2, P < 0.01). The MWP of BP and the RRP of the RR interval were similar between patients with PA and NT subjects. Adrenalectomy reduced the 24-h mean BP ( - 18 mmHg for systolic BP, P < 0.001; - 12 mmHg for diastolic BP, P < 0.01) and increased the 24-h mean heart rate ( + 8 bpm, P < 0.001). Furthermore, the diastolic MWP increased mildly ( + 32%, P < 0.05) and the RRP of the RR interval decreased dramatically ( - 75%, P < 0.01) following adrenalectomy. These results suggest that both vascular sympathetic and cardiac parasympathetic regulatory systems have minor roles in the maintenance of hypertension in patients with PA. The autonomic nervous system contributes more to the maintenance of BP following than prior to adrenalectomy. This information may be useful for the management of hypertension still persists after removal of adrenal adenoma. Keywords: Sympathetic nervous system; Parasympathetic nervous system; Power spectral analysis; Primary aldosteronism
* Corresponding author. Tel.: (81-22) 274-1111, Ext. 2520; Fax: (81-22) 274-5332. 0165-1838/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0165-1838(94)00159-6
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I. Introduction P r i m a r y a l d o s t e r o n i s m is c a u s e d by t h e excess s e c r e t i o n o f a l d o s t e r o n e f r o m an a d r e n a l a d e n o m a a n d is c h a r a c t e r i z e d by h y p e r t e n s i o n , hyp o k a l e m i a a n d m e t a b o l i c alkalosis. T h e h y p e r t e n sive state is h e m o d y n a m i c a l l y c h a r a c t e r i z e d by i n c r e a s e d p e r i p h e r a l resistance, slight e x p a n s i o n of p l a s m a v o l u m e [32] a n d i n c r e a s e d total b o d y a n d e x c h a n g e a b l e s o d i u m c o n t e n t [34]. S o d i u m r e a b s o r p t i o n in t h e distal t u b u l e o f t h e k i d n e y is i n c r e a s e d s e c o n d a r y to excess m i n e r a l o c o r t i c o i d s , causing v o l u m e expansion. A l d o s t e r o n e m a y inc r e a s e t h e total p e r i p h e r a l r e s i s t a n c e by d i r e c t effects on t h e c e n t r a l n e r v o u s system [17] a n d by i n c r e a s i n g s o d i u m influx into v a s c u l a r s m o o t h m u s c l e cells [18], t h e r e b y p o t e n t i a t i n g s m o o t h m u s c l e cell tone. Neurogenic mechanisms often are implicated in t h e p a t h o g e n e s i s o f h y p e r t e n s i o n . H o w e v e r , it r e m a i n s u n c l e a r how t h e a u t o n o m i c n e r v o u s syst e m is involved in the d e v e l o p m e n t a n d m a i n t e n a n c e o f h y p e r t e n s i o n d u e to p r i m a r y a l d o s t e r o nism. It has b e e n r e p o r t e d t h a t p l a s m a n o r e p i nephrine concentration and urinary excretion of
n o r e p i n e p h r i n e in p a t i e n t s with P A a r e lower t h a n in p a t i e n t s with e s s e n t i a l h y p e r t e n s i o n ( E H ) [7,11]. Bravo et al. have r e p o r t e d t h a t c o m b i n e d a - a n d / J - b l o c k a d e p r o d u c e s no d e t e c t a b l e c h a n g e s in BP in p a t i e n t s with P A a l t h o u g h p l a s m a n o r e p i n e p h r i n e c o n c e n t r a t i o n s a r e similar to p a t i e n t s with E H [3]. M i y a j i m a et al. have d e m o n s t r a t e d t h a t tibial nerve m u s c l e sympat h e t i c nerve activity is l o w e r in p a t i e n t s with P A t h a n in p a t i e n t s with E H [19]. A v a i l a b l e e v i d e n c e suggests t h a t the s y m p a t h e t i c n e r v o u s system cont r i b u t e s less to t h e m a i n t e n a n c e of h y p e r t e n s i o n in p a t i e n t s with P A t h a n in p a t i e n t s with E H . T h e effects of a d r e n e r g i c s t i m u l a t i o n on b l o o d p r e s s u r e , however, d e p e n d n o t only on s y m p a t h e t i c n e r v o u s system activity, b u t also on t h e n a t u r e o f t h e t a r g e t organs. Several r e p o r t s have d e m o n s t r a t e d e n h a n c e d sensitivity o f v a s c u l a r s m o o t h m u s c l e cells to v a s o c o n s t r i c t o r s u b s t a n c e s during administration of electrolyte-active s t e r o i d s [5,27]. T h e r e f o r e , t h e n e t s y m p a t h e t i c v a s c u l a r effect a p p e a r s to b e i m p o r t a n t in patients with PA. F u r t h e r m o r e , a l t h o u g h r e d u c e d p a r a s y m p a t h e t i c activity a n d i m p a i r e d b a r o r e f l e x f u n c t i o n have b e e n r e p o r t e d in p a t i e n t s with E H ,
Table 1 Clinical characteristics of 20 patients with primary aldosteronism No
Name
Sex
Age
Side of tumor
PAC (ng/dl)
PRA (ng/ml per 6 h)
Plasma K (mEq/l)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
M.N R.N M.S R.K T.K J.T H.T I.N K.S H.T K.E Y.D K.O K.S N.S S.S N.K N.K S.M Y.K
F F M F F F F F F M F F M F F F F F F F
36 34 30 43 32 30 58 36 34 52 44 35 35 61 46 38 32 51 49 25
right left left bilateral left right left right left right right right right bilateral right right right right right left
30.4 18.0 18.7 33.9 108.5 21.2 46.1 23.8 49.8 38.8 47.1 26.8 18.9 50.6 28.8 21.8 34.0 152.9 120.1 44.3
trace trace trace trace trace trace trace trace trace trace trace trace trace trace trace 3.2 trace 1.5 1.0 1.1
2.6 4.1 3.1 3.0 1.7 3.2 3.1 3.0 3.0 3.2 2.7 3.5 1.5 3.0 4.2 3.8 3.4 2.9 1.9 3.3
PAC, Plasma aldosterone concentration; PRA, Plasma renin activity, trace means the value below 1.0. Patients No. 4, 10, 16, 18 and 19 had been treated until 48 h prior to the study because of their severe hypretension.
M. Munakata et al. /Journal of the Autonomic Nervous System 52 (1995) 213-223
the pathogenic role of the depressor neural system in the maintenance of hypertension of PA is unknown. It is known that activities of the autonomic nervous system are linked to specific cardiovascular frequency oscillations. Respiratory-related oscillations of the heart rate are mediated purely by the vagus nerve. The amplitude of these oscillations reflects cardiac parasympathetic tone [2,25]. The 10-s oscillations of the BP, known as Mayer waves, are mediated by the a-adrenergic system. The amplitude of these waves has been reported to reflect sympathetic vasomotor activity [15,30]. Cross-spectral analysis between the oscillations of BP and RR interval provides an index of the baroreflex function [26,31]. Consequently, assessment of simultaneous spectral analysis of BP and RR interval oscillations may provide a non-invasive assessment of systemic neural cardiovascular regulations. In this study, we examined autonomic nervous functions in 20 patients with PA using this new technique. The results were compared relative to 54 patients with EH and 45 normotensive (NT) subjects. To further assess changes in autonomic nervous system functions following a normalization of plasma aldosterone concentration, the experiments were repeated in 18 patients with PA who underwent adrenalectomy.
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assessment of electrocardiogram, chest roentgenogram, urinalysis, peripheral blood evaluation, urinary electrolyte excretion, 24-h creatinine clearance and ambulatory blood pressure monitoring. A stimulation test for renin release using captopril (50 mg p.o.) [14] a n d / o r furosemide (40 mg i.v.) [1] was performed in all hypertensive patients. The diagnosis of PA was based on the demonstration of increased production of aldosterone, suppressed plasma renin activity and evidence of unilateral or bilateral adrenal adenoma by computed tomography, magnetic resonance imaging and adrenal scintillation scanning with and without dexamethasone treatment. Adrenal venography and simultaneous assay of adrenal venous plasma aldosterone concentrations were performed to confirm the existence of an aldosterone-producing adenoma in certain patients. Patients with idiopathic hyperaldosteronism were excluded from the present study. Eighteen patients, including two patients with bilateral adenomas, underwent surgery. Total unilateral adrenalectomy and subtotal adrenalectomy on the opposite side were performed in the two patients with bilateral adenomas. The presence of an adrenal adenoma was confirmed by histological examination. Plasma aldosterone levels normalized in all patients following the surgical treatment.
2.2. Autonomic function test 2. Materials and methods
2.1. Subjects We evaluated 20 patients with aldosteroneproducing adrenal adenomas (18 unilateral and two bilateral) ranging in age from 30 to 61 years (mean age 40 years). Clinical characteristics of the PA patients are listed in Table 1.54 patients with EH (WHO stage I or II, ranging in age from 20 to 74 years (mean age 42 years), and 45 NT subjects aged 21 to 72 years (mean age 39 years) served as controls. The mean age did not differ between the three groups. All patients, except NT subjects, were hospitalized and placed on a diet containing approx. 10 g NaC1 per day. All patients underwent fundoscopic examination, and
The study protocol was approved by the Ethics Committee of the Tohoku University School of Medicine. All subjects gave informed consent prior to participation in the study. The autonomic function test was performed in an air-conditioned room. All hypertensive patients were advised to discontinue their cardiovascular medications at least 1 week prior to the study. It was, however, difficult to stop antihypertensive therapy in 5 patients with PA (see Table 1) because of their severe hypertension. All of them were treated with long-acting calcium antagonists until 48 h prior to the study. All subjects were instructed to avoid cigarettes and beverages containing caffeine on the day of the experiment. The experiments were performed between 2:00 p.m. and
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M. Munakata et aL / Journal of the Autonomic Nert~ous System 52 (1995) 213 -223
4:00 p.m. to minimize the effects of circadian rhythm on BP and heart rate [20], variables known to be significantly affected by autonomic nervous system activity. Each subject was placed supine on a bed. The electrocardiogram (ECG) was monitored using a standard lead II. Blood pressure was monitored on the right middle finger with a digital photoplethysmographic device (Finapres 2300; Ohmeda, Englewood, CO, USA). The procedure for signal recording and analysis has been described elsewhere [22-24]. In brief, the analog ECG and BP signals were fed into a signal processor (7T-18; NEC San-ei, Tokyo, Japan) with an R wave detector accurate to within 1 ms. The systolic (SBP) and diastolic (DBP) BP were measured at each R-wave. The R R interval was calculated during this period and then digitized on a floppy disk. Data were collected for 7 min after supine rest for 20 min. The subject was then moved to the standing position and, after 5 min for hemodynamic equilibration, data were recorded for another 7 min. Off-line analysis was later performed on a personal computer (PC 9801-RX; NEC). The trendgrams of R R interval, SBP and DBP, derived from 7-min recordings, were inspected visually on the computer display. A 256-s segment without movement artifacts or premature ventricular contractions was selected for the final analysis. We calculated the Mayer wave power spectrum for BP (0.07-0.14 Hz; mmHg2), and the respiratory-related power spectrum for the R R interval (0.15-0.40 Hz; ms2), as indicators of sympathetic vasomotor and cardiac parasympathetic activities, respectively [2,15,25,30]. To examine the baroreceptor-heart rate reflex, a transfer function analysis between the oscillations of SBP and the R R interval was p e r f o r m e d simultaneously [26,31]. We have shown that the baroreflex modulates R R interval oscillations over the entire frequency range from 0.02 to 0.40 Hz. The effects are exerted more frequently and markedly at frequencies above 0.07 Hz [24]. Thus, next, we calculated the modulus of the transfer function in the Mayer wave frequency (GMayer:0.07-0.14 Hz) and that in the respiratory-frequency (GRespiratory: 0.15-0.4(I Hz) for those frequency points with a
coherence > 0.5 as indicators of baroreflex function. This method of determining arterial baroreflex activity has been validated previously by the classic phenylephrine method [26,31].
2.3. Statistical analysis All data are expressed as mean + S.D. Comparison of data among the groups was performed by an unpaired t-test or by the KolmogorovSmirnov test. Within group comparison was done by the paired t-test or by the Wilcoxon test. All statistical analyses were performed with a commercially available statistical package (SYSTAT ver 5.0, Evanston, IL, USA). A P value less than 0.05 was considered significant.
3. Results
In the PA group, all data were similar between patients received antihypertensive treatment until 48 h prior to the study and those in which treatment was discontinued at least 1 week prior to study. Thus, they were treated alltogether in the subsequent analysis. Resting finger BP measurements were higher in patients with PA than in NT subjects (150 + 22 vs. l l0 + 13 mmHg for systolic BP, P < 0.001; 81 + 10 vs. 53 + 10 mmHg for diastolic BP, P < 0.001). Also, they were similar to those obtained in patients with E H (147 + 21 mmHg for systolic BP, 7 8 + 14 mmHg for diastolic BP). The R R interval in patients with E H (840 + 127 ms) was shorter than that in NT subjects (932 + 126 ms) or PA patients (938 + 141 ms)(P < 0.01 for both). There was no difference with respect to fundoscopic changes, cardiothoracic ratios, and 24-h creatinine clearance between PA and E H groups (Fig. 1), suggesting a similar degree of organ damage between the two hypertensive groups. The duration of hypertension, the body mass index and the total cholesterol concentration also were similar between patients with PA and EH. Supine MWPs of BP of patients with PA were smaller than those of patients with E H (systolic/diastolic; 3.9 + 3.2/1.5 + 1.3 vs. 5.5 + 4.2/2.1 + 1.6 mmHg 2, P < 0.05 for both) and were similar to those of NT subjects
M. Munakata et aL /Journal of the Autonomic Nervous System 52 (1995) 213-223
(4.3 + 4.2/1.2 + 1.0 mmHg2)(Figs. 2 and 3). Supine R R P of the R R interval of patients with PA was greater than that of patients with E H (545 ++_574 vs. 302 + 464 ms 2, P < 0.01; Fig. 4) and did not differ from that of N T subjects (653 + 625 ms2). Standing MWPs of BP of patients
n
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EH NT PA Fig.'2. Mayer wave power spectra of systolic blood pressure (MWP of SBP) of essentially hypertensive patients (EH), normotensive subjects (NT) and patients with primary aldosteronism (PA). Upper panel shows the data while subjects are supine and the lower the data while standing.
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Fig. 1. Brar graphs show a degree of fundoscopic changes (Kaith-Wagner classification), cardiothoracic ratios (CTR), 24-h creatinine clearance (Ccr), body mass index (BMI), total cholesterol and duration of hypertension of essential hypertension (EH) and primary aldosteronism (PA) groups.
with PA also were smaller than those of patients with E H (7.6 _+ 6.6/3.0 _+ 3.0 vs. 17.7 +_ 23.7/7.2 + 8.3 mmHg 2, P < 0.05 for both) and were similar to those of NT subjects (6.9 _+ 4.8/2.3 + 1.7 mmHg2). (Figs. 2 and 3). Standing RRPs of the R R interval of PA, E H and N T groups were 779 ___82, 735 _+ 129 and 775 _+ 125 ms 2, respectively (n.s. among each group). The GMayer and GRespiratory values were greater in patients with PA than in patients with E H (8.1 + 4.9 vs. 5.4 + 2.5 m s / m m H g , P < 0.01 f o r GMayer and 14.6 +_ 8.9 vs. 9.8 ___5.7 m s / m m H g , P < 0.05 f o r GRespiratory) and similar to N T subjects (7.1 +_ 4.6 m s / m m H g for GMayer and 17.7 + 9.2 m s / m m H g for GRespiratory) (Fig. 5).
218
M. Munakata et al. /Journal of the Autonomic Neruous System 52 (1995) 213-223
The 24-h mean BP decreased following adrenalectomy (141 + 13 vs. 123 + 18 mmHg for systolic BP, P < 0.001; 90 + 11 vs. 78 + 11 mmHg for diastolic BP, P < 0.01) while the 24-h mean heart rate increased following adrenalectomy (66 + 6 vs. 75 + 6 bpm, P < 0.001). The day-night difference (i.e., day-time mean - night-time mean) in systolic BP, diastolic BP and heart rate (11.3 + 9.7 mmHg, 9.5 + 6.8 mmHg, 12.1 + 3.9 bpm, respectively) were not affected by adrenalectomy (10.2 __+7.2 mmHg, 6.9 + 4.6 mmHg and 15.0 + 6.6 bpm, respectively), suggesting that the decrease in BP and the increase in heart rate occurred t h r o u g h o u t the day and night. Following adrenalectomy, the supine diastolic MWP in-
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creased ( + 32%, P < 0.05) while the RRP of the R R interval decreased ( - 75%, P < 0.01) (Fig. 6). The systolic MWP did not change significantly. Both the GMayer and the GRespiratory decreased following adrenalectomy ( - 4 2 % for GMayer, and - 3 9 % for GRespiratory , P < 0.05 for both)(Fig. 7).
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Our study demonstrated that the features of both the Mayer wave power spectrum of BP and the respiratory-related power spectrum of the R R interval differ between patients with PA and patients with E H independent of the severity of the hypertension. The Mayer wave power spec-
M. Munakata et al. /Journal of the Autonomic Nervous System 52 (1995) 213-223
trum of BP and the respiratory-related power spectrum of the R R interval reflect sympathetic vasomotor and cardiac parasympathetic tone, respectively. Our data suggest that autonomic cardiovascular regulations in patients with PA differ from those of patients with EH. The sympathetic nervous activity of patients with PA has been studied with the measurements of plasma norepinephrine concentration [3,7], urinary excretion of norepinephrine [11] and tibial nerve muscle sympathetic activity [19]• The majority of the available evidence suggests a minor role of the sympathetic nervous system in the maintenance of hypertension in patients with PA. Sym-
219
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pathetic BP regulation, however, depends not only on sympathetic nerve activity but also on vascular responsiveness. Since hyperresponsiveness to several vasopressor substances has been demonstrated in mineralocorticoid excess hypertension [5,27], the net assessment of sympathetic vascular tone appears to be important. Thus, we used the Mayer wave spectrum of BP as an indicator of sympathetic vascular tone. The amplitude of this parameter is determined by both
220
M. Munakata et al. /Journal of the Autonomic Nert,ous System 52 (1995) 213-223 P=0.017 10
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a-adrenergic activity and the responsiveness of blood vessels [22]. In our study, the Mayer wave spectrum of BP in patients with PA was smaller than in patients with E H and similar to N T subjects. These results suggest that the net sympathetic vascular effect in patients with PA was smaller than in patients with EH. Thus, as previously reported, the sympathetic nervous system contributes less to the maintenance of hypertension in patients with PA than in patients with EH. Since the amplitude of Mayer waves is affected considerably by age [21], we carefully matched both age and degree of organ damage between patients with PA and EH. To our knowledge, baroreflex functions in patients with PA have not been examined. We need careful attention to apply the traditional vasoactive methods to patients with PA, since they often demonstrate very severe hypertension [4] and possibly show a hyperresponsiveness to vasoactive
agents [27]. In this study, we have adopted a new method based on transfer function analysis between the oscillations of systolic BP and the R R interval [24] to assess baroreflex function. Based on previous reports, we calculated the modulus of the transfer function at the Mayer wave frequency (GMayer) and at the respiratory frequency (G Respiratory) [26,31]. Both the GMayer and the GRespiratory were greater in patients with PA than in patients with EH, and were similar to those of N T subjects. These data suggest that baroreceptor control of the sinus node is preserved in patients with PA. Normal cardiac parasympathetic tone is further supported by the fact that respiratory-related power of the RR, which is mediated primarily by efferent vagal nerve activity [2,25] and is affected by several afferent inputs including baroreflex [24], also was normal in patients with PA. It is well known that both vagal tone and baroreflex sensitivity decrease with age and with increases in BP. However, neither age nor BP differed among patients with PA and EH. Since both parameters decreased following adrenalectomy, it can be indicated that hyperaldosteronism and its associated conditions potentiate vasodepressor neural function against high BP. Our study did not provide an explanation for this observation. However, suppression of the renin-angiotensin system may be involved. It is well known that endogenous angiotensin 1I modulates the baroreflex property. Some investigators have reported that angiotensin II decreases baroreflex sensitivity [6,9] and that the blockade of the renin angiotensin system potentiates it in normal subjects [13]. It also has been shown that intravenous infusion of angiotensin II into the vertebral artery reduced vagal nerve activity in conscious dogs [28]. Thus, suppressed angiotensin II formation appears to augment both resting vagal tone and its reflex regulation. We were unable to exclude the possibility that other factors such as hyperaldosteronism, hypervolemia, hypokalemia and metabolic alkalosis modulated these neural functions. However, there is no evidence to suggest or support this possibility. Following adrenalectomy, the MWP of DBP increased by about 30% when compared to pre-
M. Munakata et al. /Journal of the Autonomic Nervous System 52 (1995) 213-223
operative value. These results suggest that the sympathetic nervous system contributes more to the maintenance of BP following adrenalectomy than before adrenalectomy. The explanation for the increase in sympathetic vascular tone following adrenalectomy remains unclear, however, two possibilities exist. First, this may be a compensatory adaptation of the cardiovascular system to a new body fluid status. It is well known that a dynamic balance exists between blood volume and vasoconstrictor properties. Vasoconstrictive mediators, including the renin-angiotensin and sympathetic nervous systems are suppressed physiologically when extracellular fluid volume is expanded sufficiently [16]. Under volume overload, vascular resistance increases to avoid hyperperfusion through autoregulatory mechanism. The increase in total peripheral resistance, then, elicits the reflex inhibition of the central outflow of the sympathetic nerve activity. Aldosterone can augment the sympathetic nerve activity through central mechanism [17] but this effect presumably is overcome by the reflex inhibitory effect due to volume overload in patients with primary aldosteronism. Consequently, the central outflow of the sympathetic nervous activity is suppressed [19]. Since body fluid decreases following adrenalectomy, the sympathetic nervous system will be activated to compensate for a loss in body fluid. Second, the sympathetic nervous activity may be augmented by the recovery of the reninangiotensin system activity. It is known that angiotensin II is a strong modulator of sympathetic nervous system function [29]. Angiotensin II facilitates cardiovascular responses to sympathetic stimulation and depletion of endogenous angiotensin II attenuates it. Sympathetic nervous system seems to be difficult to get excited in patients with PA because of low angiotensin II levels. Recovery of the renin-angiotensin system activity following adrenalectomy, thus, may lead to activation of sympathetic activity. The MWP of SBP did not increase after adrenalectomy as that of DBP did. This means that MWP of DBP and that of SBP are mediated at least in part by different mechanisms. Possibly the MWP of DBP depends more on the sympathetic mechanism than that of SBP, since admin-
221
istration of a-adrenoceptor blocker predominantly reduced the former MWP [10]. Finally we will discuss the clinical importance of the post-operative changes in the autonomic nervous activities in adrenalectomized PA patients. Primary aldosteronism can be cured by surgical removal of adrenal adenoma. However hypertension still exists in 23-30% of the adrenalectomized patients irrespective of normalization of plasma aldosterone levels [8,12]. In our long-term follow-up study of 90 cases of surgically treated aldosterone producing adenomas, hypertension persisted in 38 patients (42%) [33]. Duration of hypertension, age and renal function were important predictors of the post-operative BP. In the present study, we found that the sympathetic vascular tone increased following adrenalectomy. The vasopressor system may be involved in the maintenance of post-operative hypertension especially in case that it potentially possesses a pathogenic predisposition. This information may justify the use of adrenergic blockers for the treatment of post-operative hypertension [4]. In conclusion, our data demonstrate that vascular sympathetic and cardiac parasympathetic regulatory systems have minor roles in the maintenance of hypertension in patients with PA. Following adrenalectomy, however, sympathetic vascular tone is increased mildly and cardiac parasympathetic tone is decreased dramatically. Thus, the autonomic nervous system is more important in the maintenance of BP following rather than prior to adrenalectomy. This information may be useful for the management of hypertension still persists after removal of adrenal adenoma.
References [1] Abe, K., lrokawa, N., Aoyagi, H., Memezawa, H., Yasujima, M., Otsuka, Y., Saito, T. and Yoshinaga, K., Circulating renin in essential hypertension: an evaluation of its significance in the Japanese population, Am. Heart J., 89 (1975) 723-730. [2] Akselrod, D., Gordon, J.B., Madwed, J.B., Snidman, N.C., Shannon, C. and Cohen, R.J., Hemodynamic regulation: Investigation by spectral analysis, Am. J. Physiol., 249 (1985) H867-H875.
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M. Munakata et al. /Journal of the Autonomic Nervous System 52 (1995) 213-223
[3] Bravo, E.L., Tarazi, R.C., Dustan, H.P. and Fouad, F.M., The sympathetic nervous system and hypertension in primary aldosteronism, Hypertension, 7 (1985) 90-96. [4] Bravo, E.L., Fouad-Tarazi, F.M., Tarazi, R.C., Pohl, M., Gifford, R.W. and Vidt, D.G., Clinical implications of primary aldosteronism with resistant hypertension, Hypertension, 11 (1988) 1-207-I-211 (Suppl. I). [51 Chobanian, A.V., Volicer, L., Tifft, C.P., Gavras, H., Liang, C. and Faxon, D., Mineralocorticoid-induced hypertension in patients with orthostatic hypotension, New Engl. J. Med., 301 (1979) 68-73. [6] Garner, M.G., Phippard, A.F., Fletcher, P.J., Maclean, J.M., Duggin, G.G., Horvath, J.S. and Tiller, D.J., Effect of angiotensin II on baroreceptor reflex control of heart rate in conscious baboons. Hypertension, 10 (1987) 628634. [7] Gordon, R.D., Bachmann A.W., Jackson, R.V. and Saar, N., Increased sympathetic activity in renovascular hypertension in man, Clin. Exp. Pharmacol. Physiol., 9 (1982) 277-281. [81 Granberg, P.O., Adamsson, U., Hamberger, B. and Lins, P.E., Surgical treatment of primary aldosteronism, Ann. Chir. Gynaecol., 72 (1983) 171-176. 191 Guo, G.B. and Abboud, F.M., Angiotensin II attenuates baroreflex control of heart rate and sympathetic activity. Am. J. Physiol., 246 (1984) H80-H89. [lll] Hashimoto, J., Imai, Y., Munakata, M. and Abe, K., Assessment of autonomic control of the short-term oscillations in R-R interval and blood pressure in conscious rats by power spectral analysis. High Blood Pressure, 3 (1994) 89-96. [11] Horky, K., Kopecka, J. and Widimsky Jr., J., Urinary excretion of catecholamines in patients with primary aldosteronism before and after unilateral adrenalectomy, Coron. Vasoact., 25 (1983) 401-412. [12] Horky, K., Widimsky Jr., J., Hradec, E., Gregorova, I. and Hradec, M., Long-term results of surgical and conservative treatment of patients with primary aldosteronism, Exp. Clin. Endocrinol. 90 (1987) 337-346. [13] Ibsen, H., Egan, B., Osterziel, K., Vander, A.J. and Julius, S., Reflex-hemodynamic adjustments and baroreflex sensitivity during converting enzyme inhibition with MK-421 in normal humans, Hypertension, 5 (1983) 1184-I-191. [14] Imai, Y., Abe, K., Otsuka, Y., Sakurai, Y., Ito, T., Sato, M., Haruyama, T., Omata, K., Hiwatari, M. and Yoshinaga, K., Exaggerated response of renin secretion to captopril (SQ 14225) in renovascular hypertension. Jpn. Heart J., 21 (1980) 303-314. [15] Inoue, K., Miyake, S., Kunashiro, M., Ogata, H., Ueta, T. and Akatsu, T., Power spectral analysis of blood pressure variability in traumatic quadriplegic humans, Am. J. Physiol., 260 (1991) H842-H847. [16] lzzo Jr., J.L., Horwitz, D., Lawton, W.J. and Keiser, H.R., Fludrocortisone suppression of sympathetic nervous activity, Clin. Pharmacol. Ther., 33 (1983) 102-106. 1171 Kageyama, Y. and Bravo, E.L., Hypertensive mechanisms
associated with centrally administered aldosterone in dogs, Hypertension, 11 (1988) 750-753. [18] Menard, M.R. and Friedman, S.M., Direct measurement of sodium influx in vascular smooth muscle, Hypertension, 7 (1985) 873-878. [19] Miyajima, E., Yamada, Y., Yoshida, Y., Matsukawa, T., Shionoiri, H., Tochikubo, O. and Ishii, M., Muscle sympathetic nerve activity in renovascular hypertension and primary aldosteronism, Hypertension, 17 (1991) 10571062. [20] Munakata, M., Imai, Y., Abe, K., Sasaki, S., Minami, N., Hashimoto, J., Sakuma, H., Ichijyo, T., Yoshizawa, M., Sekino, H. and Yoshinaga, K., Assessment of age-dependent changes in circadian blood pressure rhythm in patients with essential hypertension, J. Hypertens., 9 (1991) 407-415. [21] Munakata, M., Imai, Y., Hashimoto, J., Sasaki, S., Sakuma, H., Watanabe, N., Nishiyama, A. and Abe, K., Altered Mayer wave characteristics in young patients with essential hypertension. Ther. Res., 13 (1992) 99-102. [22] Munakata, M., Imai, Y., Sekino, H. and Abe, K., Rhythmic oscillations of blood pressure and RR interval in patients with chronic renal failure, Med. Biol. Eng. Comput., 31 (1993) sl15-s122. [23] Munakata, M., Imai, Y., Mizunashi, K., Sekino, H. and Abe, K., The role of calcium ions in the regulation of rhythmic oscillations in blood pressure. J. Hypertens., 11 (1993) s172-s173 (Suppl. 5). [24] Munakata, M., Imai, Y., Takagi, H., Nakao, M, Yamamoto, M. and Abe, K., Altered frequency-dependent characteristics of the cardiac baroreflex in essential hypertension. J. Auton. Nerv. Syst., 49 (1994) 33-45. [25] Pagani, M., Lombardi, F., Guzzeti, S., Rimoldi, O., Furlan, R., Pizzinelli, P., Sandrone, G., Malfatto, G., Dell'Orto, S., Piccaluga, E., Turiel, M., Baselli, G., Cerutti, S. and Malliani, A., Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympathovagal interaction in man and conscious dog. Circ. Res., 59 (1986) 178-193. [261 Pagani, M., Somers, V., Furlan, R., Dell'Orto, S., Conway, J., Baselli, G., Cerutti, S., Sleight, P. and Malliani, A., Changes in autonomic regulation induced by physical training in mild hypertension, Hypertension, 12 (1988) 600-610. [27] Philipp, T., Luth, B., Wucherer, G. and Distler, A., Mechanism of mineralocorticoid-induced hypertension in man. In: W. Kaufmann, G. Wambach, A. Helber, and K.A. Meurer (Eds.), Mineralocorticoids and Hypertension. Springer, New York, NY, 1983, pp. 129-139. [28] Potter, E.K. and Reid, I.A., Intravertebral angiotensin II inhibits cardiac vagal efferent activity in dogs, Neuroendocrinology, 40 (1985) 493-496. [29] Reid, I.A., Interaction between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am. J. Physiol., 262 (1992) E763-E778. [30] Rimoldi, O., Pierini, S., Ferrari, A., Cerutti, S., Pagani, M. and Malliani, A., Analysis of short-term oscillations of
M. Munakata et al. /Journal of the Autonomic Nervous System 52 (1995) 213-223
R-R and arterial pressure in conscious dogs, Am. J. Physiol., 258 (1990) H967-H976. [31] Robbe, H.W.J., Mulder, L.J.M., Ruddel, H., Langewitz, W.A., Veldman, J.B.P. and Mulder, G., Assessment of baroreflex sensitivity by means of spectral analysis, Hypertension, 10 (1987) 538-543. [32] Tarazi, R.C., Ibrahim, M.M., Bravo, E.L. and Dustan, H.P., Hemodynamic characteristics of primary aldosteronism, New Engl. J. Med., 289 (1973) 1330-1335. [33] Tsunoda, K., Imai, Y., Omata, K., Watanabe, N., Mis-
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awa, S., Munakata, M., Sakuma, H., Mimami, N., Kohzuki, M. and Abe, K., Long-term follow-up study of 90 cases of surgically treated aldosterone-producing adenoma, Jpn. J. Coll. Angiol., 33 (1993) 153 (Japanese with English abstract). [34] Williams, E.D., Boddy, K. and Brown, J.J., Body elemental composition, with particular reference to total and exchangeable sodium and potassium and total chlorine, in untreated and treated primary hyperaldosteronism, J. Hypertens., 2 (1984) 171-176.