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Am J Physiol Heart Circ Physiol 292: H1321-H1327, 2007. First published October 20, 2006; doi:10.1152/ajpheart.00874.2006
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Very low-frequency blood pressure variability depends on voltage-gated L-type Ca2+ channels in conscious rats

Amanda M. Langager, Bailey E. Hammerberg, Diane L. Rotella, and Harald M. Stauss

Department of Integrative Physiology, The University of Iowa, Iowa City, Iowa

Submitted 14 August 2006 ; accepted in final form 13 October 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The mechanisms generating high- frequency (HF) and low-frequency (LF) blood pressure variability (BPV) are reasonably well understood. However, little is known about the origin of very low-frequency (VLF) BPV. We tested the hypothesis that VLF BPV is generated by L-type Ca2+ channel-dependent mechanisms. In conscious rats, arterial blood pressure was recorded during control conditions (n = 8) and ganglionic blockade (n = 7) while increasing doses (0.01–5.0 mg·100 µl–1·h–1) of the L-type Ca2+ channel blocker nifedipine were infused intravenously. VLF (0.02–0.2 Hz), LF (0.2–0.6 Hz), and HF (0.6–3.0 Hz) BPV were assessed by spectral analysis of systolic blood pressure. During control conditions, nifedipine caused dose-dependent declines in VLF and LF BPV, whereas HF BPV was not affected. At the highest dose of nifedipine, VLF BPV was reduced by 86% compared with baseline, indicating that VLF BPV is largely mediated by L-type Ca2+ channel-dependent mechanisms. VLF BPV appeared to be relatively more dependent on L-type Ca2+ channels than LF BPV because lower doses of nifedipine were required to significantly reduce VLF BPV than to reduce LF BPV. Ganglionic blockade markedly reduced VLF and LF BPV and abolished the nifedipine-induced dose-dependent declines in VLF and LF BPV, suggesting that VLF and LF BPV require sympathetic activity to be evident. In conclusion, VLF BPV is largely mediated by L-type Ca2+ channel-dependent mechanisms. We speculate that VLF BPV is generated by myogenic vascular responses to spontaneously occurring perturbations of blood pressure. Other factors, such as sympathetic nervous system activity, may elicit a permissive effect on VLF BPV by increasing vascular myogenic responsiveness.

power spectral analysis; myogenic vascular function; nifedipine; autonomic nervous system; ganglionic blockade

BLOOD PRESSURE VARIABILITY has received considerable attention during the last decades, not only because enhanced blood pressure variability has been identified as an independent cardiovascular risk factor (33, 35) but also because the patterns of blood pressure variability may provide important insights into cardiovascular regulation (2, 23, 31). High-frequency (HF) blood pressure variability linked to respiration has been suggested to involve fluctuations in cardiac output of purely mechanical origin (23), secondary to respiratory sinus arrhythmia (2). Low-frequency (LF) blood pressure fluctuations (0.2–0.6 Hz in rats), the so-called Mayer waves (36), have been associated mostly with sympathetic modulation of vascular tone (22, 50, 52). However, very low-frequency (VLF) blood pressure fluctuations (0.02–0.2 Hz in rats) at frequencies below the frequency of Mayer waves are less well understood. A variety of factors, including catecholamines (45), the renin-angiotensin system (7, 18, 43, 44), heat stress (51), and hypovolemia (42), have been associated with VLF blood pressure variability. In addition, studies on dynamic autoregulation of local blood flow in rats demonstrated that myogenic vascular function is most effective at frequencies <0.2 Hz in the renal circulation (1, 9, 30, 53), <0.13 Hz in the mesenteric vascular bed (1), and <0.1 Hz in the cerebral circulation (27). Thus it is reasonable to assume that myogenic vascular function also contributes to VLF blood pressure variability in rats.

Myogenic vascular responses were first described by Sir William Bayliss (5) and are characterized by a vasoconstriction if perfusion pressure increases and by a vasodilatation if perfusion pressure decreases. The mechanism of the myogenic vascular response involves pressure-induced depolarization of the cell membrane, followed by opening of voltage-gate L-type Ca2+ channels (11, 12, 48, 55). In vivo, the intensity of the myogenic vascular response to pressure can be modulated by a variety of factors. For example, it has been demonstrated that catecholamines (3, 41, 54) and angiotensin II (19, 25, 47) enhance myogenic vascular responsiveness.

From these considerations, we propose that myogenic vascular responses to spontaneously occurring perturbations of arterial blood pressure are the primary mechanism generating VLF blood pressure variability. Catecholamines, the renin-angiotensin system, and other factors affecting plasma levels of catecholamines or angiotensin II (e.g., hypovolemia and heat stress) may elicit their known effects on VLF blood pressure variability by altering myogenic vascular responsiveness.

As a first step in investigating this possibility, we used the L-type Ca2+ channel blocker nifedipine to test the hypothesis that a major component of VLF blood pressure variability is mediated by Ca2+ channel-dependent mechanisms, such as myogenic vascular function. Since sympathetic {alpha}-adrenergic-mediated vasoconstriction partly depends on L-type Ca2+ channels (14, 28), we used ganglionic blockade to distinguish sympathetic modulation of vascular tone from other L-type Ca2+ channel-dependent mechanisms.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
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Animals. Experiments were performed in 15 male normotensive Wistar-Kyoto rats (WKY/NCrl, Charles River, Wilmington, MA) at an age of 62 ± 2 days (201 ± 13 g body weight). Experiments were performed in accordance with the American Physiological Society's "Guiding Principles in the Care and Use of Animals" and have been approved by the Institutional Animal Care and Use Review Committee of The University of Iowa (ACURF no.: 0307140).

Surgeries. Catheters were implanted in the femoral artery and vein 4–6 days before hemodynamic recordings as described previously (50, 52). Briefly, rats were anesthetized by using a combination of ketamine (91 mg/kg) and acepromazine (0.91 mg/kg) administered intraperitoneally. The skin in the right flank and the nape of the neck were shaved and disinfected. Through an inguinal incision, a polyethylene catheter (PE-50, inner diameter: 0.580 mm, outer diameter: 0.965 mm; Becton Dickinson) was inserted into the right femoral vein, and a short (2 cm) polyethylene catheter (PE-10, inner diameter: 0.28 mm, outer diameter: 0.61 mm; Becton-Dickinson) that was attached to a longer (15 cm) PE-50 catheter was inserted into the right femoral artery. The catheters were tunneled under the skin and exteriorized at the nape of the neck. Catheters were flushed with heparinized (20,000 IU/l) saline and sealed. All wounds were closed by suture, and buprenorphine (1 µg/100 g body wt im) was administered to prevent postoperative pain.

Experimental protocols. Experiments were conducted 4–6 days after surgery in conscious rats. During hemodynamic recordings, rats were housed in their own home cages. Arterial and venous catheters were connected to a pressure transducer (P23 ID, Gould-Statham) placed at heart level and to a syringe attached to an infusion pump, respectively. The catheters were led vertically out of the open cages so that the rats were not restrained and could move freely. The signal from the pressure transducer was amplified by a pressure processor (Series 4000, Gould) and digitized (500-Hz sampling rate, 12-bit resolution) using the freely available HemoLab software (http://www.intergate.com/~harald/HemoLab/HemoLab.html).

After a baseline recording of 30 min, the ganglionic blocker hexamethonium (1.0 mg/100 g body wt, concentration: 10 mg/ml, n = 7) or placebo (100 µl/100 g body wt saline, n = 8) was injected intravenously. Effectiveness of ganglionic blockade was confirmed by an immediate drop in arterial blood pressure of 20–30 mmHg. Three to five minutes following this bolus injection, intravenous infusion of the Ca2+ channel blocker nifedipine (diluted in dimethylsulfoxide) was started. The infusion rate was kept constant at 100 µl/h, and the nifedipine concentration was increased every 30 min. The concentrations were the following (in mg/ml): 0.1, 0.5, 1.0, 5.0, 10, and 50. Before the start of each new nifedipine concentration (every 30 min), an intravenous bolus injection of hexamethonium (1.0 mg/100 g body wt, concentration: 10 mg/ml) or placebo (100 µl/100 g body wt saline) was administered. Thus dose-response curves for the Ca2+ channel blocker nifedipine were obtained in the range from 5 to 2,500 µg·h–1·100 g body wt–1 during control conditions (n = 8) and during ganglionic blockade (n = 7).

Data analysis. From the original recordings (500-Hz sampling rate) systolic blood pressure and heart rate were derived on a beat-by-beat basis. These nonequidistant beat-by-beat time series were interpolated (cubic spline) and resampled at a new sampling rate of 12 Hz to obtain equally spaced time series. From those systolic blood pressure and heart rate time series (sampled at 12 Hz), segments of at least 3 min duration (see Table 1) were manually extracted for the baseline recording, the recording during hexamethonium application alone, and for each concentration of nifedipine according to 1) stationarity (based on visual inspection), 2) no artifacts (e.g., due to behavior), and 3) no apparent cardiac arrhythmias (e.g., extrasystoles). The mean values for systolic blood pressure and heart rate of these segments were used for statistical analysis. In addition, the segments for systolic blood pressure were used for power spectral analysis using the fast Fourier transform (FFT) algorithm (2,048 values, 50% overlapping segments, frequency resolution 0.00586 Hz). Only one segment (2,048 values) was available for the recordings during hexamethonium alone because nifedipine infusion was started 3–5 min after application of hexamethonium. The number of data points in 15 from the other 105 time series was <3,072 (but >2,048), allowing for only one segment for the FFT. The drugs used in this study may have affected animal behavior, potentially leading to different durations of the time series for the different experimental conditions. However, Table 1 shows that there was no significant effect of hexamethonium or dose of nifedipine on the length of the time series used for spectral analysis. To remove slow trends in the time series, a linear regression line was subtracted from each time series before the application of the FFT algorithm. This procedure also eliminated the so-called "DC component" at a frequency of 0 Hz, corresponding to the mean value of the time series. VLF (0.02–0.2 Hz), LF (0.2–0.6 Hz), HF (0.6–3.0 Hz), and total (0.0–3.0 Hz) spectral powers were determined as the area under the curve of the power spectra in the respective frequency bands. Absolute spectral powers were used for statistical analysis.


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  		Table 1. Length of time series for spectral analysis

 
Statistics. All data are presented as means ± SE. Statistical comparisons between baseline conditions (no drugs) and application of hexamethonium alone was performed by paired t-tests using only the rats from the hexamethonium group (n = 7). The effects of increasing doses of nifedipine (0.01 to 5.0 mg·100 µl–1·h–1, not including the baselines) during control conditions and ganglionic blockade were assessed by two-way ANOVA for one independent (control vs. hexamethonium) and one repeated measure (nifedipine doses) with post hoc Newman-Keuls tests for individual comparisons between different doses of nifedipine and post hoc Fisher tests for comparisons between control conditions and ganglionic blockade for each dose of nifedipine. These post hoc tests are based on the degrees of freedom used for the two-way ANOVA and, therefore, are adjusted for multiple comparisons. Post hoc tests were only calculated if the ANOVA revealed statistical significance. Statistical significance was assumed for P < 0.05.


   RESULTS
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DISCUSSION
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Original recordings of blood pressure and heart rate obtained during control conditions and during ganglionic blockade are shown in Fig. 1, and the quantitative analysis is provided in Fig. 2. During control conditions, blood pressure remained relatively constant up to a nifedipine dose of 0.1 mg·100 µl–1·h–1. At higher doses, a substantial decrease in blood pressure was observed. In contrast, during ganglionic blockade, blood pressure declined almost linearly throughout the range of increasing doses of the Ca2+ channel blocker, leading to lower systolic blood pressure values during ganglionic blockade at the lower doses of nifedipine (2-way ANOVA: P < 0.05 for between and within factors, not significant for interaction). The relatively large decrease in systolic blood pressure during ganglionic blockade alone compared with baseline conditions may be related to the time delay in compensatory mechanisms raising blood pressure following the sudden decline in blood pressure immediately after application of hexamethonium. Heart rate increased at higher doses of nifedipine during control conditions and ganglionic blockade. No significant differences in heart rate were determined between control conditions and ganglionic blockade (2-way ANOVA: P < 0.05 for within factor and interaction, not significant for between factor).


Figure 1
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  		Fig. 1. Representative recordings of arterial blood pressure (BP, left) and heart rate (HR, right; bpm, beats/min) during control conditions (Control, top) and ganglionic blockade (Hexamethonium, bottom). After a baseline recording (base), increasing doses of the Ca2+ channel blocker nifedipine were infused intravenously. Baseline recordings were obtained before application of nifedipine and before application of placebo or hexamethonium. The dose of the Ca2+ channel blocker was increased every 30 min.

 

Figure 2
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  		Fig. 2. Dose-response curves for systolic BP (Sys BP, left) and HR (right) for increasing doses of the Ca2+ channel blocker nifedipine during control conditions (closed circles) and ganglionic blockade by hexamethonium (open circles). Baseline recordings (base) were obtained before application of nifedipine and before application of placebo or hexamethonium. Values for systolic BP and HR obtained between application of hexamethonium and the first dose of nifedipine are also provided (hexa). #P < 0.05 vs. baseline before application of hexamethonium (paired t-test); *P < 0.05 control conditions vs. ganglionic blockade (post hoc Fisher test following 2-way ANOVA); {dagger}P < 0.05 vs. nifedipine dose of 0.01 mg·ml–1·h–1 (post hoc Newman-Keuls test following 2-way ANOVA).

 
Systolic blood pressure power spectral analysis is summarized in Fig. 3. During control conditions, nifedipine dose dependently reduced total spectral power, an index of overall blood pressure variability. At the highest dose of nifedipine (5.0 mg·100 µl–1·h–1) total blood pressure variability was reduced by 78% (from 12.8 ± 2.7 mmHg2 at baseline to 2.8 ± 0.6 mmHg2 at 5.0 mg·100 µl–1·h–1). This reduction in blood pressure variability during Ca2+ channel blockade can be explained to 61% by a reduction in VLF blood pressure variability (from 7.1 ± 1.4 to 1.0 ± 0.3 mmHg2) and to 20% by a reduction in LF blood pressure variability (from 2.4 ± 0.5 to 0.4 ± 0.1 mmHg2). The remaining 19% are related to decreased HF and ultra LF (ULF, <0.02 Hz) blood pressure variability. During ganglionic blockade, total spectral power at the lowest dose of nifedipine (0.01 mg·100 µl–1·h–1) was significantly lower than during control conditions and did not further decrease with increasing doses of nifedipine, indicating that overall blood pressure variability largely depends on the autonomic nervous system (2-way ANOVA: P < 0.05 for between and within factors and for interaction).


Figure 3
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  		Fig. 3. Absolute spectral powers of systolic blood pressure for increasing doses of the Ca2+ channel blocker nifedipine during control conditions (closed circles) and ganglionic blockade by hexamethonium (hexa, open circles). Very low-frequency (VLFSYS, 0.02–0.20 Hz), low-frequency (LFSYS, 0.2–0.6 Hz), total (totalSYS, 0.0–3.0 Hz), and high-frequency (HFSYS, 0.6–3.0 Hz) spectral powers are shown. Baseline recordings (base) were obtained before application of nifedipine and before application of placebo or hexamethonium. Spectral powers obtained between application of hexamethonium and the first dose of nifedipine are also provided (hexa). *P < 0.05 control conditions vs. ganglionic blockade (post hoc Fisher test following 2-way ANOVA); {dagger}P < 0.05 vs. nifedipine dose of 0.01 mg·ml–1·h–1 (post hoc Newman-Keuls test following 2-way ANOVA).

 
During control conditions, VLF blood pressure variability declined dose dependently as the nifedipine dose was raised above 0.01 mg·100 µl–1·h–1. Ganglionic blockade markedly reduced VLF blood pressure variability and abolished the dose-dependent decline in VLF blood pressure variability elicited by the Ca2+ channel blocker (2-way ANOVA: P < 0.05 for between and within factor and for the interaction). These data suggest that VLF blood pressure variability is largely dependent on L-type Ca2+ channels and that sympathetic nervous system activity elicits a permissive effect on the generation of VLF blood pressure variability.

During control conditions, LF blood pressure variability was significantly reduced at the two highest doses of nifedipine (1.0 and 5.0 mg·100 µl–1·h–1) when compared with the lowest dose of nifedipine (0.01 mg·100 µl–1·h–1). Ganglionic blockade markedly reduced LF spectral power of systolic blood pressure, as indicated by the finding that LF spectral power during ganglionic blockade was significantly less than during control conditions at the lowest dose of nifedipine (0.01 mg·100 µl–1·h–1) and did not decline any further with increasing doses of nifedipine (2-way ANOVA: P < 0.05 for between and within factor and for the interaction). These findings confirm other studies showing that ganglionic blockade markedly reduces LF blood pressure variability (17, 58) and is in line with the generally accepted notion that LF blood pressure variability is mainly depending on sympathetic, {alpha}-adrenergic receptor-mediated, modulation of vascular tone (21, 22, 32, 38).

HF spectral power of systolic blood pressure was significantly reduced by ganglionic blockade, whereas nifedipine did not change absolute HF blood pressure variability during both experimental conditions (2-way ANOVA: P < 0.05 for between factor, not significant for within factor and interaction).


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
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The findings that nifedipine dose dependently reduced VLF blood pressure variability and that the reduction in VLF blood pressure variability at the highest dose of nifedipine was 86% (from 7.1 ± 1.4 mmHg2 at baseline to 1.0 ± 0.3 mmHg2 at 5.0 mg·100 µl–1·h–1 of nifedipine) indicate that a major portion of VLF blood pressure variability is mediated by L-type Ca2+ channel-dependent mechanisms. In addition, the finding that ganglionic blockade markedly reduced VLF blood pressure variability and abolished the dose-dependent decline in VLF blood pressure variability suggests that sympathetic nerve activity elicits a permissive effect on VLF blood pressure variability.

These findings prompt the question as to which are the L-type Ca2+ channel-dependent mechanisms that elicit VLF blood pressure variability. L-type Ca2+ channels are fundamental for the myogenic vascular response (11, 12, 48, 55). In addition, the myogenic component of dynamic autoregulation of local blood flow in rats was found to be most effective at frequencies below 0.2 Hz in the renal (1, 9, 24, 30), below 0.13 Hz in the mesenteric (1), and below 0.1 Hz in the cerebral vascular beds (27). These frequencies correspond to the VLF band in rats. Thus myogenic vascular function may well be the major player in the mechanisms generating VLF blood pressure variability. However, L-type Ca2+ channels are also involved in the vascular actions of vasoactive substances, such as catecholamines (14, 28) and angiotensin II (29, 46). Thus, in addition to inhibition of myogenic vascular function, attenuation of the vascular actions of plasma catecholamines and angiotensin II may also contribute to the dose-dependent reduction in VLF blood pressure variability in response to nifedipine. In this regard, it is important to point out that VLF blood pressure variability represents a highly heterogeneous frequency band that has been demonstrated to be affected by intravenous catecholamine infusions (45), inhibition of the renin-angiotensin system (18, 43), hypovolemia (42), and heat stress (51). However, it is difficult to discern how nonoscillatory mechanisms, such as hypovolemia, heat stress, elevated plasma levels of catecholamines, or angiotensin II may elicit periodic fluctuations in blood pressure at very low frequencies.

We propose that VLF blood pressure variability is primarily generated by myogenic vascular responses to spontaneously occurring perturbations of arterial blood pressure. Under physiological conditions, perturbations of arterial blood pressure repeatedly occur due to arousal, exciting thoughts, visual, auditory, and tactile stimuli, and others. These perturbations of arterial blood pressure elicit myogenic vascular responses that cause active vasoconstrictions or vasodilatations. Subsequently, fluctuations in arterial blood pressure result from changes in total peripheral resistance. Because of the relatively slow time course of the myogenic vascular response (1, 9, 24, 30), these blood pressure fluctuations will manifest themselves as VLF blood pressure variability. The mystery that constant infusions of catecholamines (45) and inhibition of the renin-angiotensin system (18, 43) cause alterations in VLF blood pressure variability, even so plasma levels of catecholamines or angiotensin II are unlikely to fluctuate at very low frequencies under these experimental conditions, may be explained by the increase in myogenic vascular responsiveness elicited by catecholamines (3, 41, 54) and angiotensin II (19, 25, 47). In addition, the increase in VLF blood pressure variability observed during heat stress (51) and hypovolemia (42) may be secondary to increases in catecholamine and/or angiotensin II plasma levels under these conditions, which subsequently increase myogenic vascular responsiveness. This possibility is further supported by the finding that the increase in VLF blood pressure variability in response to intravenous infusions of catecholamines (during ganglionic blockade) reported by Radaelli et al. (45) was abolished by the L-type Ca2+ channel blocker nifedipine. Furthermore, the lower absolute VLF spectral power of systolic blood pressure at the lowest dose of nifedipine (0.01 mg·100 µl–1·h–1) during ganglionic blockade compared with control conditions in our study may as well reflect attenuated myogenic vascular responsiveness due to reduced circulating catecholamine levels during ganglionic blockade. On the basis of these findings, it is also conceivable that sympathetic nervous system activity elicits a permissive effect on VLF blood pressure variability via a catecholamine-induced increase in vascular myogenic responsiveness.

Our results also demonstrate that L-type Ca2+ channel-dependent mechanisms other than sympathetic modulation of vascular tone elicit little, if any, effects on LF blood pressure variability in rats, because nifedipine did not further reduce LF blood pressure variability after ganglionic blockade. In fact, ganglionic blockade effectively diminished LF blood pressure variability to a residual noise level, indicating that LF blood pressure variability mainly, if not completely, depends on the autonomic nervous system. However, the highest dose of nifedipine (5 mg·100 µl–1·h–1) reduced LF blood pressure variability to the same residual noise level as ganglionic blockade. We suggest that prolonged application of L-type Ca2+ channel blockers at high doses eliminates sympathetic modulation of vascular tone because sympathetic {alpha}-adrenergic-mediated vasoconstriction partly depends on L-type Ca2+ channels (14, 28) and because nifedipine depletes intracellular Ca2+ stores in smooth muscle via inhibition of L-type Ca2+ channels (15, 16, 37) and possibly by a mechanism independent of L-type Ca2+ channels in some types of arteries (10).

Another finding of our study deserves some thoughts. LF blood pressure variability was significantly reduced only at the second highest doses of nifedipine (1.0 mg·100 µl–1·h–1), whereas VLF blood pressure variability was already significantly reduced at the second lowest dose of the Ca2+ channel blocker (0.05 mg·100 µl–1·h–1). This finding indicates that VLF blood pressure variability is "relatively more" dependent on L-type Ca2+ channels than LF blood pressure variability. In addition, this finding is in line with our hypothesis that VLF blood pressure variability is primarily generated by myogenic vascular responses (that depend on L-type Ca2+ channels), whereas LF blood pressure variability is mediated by sympathetic modulation of vascular tone (that can occur in the presence of Ca2+ channel blockade if intracellular Ca2+ stores are not depleted). Interestingly, systolic blood pressure started to decrease only after the dose of nifedipine was raised above 0.1 mg·100 µl–1·h–1 during control conditions (Fig. 2). Obviously, at nifedipine doses below 0.5 mg·100 µl–1·h–1, compensatory mechanisms, including activation of the sympathetic nervous system, maintained blood pressure at its initial level. Thus enhanced sympathetic modulation of vascular tone may have contributed to the maintenance of LF blood pressure variability at nifedipine doses below 1.0 mg·100 µl–1·h–1 during control conditions.

Since transmission from sympathetic nerves to the vasculature is possible at low (0.2–0.6 Hz) frequencies (50, 52), it should also be possible at even lower frequencies such as the VLF band (0.02–0.2 Hz). Nevertheless, it appears that direct sympathetic modulation of vascular tone leading to corresponding fluctuations in blood pressure does not occur in the VLF band under physiological conditions. In addition to the data presented in the current set of experiments, this conclusion is also supported by previous studies. The gain of the transfer function between splanchnic sympathetic nerve activity and vascular resistance in the mesenteric vascular bed (that is innervated by the splanchnic nerve) in conscious rats revealed a maximum in the LF band (at 0.5 Hz) that was abolished by ganglionic blockade, indicating that sympathetic modulation of vascular tone causes LF blood pressure variability. In the VLF band, the gain of this transfer function was very low and not different between control conditions and ganglionic blockade (52), indicating that sympathetic modulation of vascular tone does not occur in the VLF band.

Therefore, one may ask why sympathetic modulation of vascular tone does not occur in the VLF band under physiological conditions. We speculate that the vasculature would be able to respond to VLF sympathetic nerve discharges with corresponding fluctuations in vascular resistance. However, sympathetic discharge patterns may simply not contain oscillatory components in the VLF range under physiological conditions. Two major mechanisms have been suggested to elicit periodic discharge patterns in sympathetic nerve activity. First, it has been demonstrated that in rats, the arterial baroreceptor reflex exhibits a resonance frequency at 0.42 Hz, close to the frequency of spontaneously occurring Mayer waves (6). Such a resonance phenomenon can generate regular, self-sustained oscillations of arterial pressure (20). Second, oscillators in the central nervous system modulating autonomic nervous system outflow to the periphery can generate periodic discharge patterns of sympathetic nerve activity. Under physiological conditions, the central sympathetic oscillator appears to be entrained to the respiratory oscillator (4, 8, 26). Thus, under physiological conditions, the resonance phenomenon of the baroreceptor reflex operates in the LF band and the central nervous system oscillator generates sympathetic nerve discharge patterns at the respiratory frequency (HF band) that are too fast to be translated into corresponding fluctuations of vascular tone and arterial blood pressure (50, 52). Thus the mechanisms generating oscillatory discharge patterns of sympathetic nerve activity are in line with our suggestion that sympathetic nerve discharge patterns do not contain oscillatory components in the VLF band under physiological conditions.

Blood pressure variability has been identified as a cardiovascular risk factor that is independent of the level of arterial blood pressure (35, 39, 57). From this finding, it has been suggested that antihypertensive drugs may be even more beneficial if they reduce not only the mean level of arterial blood pressure but also its variability (33, 34, 40). Furthermore, different components of blood pressure variability may affect cardiovascular risk differently. For example, Sega et al. (49) reported a positive association between cardiac left ventricular mass index and blood pressure variability that was limited to erratic rather than cyclic components of blood pressure variability (49). In our study, 50–60% of total blood pressure variability was confined in the VLF range during control conditions. Since VLF blood pressure variability was found to be largely mediated by Ca2+ channel-dependent mechanisms, Ca2+channel blockers may be very effective in reducing blood pressure variability and, therefore, may be highly cardioprotective drugs. Indeed, treatment of spontaneously hypertensive rats with a combination of the Ca2+ channel blocker nitrendipine and the beta-blocker atenolol ameliorated cardiac and vascular hypertrophy (56), while no organ protection was observed by antihypertensive treatment with hydralazine (13). Furthermore, multiple regression analysis demonstrated that the beneficial effects of the drug combination of nitrendipine and atenolol are related to reduced overall blood pressure variability (56). Further studies are needed to investigate the effect of specific spectral components of blood pressure variability on end-organ damage and on the impact of different classes of antihypertensive drugs on specific components of blood pressure variability.

In conclusion, our study demonstrates that VLF blood pressure variability largely depends on L-type Ca2+ channel-dependent mechanisms. We propose that under physiological conditions, VLF blood pressure variability is generated by myogenic vascular responses to spontaneously occurring perturbations of arterial blood pressure. We further propose that the sympathetic nervous system elicits its actions on VLF blood pressure variability by a catecholamine-induced increase in vascular myogenic responsiveness, whereas sympathetic effects on LF blood pressure variability are mediated by periodic discharge patterns of peripheral sympathetic nerves, innervating the vasculature.


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This research was supported by a grant from the American Heart Association (AHA Grant 0630329N) and a generous start-up package provided to H. M. Stauss by the College of Liberal Arts and Sciences at The University of Iowa.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. M. Stauss, Dept. of Integrative Physiology, The Univ. of Iowa, 410 Field House, Iowa City, IA 52242 (e-mail: harald-stauss{at}uiowa.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
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 DISCUSSION
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