Published online before print August 18, 2008, doi: 10.1161/HYPERTENSIONAHA.108.114355
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(Hypertension. 2008;52:702.)
© 2008 American Heart Association, Inc.
Original Articles |
Role of the Multidomain Protein Spinophilin in Blood Pressure and Cardiac Function Regulation
From the Max Delbrück Center for Molecular Medicine (A.C.d.C.G., R.P., M.T., A.H., M.W., M.B., F.C.L., V.G.), Berlin, Germany; the Institute of Clinical Pharmacology (J.T., J.J.), Hannover Medical School, Hannover, Germany; the Department of Medicine (A.D.), Division of Clinical Pharmacology, Autonomic Dysfunction Service, Vanderbilt University School of Medicine, Nashville, Tenn; the Charite University Medicine (M.G.), Section Nephrology/Intensive Care; and the Medical Faculty of the Charite (F.C.L.), Franz Volhard Clinic, HELIOS Klinikum, Berlin, Germany.
Correspondence to Volkmar Gross, MD, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. E-mail vgross{at}mdc-berlin.de
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Abstract |
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Spinophilin controls intensity/duration of G protein-coupled receptor signaling and thereby influences synaptic activity. We hypothesize that spinophilin affects blood pressure through central mechanisms. We measured blood pressure and heart rate in SPL-deficient (SPL–/–), heterozygous SPL-deficient (SPL+/–), and wild-type (SPL+/+) mice by telemetry combined with fast Fourier transformation. We also assessed peripheral vascular reactivity and performed echocardiography. SPL–/– had higher mean arterial pressure than SPL+/– and SPL+/+ (121±2, 112±1, and 113±1 mm Hg). Heart rate was inversely related to spinophilin expression (SPL–/– 565±0.4, SPL+/– 541±5, SPL+/+ 525±8 bpm). The blood pressure response to prazosin, trimethapane, and the heart rate response to metoprolol were stronger in SPL–/– than SPL+/+ mice, whereas heart rate response to atropine was attenuated in SPL–/–. Mesenteric artery vasoreactivity after angiotensin II, phenylephrine, and the thromboxane mimetic (U46619) as well as change in heart rate, stroke volume, and cardiac output after dobutamine were similar in SPL–/– and SPL+/+. Baroreflex sensitivity was attenuated in SPL–/– compared with SPL+/– and SPL+/+, which was confirmed by pharmacological testing. Heart rate variability parameters were attenuated in SPL–/– mice. We suggest that an increase in central sympathetic outflow participates in blood pressure and heart rate increases in SPL–/– mice. The elevated blood pressure in SPL–/– mice was associated with attenuated baroreflex sensitivity and decreased parasympathetic activity. Our study is the first to show a role for the spinophilin gene in blood pressure regulation.
Key Words: autonomic nervous system • blood pressure regulation • spectral analysis • spinophilin-deficient mice • telemetry
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Introduction |
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The intensity and duration of G protein-coupled receptor (GPCR) signaling are regulated by small interacting proteins, including regulators of G protein signaling (RGS) and spinophilin (SPL). RGS2 accelerates guanosine triphosphatase activity, terminates GPCR-dependent signaling,1,2 and thereby affects blood pressure (BP) control in the whole animal.3–7 SPL also regulates GPCRs, which results in signal attenuation, at least in
-adrenoreceptors (-AR).8,9 Furthermore, SPL recruits RGS proteins to the GPCR complex10 and thereby increases the efficiency of RGS2 on Ca2+ signaling blockade after -AR stimulation. In this way, SPL deletion should have similar effects on BP regulation as RGS2 deletion. However, the mechanisms by which SPL affects BP regulation may be different from those described for RGS2. SPL is especially enriched in neuronal dendritic spines and is involved in the regulation of spine density and synaptic activity, including glutamatergic transmission.11 Glutamate transmission is believed to play an important role for regulating sympathetic outflow and autonomic control of the cardiovascular system through the nucleus tractus solitarii.12–14 We hypothesized that SPL influences BP regulation mainly by modulating central sympathetic/parasympathetic outflow. We measured BP and heart rate (HR) in unrestrained homozygous SPL-deficient (SPL–/–), heterozygous SPL-deficient (SPL+/–), and wild-type (SPL+/+) mice by telemetry combined with fast Fourier transform analysis of mean arterial BP (MAP) and HR to describe spontaneous baroreflex and HR variability (HRV) coupled with pharmacological autonomic testing. We also assessed peripheral vascular reactivity in SPL–/– and SPL+/+ mice and performed echocardiography. |
Methods |
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Animals
The experiments were performed in adult, 12- to 16-week-old C57Bl6/129SvJ male SPL–/– mice weighing 24±0.5 g, male SPL+/– mice weighing 25±1 g, and male SPL+/+ mice weighing 25±0.5 g. The generation of SPL-deficient mice was described by Feng et al.11 All animals used in this study were derived from breeder pairs supplied through the courtesy of Dr P. Greengard (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY) and Dr P. B. Allen (Department of Psychiatry, Yale University School of Medicine, New Haven, Conn) and were bred in our animal facility. The animals were allowed free access to standard chow (0.25% sodium; SNIFF Spezialitäten GmbH, Soest, Germany) and drinking water ad libitum. The local council on animal care approved the study according to requirements of the American Physiological Society. Our approaches to radiotelemetry, spectral analysis, baroreflex sensitivity, pharmacological testing, behavioral stress, vascular reactivity, echocardiography, and biostatistics have been described earlier.3,4,6 Details are available in the online data supplement (see http://hyper.ahajournals.org).
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Results |
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Blood Pressure and Heart Rate in Conscious SPL–/–, SPL+/–, and SPL+/+ Mice
In Figure 1, day/night MAP (upper panel, left), HR values (lower panel, left), and the averages for the 12 hours day and night MAP (upper panel, right) and HR (lower panel, right) values calculated over 3 days in SPL–/–, SPL+/–, and SPL+/+ mice are given. Both parameters showed clear-cut day/night rhythm. SPL–/– mice had increased MAP during the day (119±3 versus 109±3 and 109±2 mm Hg) and night (129±3 versus 119±2 or 118±2 mm Hg), compared with SPL+/+ or SPL+/– mice. HR was also higher in SPL–/– (day: 542±14, night: 592±17 bpm) compared with SPL+/+ (day: 488±9, night: 527±12 bpm) and SPL+/– (day: 503±20, night: 550±7 bpm). Whereas BP levels in SPL+/+ and SPL+/– were similar, HR increased continuously from SPL+/+ to SPL–/– mice.
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Baroreflex Function and Heart Rate Variability
Baroreflex sensitivity (BRS) calculated by cross-spectral analysis in the low-frequency (LF) band (BRS-LF) or with the sequence method (BRS-up) revealed a stepwise decrease of this parameter from SPL+/+ to SPL–/– (Figure 2, left and middle panels). BRS-up leveled in SPL–/– 1.2±0.1, in SPL+/– 2.0±0.0.4, and in SPL+/+ 2.5±0.3 ms/mm Hg. The respective values for BRS-LF were in SPL–/– 2.2±0.3, in SPL+/– 3.5±0.8, and in SPL+/+ mice 4.4±0.5 ms/mm Hg. LF of HR spectra (LF-HRV) were strongly attenuated in SPL–/– (SPL–/– 7.3±2.1, SPL+/– 29.9±11.6, SPL+/+ 42.1±7.8; Figure 2, right panel). Total power (SPL+/+ 70.0±9.5 ms2, SPL–/– 34.1±5.8 ms2) and root mean square of successive differences (SPL+/+ 7.1±0.7 ms, SPL–/– 3.6±0.3 ms) were also lower in SPL–/– mice (Figure S1).
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Pharmacological Testing
We blockaded peripheral 1-adrenergic receptors with prazosin (Figure 3, upper left panel) and used ganglionic blockade with trimethaphane to investigate the sympathetic drive to the periphery (Figure 3, lower left panel). Prazosin at 0.5 and 1 mg/kg decreased MAP more in SPL–/– (
MAP 10±2 and 16±2 mm Hg) than in SPL+/+ mice ( MAP 3±1 and 6±3 mm Hg). Trimethaphane at 120 mg/kg decreased MAP in SPL–/– more than in SPL+/+ ( MAP 33±3 versus 17±4 mm Hg). Metoprolol at 8 mg/kg (Figure 3, upper right panel) decreased HR stronger in SPL–/– ( HR 69±5 bpm) than in SPL+/+ mice ( HR 38±9 bpm). The increase in HR after 4 mg/kg atropine (Figure 3, lower right panel) was smaller in SPL–/– mice ( HR 78±5 bpm) than in SPL+/+ mice ( HR 119±5 bpm).
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Pharmacological Baroreflex
To assess BRS, HR responses to BP increases induced by intravenous bolus injection of phenylephrine (PE) at doses of 2.5, 5, and 10 µg/kg were measured in SPL–/– and SPL+/+ mice. The HR decrease ( HR) relative to the prestimulation level in response to the increase in MAP ( MAP) was obtained and averaged for each PE dose. The dose-dependent slopes of the baroreflex function ( HR/ MAP) for SPL–/– and SPL+/+ mice are shown (Figure 4). Whereas at 2.5 µg/kg, PE HR/ MAP was not different between SPL–/– (2.7±0.5 ms/mm Hg) and SPL+/+ (3.2±0.8 ms/mm Hg) mice, at 5 and 10 µg/kg PE, the quotient HR/ MAP was significantly lower in SPL–/– mice compared with SPL+/+ mice. In SPL–/– mice, HR/ MAP leveled at 0.9±1.3 ms/mm Hg (5 µg/kg PE) and 3.9±1.2 ms/mm Hg (10 µg/kg PE). The respective values for SPL+/+ mice were 6.4±2.3 ms/mm Hg and 10.1±3.2 ms/mm Hg.
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Behavioral Stress Reaction
MAP increased initially in SPL–/– mice to 138±2 and in SPL+/+ mice to 140±2 mm Hg and declined thereafter in the new environment. In SPL–/– mice, the values decreased during the first 40 minutes to 127±1 mm Hg in SPL–/– and in SPL+/+ mice to 110±1 mm Hg. The BP changes were expressed in percentage of the maximum response for each mouse. The BP decline was slower in SPL–/– than in SPL+/+ mice, as shown by the different slopes (Figure S2, upper panel). The HR increased initially in SPL+/+ mice to 683±10 and in SPL–/– mice to 694±5 bpm. The decline, calculated with absolute HR values (SPL+/+ 471±10, SPL–/– mice 560±15 bpm) or as percentage of maximum HR increase, was also different between the groups (Figure S2, lower panel).
Vascular Reactivity
The dose–response curves for angiotensin II (upper panel), for PE (middle panel), and for U46619 (lower panel) were not changed in mesenteric arteries from SPL–/– compared with SPL+/+ mice (Figure S3).
Stress-Echocardiography
Echocardiographic parameters describing left ventricular geometry and the reaction of left ventricular function to sympathetic stimulation with dobutamine (stroke volume, HR, and cardiac output) were not different between SPL–/– and SPL+/+ mice (Table S1).
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Discussion |
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The basic observation in our study was that disruption of the spl gene in mice increases BP and HR and impairs autonomic BP regulation. SPL–/– mice showed a stronger HR decrease after β1-AR blockade, a stronger decrease of BP after ganglionic and
1-AR blockade, and a decrease of BRS. On the other hand, no differences in both the vasoreactivity of isolated mesenteric arteries to vasoconstrictors and in the reaction of left ventricular function to dobutamine stimulation were found. These findings suggest a centrally increased sympathetic tone and an increased peripheral vascular resistance in spl gene-deleted mice compared with controls.
Small interacting proteins regulate the intensity and duration of GPCR signaling. SPL modulates at least 2 subfamilies of GPCR, the 2-AR and the D2 dopamine receptor,15–18 by blocking G protein receptor kinase and thereby attenuating receptor phosphorylation.9 Furthermore, SPL regulates GPCR signaling by recruiting RGS proteins and thereby reduces the intensity of Ca2+ signaling.10 In this way, SPL deletion has similar effects as RGS2 deletion. In accord with this view, SPL–/– mice displayed approximately 10 mm Hg higher BP during day and night than SPL+/+ mice. This BP increase was similar to what we observed in RGS2–/– mice3 and was not associated with cardiac hypertrophy, at least in the timeframe of our study. We also found that SPL+/– mice had similar BP values compared with SPL+/+ mice, which suggests that the loss of one spl gene copy was compensated.
The most likely explanation for the BP increase in SPL–/– mice is an increase in total peripheral resistance, because SPL–/– mice showed a stronger BP decrease after 1-AR blockade with prazosin than SPL+/+ mice. However, the sensitivity of mesenteric vessels to PE and other vasoconstrictors was not different between SPL–/– and SPL+/+ mice. Echocardiographic data at rest and HR, stroke volume, and cardiac output after dobutamine stimulation were not different in SPL–/– and SPL+/+ mice.
We attribute the stronger decrease in BP after 1-AR blockade in SPL–/– mice to an increased sympathetic tone rather than to increased sensitivity and/or number of 1-AR in the peripheral vasculature. This view is supported by the stronger effects of ganglionic blockade in SPL–/– than SPL+/+ mice. In this respect, SPL–/– mice were different from RGS2–/– mice, in which we found an increased vascular sensitivity to vasoconstrictors.4 Moreover, the BP increase in SPL–/– mice was associated with an increase of HR, a combination that is typically found when the sympathetic arm of the autonomic nervous system is activated.19
In mice with overexpression of cardiac Gs, similar to SPL–/–, an elevated HR and BP was described and discussed as enhanced β-adrenergic signaling.20 Besides this issue, we found a stronger decrease in HR after β1-adrenergic blockade in SPL–/– mice than SPL+/+ mice. This sympathetic activation in SPL–/– mice may also be responsible for the exaggerated response of SPL–/– to environmental stress. MAP and HR declined more slowly in SPL–/– than in SPL+/+ when the mice were placed in a new environment.
To provide further insight into autonomic control of the cardiovascular system in SPL–/– mice, we used HRV and determined spontaneous BRS. Spontaneous BRS, calculated with the sequence technique and with spectral function analysis of spontaneous changes in systolic blood pressure and HR, was decreased in SPL–/– mice. Blunted baroreceptor reflex HR control has been described as a characteristic response in hypertension with high sympathetic tone,21,22 a combination we observed in the SPL–/– mice. The change in HR regulation was also reflected in the LF-HRV data. In humans, LF of HRV is predominantly influenced by the sympathetic tone, whereas the high-frequency component of HRV is mainly vagally controlled. On the contrary, in mice, high-frequency oscillations are at least a part of mechanical origins, whereas LF oscillations of HRV are mainly under parasympathetic control.3,23–25 Because LF-HRV was decreased in SPL–/– mice, we suggest a decreased parasympathetic activity in these mice. Furthermore, SPL–/– showed a reduction in root mean square of successive differences and a smaller BP decrease after atropine than SPL+/+ mice, which underlines this assumption. Experimental and clinical evidence has been provided that an increase in sympathetic activity contributes to a decrease in BRS.26–28 Therefore, the attenuated BRS in SPL–/– mice could be caused by an increase in sympathetic tone and/or a decrease in parasympathetic tone in these mice.
The spontaneous baroreflex describes the BRS at the operating point of the BP and may differ from the maximum baroreflex gain. To validate spontaneous BRS as a valid parameter describing the baroreflex in mice, we measured changes in MAP and HR to increasing concentrations of PE. The baroreflex gain of this pharmacological baroreflex was also attenuated in SPL–/– mice. To our knowledge, this is the first study that compared both methods in mice. This result underlines the validity of spontaneous BP and HR changes to characterize BRS in conscious mice as previously shown in humans.29,30
The mechanism of increased central sympathetic tone in SPL–/– mice is an open question. SPL attenuates signaling of 2-AR,9 including the 2A-ARs, which are mainly responsible for central sympathetic outflow. Deletion of the spl gene should result in prolongation of 2-AR activation with the result of a decrease in sympathetic drive and a reduction in BP and HR. This view is not supported by our results.
Stimulation of N-methyl-D-aspartic acid receptors within the paraventricular nucleus increases sympathetic tone, which is associated with an increase of BP and HR.12,31 Activation of 1-ARs or 2-ARs inhibits N-methyl-D-aspartic acid receptor currents. SPL selectively facilitates RGS2/4 modulation of 1-AR effects on N-methyl-D-aspartic acid receptor currents.32 We speculate that deletion of the spl gene attenuates the RGS2/4 effect and decrease 1-ARs dependent inhibition of N-methyl-D-aspartic acid receptors. As a consequence, centrally originated sympathetic tone could increase. Another binding partner of SPL is protein phophatase-1,33 which modulates the activity of a variety of ion channels, thereby affecting receptors, including the glutamate receptor.11,33,34 Glutamate receptors are involved in cardiovascular reflexes and play a role in regulating sympathetic tone and cardiovascular function.12
Our data suggest that an increase in the sympathetic peripheral outflow to the resistance vessels plays a role for increase of BP and HR in SPL–/– mice. The elevated BP in SPL–/– mice was associated with an attenuated baroreceptor reflex and compromised parasympathetic activity. Despite the pathways and the cellular mechanisms into how SPL affects BP regulation are not defined, our study is the first to show that the spl gene is involved in BP regulation. Taking into consideration that an increased sympathetic outflow plays an important role in hypertension and that stimulation of cardiac nerves is thought to be a powerful predictor of death in heart failure, a reduced expression of SPL may contribute to the changes in BP regulation through the autonomic nervous system and thereby contribute to an increase of BP.
Perspectives
Our data serve to add spl to the list of genes important for BP regulation and probably the development of hypertension. The cardiovascular function of the human homolog should be pursued.
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Acknowledgments |
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We thank Ilona Kamer (Max Delbrück Center for Molecular Medicine, Berlin, Germany) and Diana Herold (Charite University Medicine, Section Nephrology/Intensive Care and Franz Volhard Clinic at the MDC) for technical assistance.
Source of Funding
The Deutsche Forschungsgemeinschaft supported this study (Gr 1112/13-1; Go 766/5-5).
Disclosures
None.
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Footnotes |
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The first 2 authors contributed equally.
Presented in part at the ESH/ISH Congress 2008 Berlin, Germany, as well as at EUROBAVAR 2008, Brussels, Belgium.
Received April 4, 2008; first decision April 23, 2008; accepted July 24, 2008.
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