on August 18, 2008
Published online before print August 18, 2008, doi: 10.1161/HYPERTENSIONAHA.108.114355
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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. * To whom correspondence should be addressed. E-mail: vgross{at}mdc-berlin.de.
Abstract—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.
Role of the Multidomain Protein Spinophilin in Blood Pressure and Cardiac Function Regulation
Andrey C. da Costa-Goncalves;
Key words: autonomic nervous system • blood pressure regulation • spectral analysis • spinophilin-deficient mice • telemetry
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