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.