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Central angiotensin II (AngII) plays an important role in the regulation of the sympathetic nervous system. The underlining molecular mechanisms are largely unknown. Spinophilin (SPL) is a regulator of G protein-coupled receptor signaling. Deletion of SPL induces sympathetically mediated arterial hypertension in mice. We tested the hypothesis that SPL restrains blood pressure (BP) by regulating AngII activity. We equipped SPL(-/-) and SPL(+/+) mice with telemetric devices and applied AngII (1.0 mg kg(-1) day(-1), minipumps) or the AngII subtype 1 receptor (AT1-R) blocker valsartan (50 mg kg(-1) day(-1), gavage). We assessed autonomic nervous system activity through intraperitoneal application of trimethaphan, metoprolol, and atropine. We also tested the effect of intracerebroventricular (icv) AngII on blood pressure in SPL(-/-) and in SPL(+/+) mice. Chronic infusion of AngII upregulates SPL expression in the hypothalamus of SPL(+/+) mice. Compared with SPL(+/+) mice, SPL(-/-) mice showed a greater increase in daytime BP with AngII (19.2 ± 0.8 vs. 13.5 ± 1.6 mmHg, p < 0.05). SPL(-/-) showed a greater depressor response to valsartan. BP and heart rate decreased more with trimethaphan and metoprolol in AngII-treated SPL(-/-) than in AngII-treated SPL(+/+) mice. SPL(-/-) mice responded more to icv AngII. Furthermore, brainstem AT1-R and AngII type 2 receptor (AT2-R) expression was reduced in SPL(-/-) mice. AngII treatment normalized AT1-R and AT2-R expression levels. In summary, our findings suggest that SPL restrains AngII-mediated sympathetic nervous system activation. SPL is a hitherto unrecognized molecule with regard to central blood pressure control and may pave the way to novel strategies for the treatment of hypertension.

Angiotensin II (Ang II) activates signalling pathways predominantly through the G-protein-coupled Ang II type 1 receptor (AT(1)R). The regulator of G protein signalling 2 (RGS2) is a negative G protein regulator. We hypothesized that RGS2 deletion changes blood pressure regulation by increasing the response to Ang II. To address this issue, we infused Ang II (0.5 mg kg(-1) day(-1)) chronically into conscious RGS2-deleted (RGS2(-/-)) and wild-type (RGS2(+/+)) mice, measured mean arterial blood pressure and heart rate (HR) with telemetry and assessed vasoreactivity and gene expression of AT(1A), AT(1B) and AT(2) receptors. Angiotensin II infusion increased blood pressure more in RGS2(-/-) than in RGS2(+/+) mice, while HR was not different between the groups, indicating a resetting of the baroreceptor reflex. Urinary catecholamine excretion was similar in Ang II-infused RGS2(-/-) and RGS2(+/+) mice, indicating a minor role of sympathetic tone for blood pressure differences. Myogenic tone and vasoreactivity in response to Ang II, endothelin-1 and phenylephrine were increased in isolated renal interlobar arterioles of RGS2(-/-) mice compared with RGS2(+/+) mice. The AT(1A), AT(1B) and AT(2) receptor gene expression was not different between RGS2(-/-) and RGS2(+/+) mice. Our findings suggest that RGS2 deletion promotes Ang II-dependent hypertension primarily through an increase of myogenic tone and vasoreactivity, probably by sensitization of AT(1) receptors.