Autonomic nervous system and blood pressure regulation in RGS2-deficient mice

Abstract

. Autonomic nervous system and blood pressure regulation in RGS2-deficient mice. Am J Physiol Regul Integr Comp Physiol 288: R1134-R1142, 2005. First published January 20, 2005; doi:10.1152/ajpregu.00246.2004.-Regulator of G protein signaling (RGS2) deletion in mice prolongs signaling by G protein-coupled vasoconstrictor receptors and increases blood pressure. However, the exact mechanism of the increase in blood pressure is unknown. To address this question we tested autonomic nervous system function and blood pressure regulation in RGS2-deficient mice (RGS2 Ϫ/Ϫ). We measured arterial blood pressure and heart rate (HR) with telemetry, computed time and frequency-domain measures for blood pressure and HR variability (HRV) as well as baroreflex sensitivity [BRS-low frequency (LF)], and assessed environmental stress sensitivity. Mean arterial blood pressure (MAP) was ϳ10 mmHg higher in RGS2 Ϫ/Ϫ compared with RGS2 ϩ/ϩ mice, while HR was not different between the groups, indicating a resetting of the baroreceptor reflex. Atropine increased MAP more in RGS2 Ϫ/Ϫ than in RGS2 ϩ/ϩ mice while HR responses were not different. Urinary norepinephrine excretion was higher in RGS2 Ϫ/Ϫ than in RGS2 ϩ/ϩ mice. The blood pressure decrease following prazosin was more pronounced in RGS2 Ϫ/Ϫ mice than in RGS2 ϩ/ϩ mice. The LF and high-frequency (HF) power of HRV were reduced in RGS2 Ϫ/Ϫ compared with controls while BRS-LF and SBP-LF were not different. Atropine and atropine ϩ metoprolol markedly reduced the HRV parameters in the time (RMSSD) and frequency domain (LF, HF, LF/HF) in both strains. Environmental stress sensitivity was increased in RGS2 Ϫ/Ϫ mice compared with controls. We conclude that the increase in blood pressure in RGS2 Ϫ/Ϫ mice is not solely explained by peripheral vascular mechanisms. A central nervous system mechanism might be implicated by an increased sympathetic tone. This state of affairs could lead to a baroreceptor-HR reflex resetting, while BRS remains unimpaired.G protein-coupled receptors; RGS2-deficient mice; autonomic nervous system; heart rate variability; spectral analysis; baroreflex; telemetry G PROTEIN-COUPLED RECEPTORS (GPCRs) are important in cardiovascular regulation. Hormones such as norepinephrine, epinephrine, endothelin-1, thrombin, ANG II, and serotonin all bind to GPCRs to stimulate G protein-signaling cascades. The binding to G␣q-coupled receptors results in activation of a cascade that causes vasoconstriction (37). The duration and intensity of G␣q-coupled receptor signaling is regulated by GTPase-activating proteins (GAPs), which accelerate the return of the activated G␣ subunit to its inactive form. Regulators of G protein signaling (RGS) proteins are components of the G protein-coupled receptor signaling pathway, and RGS2 is a potent regulator of G␣q (10). RGS2 accelerates the rate of G protein deactivation by stimulating GTP hydrolysis. As a result, disruption of the RGS2 gene in mice increased blood pressure and markedly prolonged vasoconstrictor responses of the peripheral resistan...

Selective Loss of Fine Tuning of Gq/11 Signaling by RGS2 Protein Exacerbates Cardiomyocyte Hypertrophy

“…Targeted deletion of RGS2 in mice leads to a hypertensive phenotype, presumably due to prolonged G q/11 signaling and vasoconstriction in the vasculature (51,52). Central nervous mechanisms (an enhanced sympathetic tone that could lead to a resetting of the baroreceptor reflex) appear to also contribute to blood pressure elevation in this model (53). To date, very little is known about the cardiac phenotype of RGS2KO.…”

Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

“…After recovery for 15 days, data were recorded under baseline conditions. Autonomic nerve activity was assessed by monitoring spontaneous changes in blood pressure and heart rate as described earlier (41).…”

Identification of a cAMP-response Element in the Regulator of G-protein Signaling-2 (RGS2) Promoter as a Key Cis-regulatory Element for RGS2 Transcriptional Regulation by Angiotensin II in Cultured Vascular Smooth Muscles

“…8A). These observations raise the possibility that the three human RGS2 SNPs might negatively affect RGS2 mRNA expression, which might be expected to predispose to hypertension by analogy with effects of reduced RGS2 expression on blood pressure in genetically modified mice (3)(4)(5)(6)(7).…”

“…RGS2 is expressed ubiquitously, and its major biological function is to serve as a GTPase-activating protein that preferentially attenuates heterotrimeric G protein G␣ q/11 GTPase activity (2). Several independent studies have demonstrated that Rgs2 knock-out mice have severe hypertension (3)(4)(5)(6)(7), suggesting that RGS2 plays a critical role in blood pressure homeostasis. Interestingly, heterozygous Rgs2 knockout mice are also hypertensive, and their blood pressures are virtually identical to homozygous Rgs2 knock-out mice (3), indicating that two functional Rgs2 alleles are required for normal blood pressure homeostasis.…”