NO-dependent Blood Pressure Regulation in RGS2-deficient Mice

Overview

Journal Am J Physiol Regul Integr Comp Physiol

Publisher American Physiological Society

Specialty Physiology

Date 2005 Nov 5

PMID 16269576

Citations 11

Authors

Michael Obst

Jens Tank

Ralph Plehm

Kendall J Blumer

Andre Diedrich

Jens Jordan

Friedrich C Luft

Volkmar Gross

Affiliations

Soon will be listed here.

Abstract

The regulator of G protein signaling (RGS) 2, a GTPase-activating protein, is activated via the nitric oxide (NO)-cGMP pathway and thereby may influence blood pressure regulation. To test that notion, we measured mean arterial blood pressure (MAP) and heart rate (HR) with telemetry in N(omega)-nitro-l-arginine methyl ester (l-NAME, 5 mg l-NAME/10 ml tap water)-treated RGS2-deficient (RGS2(-/-)) and RGS2-sufficient (RGS2(+/+)) mice and assessed autonomic function. Without l-NAME, RGS2(-/-) mice showed during day and night a similar increase of MAP compared with controls. l-NAME treatment increased MAP in both strains. nNOS is involved in this l-NAME-dependent blood pressure increase, since 7-nitroindazole increased MAP by 8 and 9 mmHg (P < 0.05) in both strains. The l-NAME-induced MAP increase of 14-15 mmHg during night was similar in both strains. However, the l-NAME-induced MAP increase during the day was smaller in RGS2(-/-) than in RGS2(+/+) (11 +/- 1 vs. 17 +/- 2 mmHg; P < 0.05). Urinary norepinephrine and epinephrine excretion was higher in RGS2(-/-) than in RGS2(+/+) mice. The MAP decrease after prazosin was more pronounced in l-NAME-RGS2(-/-). HR variability parameters [root mean square of successive differences (RMSSD), low-frequency (LF) power, and high-frequency (HF) power] and baroreflex sensitivity were increased in RGS2(-/-). Atropine and atropine plus metoprolol markedly reduced RMSSD, LF, and HF. Our data suggest an interaction between RGS2 and the NO-cGMP pathway. The blunted l-NAME response in RGS2(-/-) during the day suggests impaired NO signaling. The MAP increases during the active phase in RGS2(-/-) mice may be related to central sympathetic activation and increased vascular adrenergic responsiveness.

Citing Articles

cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice.

Shvedova M, Litvak M, Roberts Jr J, Fukumura D, Suzuki T, Sencan I J Cereb Blood Flow Metab. 2019; 39(12):2379-2391.

PMID: 31423931 PMC: 6893979. DOI: 10.1177/0271678X19870583.

Anti-hypertensive mechanisms of cyclic depsipeptide inhibitor ligands for G class G proteins.

Meleka M, Edwards A, Xia J, Dahlen S, Mohanty I, Medcalf M Pharmacol Res. 2019; 141:264-275.

PMID: 30634050 PMC: 6417918. DOI: 10.1016/j.phrs.2019.01.012.

Digoxin-Mediated Upregulation of RGS2 Protein Protects against Cardiac Injury.

Sjogren B, Parra S, Atkins K, Karaj B, Neubig R J Pharmacol Exp Ther. 2016; 357(2):311-9.

PMID: 26941169 PMC: 4851323. DOI: 10.1124/jpet.115.231571.

Regulation of Gβγi-dependent PLC-β3 activity in smooth muscle: inhibitory phosphorylation of PLC-β3 by PKA and PKG and stimulatory phosphorylation of Gαi-GTPase-activating protein RGS2 by PKG.

Nalli A, Kumar D, Al-Shboul O, Mahavadi S, Kuemmerle J, Grider J Cell Biochem Biophys. 2014; 70(2):867-80.

PMID: 24777815 PMC: 4184950. DOI: 10.1007/s12013-014-9992-6.

Neuropeptide y gates a stress-induced, long-lasting plasticity in the sympathetic nervous system.

Wang Q, Wang M, Whim M J Neurosci. 2013; 33(31):12705-17.

PMID: 23904607 PMC: 3728685. DOI: 10.1523/JNEUROSCI.3132-12.2013.

References

Just A, Faulhaber J, Ehmke H . Autonomic cardiovascular control in conscious mice. Am J Physiol Regul Integr Comp Physiol. 2000; 279(6):R2214-21. DOI: 10.1152/ajpregu.2000.279.6.R2214. View

Zhong H, Neubig R . Regulator of G protein signaling proteins: novel multifunctional drug targets. J Pharmacol Exp Ther. 2001; 297(3):837-45. View

Picker O, Scheeren T, ARNDT J . Nitric oxide synthases in vagal neurons are crucial for the regulation of heart rate in awake dogs. Basic Res Cardiol. 2001; 96(4):395-404. DOI: 10.1007/s003950170048. View

Patel K, Li Y, Hirooka Y . Role of nitric oxide in central sympathetic outflow. Exp Biol Med (Maywood). 2001; 226(9):814-24. DOI: 10.1177/153537020122600902. View

Westermann J, Hubl W, Kaiser N, Salewski L . Simple, rapid and sensitive determination of epinephrine and norepinephrine in urine and plasma by non-competitive enzyme immunoassay, compared with HPLC method. Clin Lab. 2002; 48(1-2):61-71. View

Janssen B, Smits J . Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification. Am J Physiol Regul Integr Comp Physiol. 2002; 282(6):R1545-64. DOI: 10.1152/ajpregu.00714.2001. View

Gross V, Plehm R, Tank J, Jordan J, Diedrich A, Obst M . Heart rate variability and baroreflex function in AT2 receptor-disrupted mice. Hypertension. 2002; 40(2):207-13. DOI: 10.1161/01.hyp.0000027279.69240.75. View

Obst M, Gross V, Janke J, Wellner M, Schneider W, Luft F . Pressure natriuresis in AT(2) receptor-deficient mice with L-NAME hypertension. J Am Soc Nephrol. 2003; 14(2):303-10. DOI: 10.1097/01.asn.0000043904.26730.11. View

Heximer S, Knutsen R, Sun X, Kaltenbronn K, Rhee M, Peng N . Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J Clin Invest. 2003; 111(4):445-52. PMC: 151918. DOI: 10.1172/JCI15598. View

10.

Tang K, Wang G, Lu P, Karas R, Aronovitz M, Heximer S . Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med. 2003; 9(12):1506-12. DOI: 10.1038/nm958. View

11.

Kawabata A, Kubo S, Nakaya Y, Ishiki T, Kuroda R, Sekiguchi F . Distinct roles for protease-activated receptors 1 and 2 in vasomotor modulation in rat superior mesenteric artery. Cardiovasc Res. 2004; 61(4):683-92. DOI: 10.1016/j.cardiores.2003.11.030. View

12.

Tank J, Jordan J, Diedrich A, Obst M, Plehm R, Luft F . Clonidine improves spontaneous baroreflex sensitivity in conscious mice through parasympathetic activation. Hypertension. 2004; 43(5):1042-7. DOI: 10.1161/01.HYP.0000125884.49812.72. View

13.

Dupuis M, Soubrier F, Brocheriou I, Raoux S, Haloui M, Louedec L . Profiling of aortic smooth muscle cell gene expression in response to chronic inhibition of nitric oxide synthase in rats. Circulation. 2004; 110(7):867-73. DOI: 10.1161/01.CIR.0000138850.72900.FE. View

14.

Obst M, Gross V, Luft F . Systemic hemodynamics in non-anesthetized L-NAME- and DOCA-salt-treated mice. J Hypertens. 2004; 22(10):1889-94. DOI: 10.1097/00004872-200410000-00010. View

15.

DeBoer R, Karemaker J, Strackee J . Hemodynamic fluctuations and baroreflex sensitivity in humans: a beat-to-beat model. Am J Physiol. 1987; 253(3 Pt 2):H680-9. DOI: 10.1152/ajpheart.1987.253.3.H680. View

16.

Bult H, Boeckxstaens G, Pelckmans P, Jordaens F, Van Maercke Y, Herman A . Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature. 1990; 345(6273):346-7. DOI: 10.1038/345346a0. View

17.

Moncada S, Palmer R, Higgs E . Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991; 43(2):109-42. View

18.

Vincent S, Kimura H . Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience. 1992; 46(4):755-84. DOI: 10.1016/0306-4522(92)90184-4. View

19.

Mattes A, Witte K, Hohmann W, Lemmer B . PHARMFIT--a nonlinear fitting program for pharmacology. Chronobiol Int. 1991; 8(6):460-76. DOI: 10.3109/07420529109059182. View

20.

Matsuoka H, Nishida H, Nomura G, Van Vliet B, Toshima H . Hypertension induced by nitric oxide synthesis inhibition is renal nerve dependent. Hypertension. 1994; 23(6 Pt 2):971-5. DOI: 10.1161/01.hyp.23.6.971. View