Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice
Nadine Beetz, … , Ulrich Broeckel, Lutz Hein
Nadine Beetz, … , Ulrich Broeckel, Lutz Hein
Published November 23, 2009
Citation Information: J Clin Invest. 2009;119(12):3597-3612. https://doi.org/10.1172/JCI38433.
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Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice

Abstract

Hypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributing significantly to an individual’s lifetime risk of developing the condition. Here, we investigated the role of the G protein regulator phosducin (Pdc) in hypertension. Mice with a targeted deletion of the gene encoding Pdc (Pdc–/– mice) had increased blood pressure despite normal cardiac function and vascular reactivity, and displayed elevated catecholamine turnover in the peripheral sympathetic system. Isolated postganglionic sympathetic neurons from Pdc–/– mice showed prolonged action potential firing after stimulation with acetylcholine and increased firing frequencies during membrane depolarization. Furthermore, Pdc–/– mice displayed exaggerated increases in blood pressure in response to post-operative stress. Candidate gene–based association studies in 2 different human populations revealed several SNPs in the PDC gene to be associated with stress-dependent blood pressure phenotypes. Individuals homozygous for the G allele of an intronic PDC SNP (rs12402521) had 12–15 mmHg higher blood pressure than those carrying the A allele. These findings demonstrate that PDC is an important modulator of sympathetic activity and blood pressure and may thus represent a promising target for treatment of stress-dependent hypertension.

Authors

Nadine Beetz, Michael D. Harrison, Marc Brede, Xiangang Zong, Michal J. Urbanski, Anika Sietmann, Jennifer Kaufling, Michel Barrot, Mathias W. Seeliger, Maria Augusta Vieira-Coelho, Pavel Hamet, Daniel Gaudet, Ondrej Seda, Johanne Tremblay, Theodore A. Kotchen, Mary Kaldunski, Rolf Nüsing, Bela Szabo, Howard J. Jacob, Allen W. Cowley Jr., Martin Biel, Monika Stoll, Martin J. Lohse, Ulrich Broeckel, Lutz Hein

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Figure 5

Sympathetic activity is increased in Pdc-deficient mice.

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Sympathetic activity is increased in Pdc-deficient mice. (A) Schematic i...
(A) Schematic illustration of the fate of norepinephrine after release from sympathetic nerves and its metabolism to DHPG via monoaminoxidase (MAO) or to NMN via catechol-O-methyl­transferase (COMT). α2ABC, α2 adrenoceptor subtypes A, B, and C. (B and C) Circulating plasma norepinephrine levels were elevated in Pdc–/– mice, but epinephrine concentrations were not altered (n = 6–9; ***P < 0.001). (D) Renal elimination of norepinephrine was increased in Pdc–/– mice at night (n = 18–26; **P < 0.01). (E and F) Norepinephrine metabolites DHPG and NMN were increased in cardiac tissue of Pdc–/– compared with Pdc+/+ animals (n = 6–7; *P < 0.05). (G) Decrease of SBP after i.p. injection of 30 μg/kg clonidine in Pdc–/– and Pdc+/+ animals (n = 6–8; *P < 0.05). (H) Inhibition of [3H]norepinephrine release by the α2 adrenoceptor agonist medetomidine did not differ between genotypes (n = 5–6 atria per genotype). (I) Electrically evoked release of [3H]norepinephrine from isolated cardiac right atria after stimulation with 20 pulses at 50 Hz (n = 5–6 atria). (J and K) Western blots to determine tyrosine hydroxylase (TH) expression in cardiac ventricles of Pdc+/+ and Pdc–/– mice. Tyrosine hydroxylase expression was normalized to G protein β levels (Gβ) (n = 4–5 hearts).