Chronic sympathetic activation promotes downregulation of ß-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction
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Chronic sympathetic activation promotes downregulation of ß-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction. / Soltysinska, Ewa; Thiele, Stefanie; Osadchiy, Oleg; Olesen, Søren-Peter.
In: Pflügers Archiv - European Journal of Physiology, Vol. 462, No. 4, 2011, p. 529-43.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Chronic sympathetic activation promotes downregulation of ß-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction
AU - Soltysinska, Ewa
AU - Thiele, Stefanie
AU - Osadchiy, Oleg
AU - Olesen, Søren-Peter
PY - 2011
Y1 - 2011
N2 - It is uncertain if downregulation of ß-adrenoceptor signaling pathway is promoted by an enhanced adrenergic tone at an early stage of cardiac disease, or it develops secondary to detrimental local myocardial changes in advanced heart failure. We examined the integrity of ß-adrenoceptor signaling pathway upon chronic infusion of isoproterenol, a ß-adrenoceptor agonist, at a dose producing no structural left ventricular (LV) remodeling and systolic dysfunction. Subcutaneous isoproterenol infusion (400 µg kg(-1) h(-1) over 16 days) to guinea pigs using osmotic minipumps produced no change in cardiac weights, LV internal dimensions, myocyte cross-sectional area, extent of interstitial fibrosis, and basal contractile function. Isolated, perfused heart preparations from isoproterenol-treated guinea pigs exhibited attenuated responsiveness to acute ß-adrenoceptor stimulation, as evidenced by reduced LV developed pressure increase, less shortening of LV epicardial monophasic action potential and effective refractory period, and less myocardial cyclic adenosine monophosphate elevation, in response to isoproterenol exposure, when compared to saline-treated controls. Pharmacological responses to forskolin, an activator of the adenylate cyclase catalytic subunit, were well preserved in isoproterenol-treated hearts. Downregulation of ß-adrenoceptor-mediated effects upon chronic isoproterenol infusion was associated with markedly reduced stimulatory G-protein a-subunit (G(sa)) myocardial expression levels. No change in expression levels of ß-adrenoceptors, G-protein-coupled receptor kinase 2, inhibitory G-protein a-subunit (G(ia2)), and Ca(v)1.2 and K(v)7.1 ion channels was determined in isoproterenol-treated hearts. We therefore conclude that sustained adrenergic overstimulation may promote downregulation of myocardial ß-adrenoceptor-mediated effects independently of structural LV remodeling and systolic failure, an effect attributed to ß-adrenoceptor uncoupling from adenylate cyclase due to reduced G(sa)-protein expression.
AB - It is uncertain if downregulation of ß-adrenoceptor signaling pathway is promoted by an enhanced adrenergic tone at an early stage of cardiac disease, or it develops secondary to detrimental local myocardial changes in advanced heart failure. We examined the integrity of ß-adrenoceptor signaling pathway upon chronic infusion of isoproterenol, a ß-adrenoceptor agonist, at a dose producing no structural left ventricular (LV) remodeling and systolic dysfunction. Subcutaneous isoproterenol infusion (400 µg kg(-1) h(-1) over 16 days) to guinea pigs using osmotic minipumps produced no change in cardiac weights, LV internal dimensions, myocyte cross-sectional area, extent of interstitial fibrosis, and basal contractile function. Isolated, perfused heart preparations from isoproterenol-treated guinea pigs exhibited attenuated responsiveness to acute ß-adrenoceptor stimulation, as evidenced by reduced LV developed pressure increase, less shortening of LV epicardial monophasic action potential and effective refractory period, and less myocardial cyclic adenosine monophosphate elevation, in response to isoproterenol exposure, when compared to saline-treated controls. Pharmacological responses to forskolin, an activator of the adenylate cyclase catalytic subunit, were well preserved in isoproterenol-treated hearts. Downregulation of ß-adrenoceptor-mediated effects upon chronic isoproterenol infusion was associated with markedly reduced stimulatory G-protein a-subunit (G(sa)) myocardial expression levels. No change in expression levels of ß-adrenoceptors, G-protein-coupled receptor kinase 2, inhibitory G-protein a-subunit (G(ia2)), and Ca(v)1.2 and K(v)7.1 ion channels was determined in isoproterenol-treated hearts. We therefore conclude that sustained adrenergic overstimulation may promote downregulation of myocardial ß-adrenoceptor-mediated effects independently of structural LV remodeling and systolic failure, an effect attributed to ß-adrenoceptor uncoupling from adenylate cyclase due to reduced G(sa)-protein expression.
KW - Adrenergic beta-Agonists
KW - Animals
KW - Calcium Channels, L-Type
KW - Cyclic AMP
KW - Down-Regulation
KW - Forskolin
KW - G-Protein-Coupled Receptor Kinase 2
KW - GTP-Binding Protein alpha Subunits, Gs
KW - Guinea Pigs
KW - Isoproterenol
KW - KCNQ1 Potassium Channel
KW - Male
KW - Myocardial Contraction
KW - Myocardium
KW - Receptors, Adrenergic, beta
KW - Refractory Period, Electrophysiological
KW - Signal Transduction
KW - Systole
KW - Ventricular Remodeling
U2 - 10.1007/s00424-011-1005-7
DO - 10.1007/s00424-011-1005-7
M3 - Journal article
C2 - 21811789
VL - 462
SP - 529
EP - 543
JO - Pflügers Archiv - European Journal of Physiology
JF - Pflügers Archiv - European Journal of Physiology
SN - 0031-6768
IS - 4
ER -
ID: 38506286