Chronic sympathetic activation promotes downregulation of ß-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction

TY - JOUR

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 - 2011/10

Y1 - 2011/10

N2 - It is uncertain if downregulation of β-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 β-adrenoceptor signaling pathway upon chronic infusion of isoproterenol, a β-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 β-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 β-adrenoceptor-mediated effects upon chronic isoproterenol infusion was associated with markedly reduced stimulatory G-protein α-subunit (G sα) myocardial expression levels. No change in expression levels of β-adrenoceptors, G-protein-coupled receptor kinase 2, inhibitory G-protein α-subunit (G iα2), and Ca v1.2 and K v7.1 ion channels was determined in isoproterenol-treated hearts. We therefore conclude that sustained adrenergic overstimulation may promote downregulation of myocardial β-adrenoceptor-mediated effects independently of structural LV remodeling and systolic failure, an effect attributed to β-adrenoceptor uncoupling from adenylate cyclase due to reduced G sα-protein expression.

AB - It is uncertain if downregulation of β-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 β-adrenoceptor signaling pathway upon chronic infusion of isoproterenol, a β-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 β-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 β-adrenoceptor-mediated effects upon chronic isoproterenol infusion was associated with markedly reduced stimulatory G-protein α-subunit (G sα) myocardial expression levels. No change in expression levels of β-adrenoceptors, G-protein-coupled receptor kinase 2, inhibitory G-protein α-subunit (G iα2), and Ca v1.2 and K v7.1 ion channels was determined in isoproterenol-treated hearts. We therefore conclude that sustained adrenergic overstimulation may promote downregulation of myocardial β-adrenoceptor-mediated effects independently of structural LV remodeling and systolic failure, an effect attributed to β-adrenoceptor uncoupling from adenylate cyclase due to reduced G sα-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

SN - 0031-6768

VL - 462

SP - 529

EP - 543

JO - Pflügers Archiv - European Journal of Physiology

JF - Pflügers Archiv - European Journal of Physiology

IS - 4

ER -