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

Abstract

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(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 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.

Increased Efferent Cardiac Sympathetic Nerve Activity and Defective Intrinsic Heart Rate Regulation in Type 2 Diabetes

“…Surprisingly, the b 1 -AR expression in the right atrium was increased (17%), with an associated reduction of G s expression (39%). This could indicate specific uncoupling of the b 1 -AR from its downstream signaling proteins (48). A: Unpaced isolated type 2 diabetic hearts (open circles) required a higher b-AR agonist (dobutamine) concentration to achieve a given absolute HR compared with nondiabetic hearts (closed circles).…”

Morphological and functional characteristics of models of experimental myocardial injury induced by isoproterenol

“…Recently, Soltysinska et al (2011a) provided experimental evidence, that sustained sympathetic activation by very low dose of isoproterenol infusion (400 µg/kg·h over 16 days) may promote downregulation of myocardial β-adrenergic receptor-mediated effects associated with markedly reduced G sα -protein expression. These changes could represent an early negative feedback to enhanced adrenergic tone.…”

State of the art paper The role of G protein coupled receptor kinases in neurocardiovascular pathophysiology

“…In these patients, the plasma concentration of catecholamines is elevated, providing evidence of sympathetic stimulation [42]. In patients with dilated cardiomyopathy β-AR responsiveness of the myo cardium is diminished [42]. It has been reported [43] that in these patients the expression of β1-AR is reduced at the mRNA and protein level.…”

“…This disturbed β-AR function could be based on an elevated sympathetic tone observed in patients with HF [40,41]. In these patients, the plasma concentration of catecholamines is elevated, providing evidence of sympathetic stimulation [42]. In patients with dilated cardiomyopathy β-AR responsiveness of the myo cardium is diminished [42].…”