β-Adrenergic stimulation and myocardial function in the failing heart

Abstract

The sympathetic nervous system provides the most powerful stimulation of cardiac function, brought about via norepinephrine and epinephrine and their postsynaptic beta-adrenergic receptors. More than 30 years after the first use of practolol in patients with heart failure beta blockers are now the mainstay of the pharmacological treatment of chronic heart failure. Many aspects of their mechanism of action are well understood, but others remain unresolved. This review focuses on a number of questions that are key to further developments in the field. What accounts for and what is the role of beta-adrenergic desensitization, a hallmark of the failing heart? Is part of this adaptation predominantly beneficial and should therefore be reinforced, another part mainly maladaptive and therefore a target for antagonists? Which lessons can be drawn from studies in genetically engineered mice, which from (pharmaco) genetic studies? Finally, what are promising targets downstream of beta-adrenergic receptors that go beyond the current neurohumoral blockade?

Cardiac function in an endothermic fish: cellular mechanisms for overcoming acute thermal challenges during diving

“…However, changes in the shape of the rainbow trout AP have been shown to offset the acute effect of temperature on I Ca [22], suggesting compensatory interplay between thermal sensitivity of the different components of excitation-contraction coupling in fish. The activity of key ion channels and ion pumps involved in excitation-contraction coupling are also modified by AD [17,37] through the b-adrenergic receptor cascade and associated downstream signalling and phosphorylation events. Indeed, AD acting through cAMP-PKA-dependent phosphorylation of proteins has been shown to alter AP duration (APD) in fish heart [38] and to increase D[Ca 2þ ] i through augmentation of both I Ca and SERCA function [39].…”

Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging

“…Two of the best studied alterations of failing myocyte function are (a) desensitization of the β-adrenergic signaling system (1,2) and (b) alterations of intracellular Ca 2+ handling (3,4). The latter include decreased diastolic sarcoplasmic reticulum (SR) Ca 2+ uptake via the SR Ca 2+ ATPase (SERCA2a) and relatively increased diastolic sarcolemmal Ca 2+ efflux through the Na + /Ca 2+ -exchanger (NCX), prolonged Ca 2+ transients, and enhanced propensity for SR Ca 2+ release (Ca 2+ leak) via SR ryanodine receptor/Ca 2+ -release channel (RyR2) during diastole (5).…”

Phosphodiesterase 2: anti-adrenergic friend or hypertrophic foe in heart disease?

“…Chronically, this leads to attenuated cardiac β-AR responsiveness mainly as a result of a decrease in β 1 -AR density, uncoupling from stimulatory G proteins (Gs) through higher β-AR kinase (βARK), deactivation of phosphatase inhibitor 1, and higher levels of inhibitory G proteins (G i ) (Bristow et al 1982;El-Armouche and Eschenhagen 2009;El-Armouche et al 2008). In concert, these molecular alterations are assumed to be the basis for the blunted responses to catecholamines in the failing heart, a phenomenon called Bβ-AR desensitization.^On the one hand, these changes may contribute to the progression of HF by further compromising the contractile performance of the failing heart.…”