Epinephrine Activates Both Gs and Gi Pathways, but Norepinephrine Activates Only the Gs Pathway through Human β2-Adrenoceptors Overexpressed in Mouse Heart

Abstract

Isoproterenol increases and decreases contractile force at low and high concentrations, respectively, through ␤ 2 -adrenoceptors overexpressed in transgenic mouse heart (TG4), consistent with activation of both G s and G i proteins. Using TG4 hearts, we demonstrated that epinephrine behaves like isoproterenol, but norepinephrine does not. Epinephrine both increased (Ϫlog EC 50 M ϭ 9.4) and decreased (Ϫlog EC 50 M ϭ 6.5) left atrial force. Pertussis toxin (PTX) abolished the negative inotropic effects of epinephrine, consistent with mediation through G i protein. Norepinephrine only increased contractile force (Ϫlog EC 50 M ϭ 7.5). Norepinephrine (10 -100 M) prevented the positive inotropic effects but hardly affected the negative inotropic effects of epinephrine. Cardiodepressive epinephrine concentrations (1-10 M) antagonized the positive inotropic effects of norepinephrine. In the free wall of TG4 right ventricle, norepinephrine and low epinephrine concentrations caused positive inotropic effects, and high epinephrine concentrations caused PTX-sensitive negative inotropic effects, as observed in the left atrium. Epinephrine (10 nM), a concentration causing maximum increase in contractile force, and norepinephrine (1 and 100 M) increased cAMP-dependent protein kinase activity in TG4 left ventricle. Cardiodepressive concentrations of epinephrine (1 and 100 M) did not increase cAMP-dependent protein kinase activity. The inotropic results were simulated with a model of two ␤ 2 -adrenoceptor sites. For one site involved in receptor coupling to G s , both epinephrine and norepinephrine compete. The other site, recognized by epinephrine but not by norepinephrine, leads to receptor G i coupling.

A Transient Receptor Potential Vanilloid 4-Dependent Mechanism of Hyperalgesia Is Engaged by Concerted Action of Inflammatory Mediators

“…For example, although most of the functions of the ␤ 2 -adrenergic receptor are mediated through G s -protein and the cAMP/PKA pathway, this receptor can also couple to G i -protein, which is cAMPindependent and initiates other signaling events (Xiao et al, 1995;Daaka et al, 1997). Similarly, in the heart, lower concentrations (10 nM) of epinephrine can activate G s (10 nM epinephrine), whereas higher concentrations (1-100 M) activate G i pathways (Heubach et al, 2004). In fact, we have demonstrated that the activation of a G i /Ras/extracellular signal-regulated kinase signaling pathway produces inflammatory pain that is independent of PKA or PKC⑀ pathways .…”

Epidemiology and pathophysiology of Takotsubo syndrome

“…Several studies demonstrate that it has a bellshaped dose-response relationship for myocardial contraction, and at the highest doses epinephrine is a negative inotrope via the β2AR 73,74 . This is a pharmacological property of the βAR known as stimulus trafficking, where high epinephrine levels result in a switch from the Gs stimulatory to the cardioinhibitory Gi secondary messenger pathway within the cardiomyocyte 68,73 .…”

“…Several studies demonstrate that it has a bellshaped dose-response relationship for myocardial contraction, and at the highest doses epinephrine is a negative inotrope via the β2AR 73,74 . This is a pharmacological property of the βAR known as stimulus trafficking, where high epinephrine levels result in a switch from the Gs stimulatory to the cardioinhibitory Gi secondary messenger pathway within the cardiomyocyte 68,73 . β2AR-Gi pathway activation is cardioprotective via activation of a number of antiapoptotic pathways 75 and this may minimise the toxic effects of vasospastic ischaemia, pressure-induced injury from high intracavity pressures, and the excessive catecholaminergic stimulation upon the myocardium.…”

Takotsubo cardiomyopathy in a patient with an ascending colon mass

“…Cellularly, histologic changes such as structural alteration of myocytes and intracytoplasmic accumulation of glycogen stores occur in Takotsubo and improve with clinical recovery of cardiac dysfunction [6]. Molecularly, elevated catecholamines are involved in a signalling switch from a stimulatory ionotropic response to an inhibitory ionotropic response [7]. Apart from these, many physical and emotional stressors are considered as the possible precipitants of TTC.…”