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

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Abstract
Isoproterenol increases and decreases contractile force at low and high concentrations, respectively, through β2-adrenoceptors overexpressed in transgenic mouse heart (TG4), consistent with activation of both Gs and Gi proteins. Using TG4 hearts, we demonstrated that epinephrine behaves like isoproterenol, but norepinephrine does not. Epinephrine both increased (-log EC50M = 9.4) and decreased (-log EC50M = 6.5) left atrial force. Pertussis toxin (PTX) abolished the negative inotropic effects of epinephrine, consistent with mediation through Gi protein. Norepinephrine only increased contractile force (-log EC50M = 7.5). Norepinephrine (10-100 μM) prevented the positive inotropic effects but hardly affected the negative inotropic effects of epinephrine. Cardiodepressive epinephrine concentrations (1-10 μM) 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 μM) increased cAMP-dependent protein kinase activity in TG4 left ventricle. Cardiodepressive concentrations of epinephrine (1 and 100 μM) did not increase cAMP-dependent protein kinase activity. The inotropic results were simulated with a model of two β2-adrenoceptor sites. For one site involved in receptor coupling to Gs, both epinephrine and norepinephrine compete. The other site, recognized by epinephrine but not by norepinephrine, leads to receptor Gi coupling.

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