RESPONSE TO CARDIAC SYMPATHETIC ACTIVATION IN TRANSGENIC MICE OVEREXPRESSING BETA(2)-ADRENERGIC RECEPTOR

Transgenic mice have been created with 200-fold overexpression of beta (2)-adrenergic receptors specifically in the heart. Cardiac function w as studied in these transgenic mice and their controls at baseline and during isoproterenol perfusion or sympathetic nerve stimulation. The model used was an in situ buffer-perfused, innervated heart, and the l eft ventricle maximal derivative of pressure over time (dP/dt(max)) an d heart rate (HR) were measured. Basal HR and dP/dt(max) were 30-40% h igher in hearts from transgenic mice than controls. Electrical stimula tion of sympathetic nerves (2, 4, and 8 Hz) or infusion of isoproteren ol markedly increased HR and dP/dt(max) in control hearts. Hearts from transgenic mice did not respond to isoproterenol. However, hearts fro m transgenic mice retained the HR response to nerve stimulation, and a small increase in dP/dt(max) was also detected. Atenolol inhibited th e response to nerve stimulation in control hearts but not that in hear ts from transgenic mice. ICI-118551 inhibited the response in transgen ic hearts. Basal HR and dP/dt(max) were decreased by ICI-118551 only i n transgenic hearts. Thus overexpression of cardiac beta(2)-receptors modifies beta-adrenergic activity, but the responses to endogenous and exogenous adrenergic stimulation are affected differently.