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 was 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 left ventricle maximal derivative of pressure over time (dP/dtmax) and heart rate (HR) were measured. Basal HR and dP/dtmax were 30-40% higher in hearts from transgenic mice than controls. Electrical stimulation of sympathetic nerves (2, 4, and 8 Hz) or infusion of isoproterenol markedly increased HR and dP/dtmax in control hearts. Hearts from transgenic mice did not respond to isoproterenol. However, hearts from transgenic mice retained the HR response to nerve stimulation, and a small increase in dP/dtmax was also detected. Atenolol inhibited the response to nerve stimulation in control hearts but not that in hearts from transgenic mice. ICI-118551 inhibited the response in transgenic hearts. Basal HR and dP/dtmax were decreased by ICI-118551 only in 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.
Du
X J
XJ
Baker Medical Research Institute, Melbourne, Victoria, Australia.
Vincan
E
E
Woodcock
D M
DM
Milano
C A
CA
Dart
A M
AM
Woodcock
E A
EA
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D004558:Electric Stimulation; D006329:Heart Conduction System / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D011412:Propanolamines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013233:Stellate Ganglion / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C026777:ICI 118551; D001262:Atenolol; D007545:Isoproterenol