Chronic infusion of beta-adrenoceptor antagonist and inverse agonists decreases elevated protein kinase A activity in transgenic mice with cardiac-specific overexpression of human beta 2-adrenoceptor.
Neutral antagonists and inverse agonists can produce different cellular responses in some systems. The effects of chronic (14-day) infusion of three ligands, ICI-118,551, carvedilol, and alprenolol were examined in cardiac tissue from wild-type and transgenic mice with cardiac-specific overexpression of the human beta2-adrenoceptor. These ligands vary in their negative efficacy at the human beta2-adrenoceptor, with two (ICI-118,551 and carvedilol) behaving as inverse agonists and one (alprenolol) behaving as a neutral antagonist. Cardiac tissue from the transgenic mice exhibited elevated levels of protein kinase A activity and G protein receptor kinase-2. Fourteen-day infusions of the three ligands lowered the elevated levels of protein kinase A activity of the transgenic hearts to control levels. Alprenolol and carvedilol also decreased G protein receptor kinase-2 amounts to control levels. The left atria from transgenic mice exhibited an impaired inotropic response to histamine relative to responses of wild-type mice atria. Infusions of the inverse agonists and a neutral antagonist at the beta2-adrenoceptor significantly restored the impaired histamine response. Restoration of protein kinase A activity and the impaired histamine responses in the atria from transgenic mice can be observed following 14-day infusions of both a neutral antagonist and inverse agonists. The reversal of the effects of the transgene by both inverse agonists and a neutral antagonist suggests that agonist occupancy, and not spontaneous activity, of the beta2-adrenoceptor is producing the elevated protein kinase A activity and the impaired histamine response.
University of Houston, Department of Pharmacological and Pharmaceutical Sciences, Texas 77204-5037, USA.
Xiushi
X
Liu
Zsuzsanna
Z
Callaerts-Vegh
Kenda L J
KL
Evans
Richard A
RA
Bond
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000526:Alprenolol / Q000008:administration & dosage; D000818:Animals; D002227:Carbazoles / Q000008:administration & dosage; D000077261:Carvedilol; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006325:Heart Atria / Q000187:drug effects / Q000201:enzymology; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D015918:Infusion Pumps, Implantable; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology*; D011412:Propanolamines / Q000008:administration & dosage; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis* / Q000235:genetics
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D000077261:Carvedilol; C026777:ICI 118551; D000526:Alprenolol; D017868:Cyclic AMP-Dependent Protein Kinases