β-adrenergic cardiac hypertrophy is mediated primarily by the β₁-subtype in the rat heart

Myocardial β-adrenergic receptors (β-ARs) consist of β₁- and β₂-subtypes, which mediate distinct signaling mechanisms. We examined which β-AR subtype mediates cardiac hypertrophy. The β₂-subtype is predominant in neonatal rat cardiac myocytes (β₁, 36% ν β₂, 64%), while the β₁-subtype predominates in the adult rat heart (59% ν 41%). Stimulation of cultured cardiac myocytes in vitro with isoproterenol (ISO), an agonist for β₁- and β₂-ARs, caused hypertrophy of myocytes along with increases in transcription of atrial natriuretic factor (ANF) and actin reorganization. All of these ISO-mediated myocyte responses in vitro were inhibited by a β₁-AR antagonist, betaxolol, but not by a β₂-AR antagonist. ICI 118551. Pertussis toxin failed to affect ISO-induced increases in total protein/DNA content and ANF transcription in vitro. ISO increased LV weight/body weight and ANF transcription in the adult rat in vivo, which were also inhibited by betaxolol but not by ICI 118551. These results suggest that β-AR stimulated hypertrophy is mediated by the β₁-subtype and by a pertussis toxin-insensitive mechanism.