OVEREXPRESSION OF NERVE GROWTH-FACTOR IN THE HEART ALTERS ION-CHANNELACTIVITY AND BETA-ADRENERGIC SIGNALING IN AN ADULT TRANSGENIC MOUSE

1. The electrophysiological and pharmacological properties of cardiac myocytes from the hearts of adult transgenic mice engineered to overex press nerve growth factor (NGF) in the heart were studied. 2. There wa s a 12% increase in the ventricular myocyte capacitance in NGF myocyte s consistent with cardiac hypertrophy, and action potential duration a t 90% repolarization (APD(90)) was prolonged by 142% compared with wil d-type (WT) myocytes. This was due, at least in part, to a decrease in the density of two K+ currents, I-to and I-K(ur), which were signific antly reduced in NGF mice with no change in their electrophysiological characteristics. We found no change in the current density or electro physiological properties of the L-type Ca2+ current. 3. The effect on I-to and I-K(ur) of TEA and 4-aminopyridine (4-AP) was not different i n cells isolated from WT and NGF mice. The prolongation of APD observe d in NGF cells was mimicked in WT cells by exposure to 1 mM 4-AP, whic h partially blocked I-to, completely blocked I-K(ur) and increased APD (90) by 157%. 4. The isoprenaline-induced increase in I-Ca was signifi cantly smaller in NGF myocytes than in WT myocytes. This was not due t o a decrease in beta-adrenergic receptor (P-AR) density, as this was i ncreased in NGF tissue by 55%. Analysis of beta-AR subtypes showed tha t this increase was entirely due to an increase in beta(2)-AR density with no change in beta(1)-ARs. 5. The response of the beta-AR-coupled adenylyl cyclase system to isoprenaline, Gpp(NH)p and forskolin was st udied by measuring cAMP production. In NGF tissue, isoprenaline elicit ed a significantly smaller response than in WT myoyctes and this was n ot due to reduced adenylyl cyclase activity as the responses of NGF ti ssue to guanylylimidodiphosphate (Gpp(NH)p) and forskolin were unaffec ted. 6. In conclusion, the overexpression of NGF in the mouse heart re sulted in a decrease in the current density of two K+ channels, which contributed to the prolongation of the cardiac action potential. Despi te an increase in beta(2)-AR density in the hearts of the NGF mice, th e response to isoprenaline was diminished, and this was due to an unco upling of the beta-ARs from the intracellular signalling cascade. Thes e potentially pathological changes may be involved in the occurrence o f ventricular arrhythmias in cardiac hypertrophy and failure, and this mouse provides a novel model in which to study such changes.