Epidermal growth factor increases if in rabbit SA node cells by activating a tyrosine kinase

Abstract

Our previous results have demonstrated that tyrosine kinase inhibition reduces i f in rabbit SA node myocytes, suggesting that tyrosine kinases regulate i f. One receptor tyrosine kinase the EGF receptor kinase is known to increase heart rate. To determine if this action is mediated through changes in i f, we examined the effect of epidermal growth factor (EGF) on i f with the permeabilized patch-clamp technique. 0.1 μM EGF increased i f amplitude in response to single-step hyperpolarizations in the diastolic range of potentials. This increase was 20±3%, n=11 at −75 mV. This effect is caused by activating a tyrosine kinase because 50 μM genistein, a tyrosine kinase inhibitor, eliminated this EGF action. A two-step pulse protocol showed that maximal i f conductance was increased by EGF. We further examined this conductance change by constructing the activation curve. The maximal i f conductance was increased by 23% with no change in midpoint, V 1/2, control=−74±2 mV, V 1/2 EGF=−74±1 mV. Thus EGF acts via a tyrosine kinase to increase maximal i f conductance with no change in the voltage dependence of activation. These results suggest that EGF effects on i f contribute to the positive chronotropic effect of EGF on SA node.