Modulation of a Delayed-Rectifier K+ Current by Angiotensin II in Rat Sympathetic Neurons

Abstract

It is well known that angiotensin II (Angio II) mimics most of the muscarinic-mediated excitatory actions of acetylcholine on superior cervical ganglion neurons. For instance, in addition to depolarization and stimulation of norepinephrine release, muscarinic agonists and Angio II modulate the M-type K+ current and the N-type Ca2+ current. We recently found that muscarinic receptors modulate the delayed rectifier current IKV as well. Therefore a whole cell patch-clamp experiment was carried out in rat cultured sympathetic neurons to assess whether Angio II modulates IKV. We found that Angio II increased IKV by about 30% with a time constant of approximately 30 s. In comparison, inhibition of M-current was faster (τ ∼ 8 s) and stronger (∼61%). Modulation of IKV was disrupted by the AT1 receptor-antagonist losartan but not by the AT2-antagonist PD123319. IKV enhancement was reduced by the G-protein inhibitor GDP-β-S, whereas current modulation remained unaltered after cell treatment with pertussis toxin. The peptidergic modulation of IKV was severely disrupted when internal ATP was replaced by its nonhydrolyzable analogue AMP-PNP. Angio II enhanced IKV and further reduced the stimulatory action of a muscarinic agonist on IKV. Likewise, the muscarinc agonist enhanced IKV and occluded the effect of Angio II on IKV. We have also found that the protein kinase C activator PMA enhanced IKV, thereby mimicking and further attenuating the action of Angio II on IKV. These results suggest that AT1 receptors by coupling to pertussis toxin–insensitive G proteins, stimulate an ATP-dependent and PKC-mediated pathway to modulate IKV.