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