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 Ca(2+) current. We recently found that muscarinic receptors modulate the delayed rectifier current I(KV) as well. Therefore a whole cell patch-clamp experiment 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 about 30% with a time constant of approximately 30 s. In comparison, inhibition of M-current was faster (tau approximately 8 s) and stronger ( approximately 61%). Modulation of I(KV) was disrupted by the AT(1) receptor-antagonist losartan but not by the AT(2)-antagonist PD123319. I(KV) enhancement was reduced by the G-protein inhibitor GDP-beta-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 AT(1) receptors by coupling to pertussis toxin-insensitive G proteins, stimulate an ATP-dependent and PKC-mediated pathway to modulate I(KV).