Dual mechanisms of angiotensin-induced activation of mouse sympathetic neurones.

Ang II directly activates neurones in sympathetic ganglia. Our goal was to define the electrophysiological basis of this activation. Neurones from mouse aortic-renal and coeliac ganglia were identified as either 'tonic' or 'phasic'. With injections of depolarizing currents, action potentials (APs) were abundant and sustained in tonic neurones (TNs) and scarce or absent in phasic neurones (PNs). Resting membrane potentials were equivalent in TNs (-48 +/- 2 mV, n = 18) and PNs (-48 +/- 1 mV, n = 23) while membrane resistance was significantly higher in TNs. Ang II depolarized and increased membrane resistance equally in both TNs (n = 8) and PNs (n = 8) but it induced APs only in TNs, and enhanced current-evoked APs much more markedly in TNs (P < 0.05). The AT1 receptor antagonist losartan (2 microm, n = 6) abolished all responses to Ang II, whereas the AT2 receptor blocker PD123,319 had no effect. The transient K+ current (IA), which was more than twice as large in TNs as in PNs, was significantly inhibited by Ang II in TNs only whereas the delayed sustained K+ current (IK), which was comparable in both TNs and PNs, was not inhibited. M currents were more prominent in PNs and were inhibited by Ang II. The IA channel blocker 4-aminopyridine triggered AP generation in TNs and prevented the Ang II-induced APs but not the depolarization. Blockade of M currents by oxotremorine M or linopirdine prevented the depolarizing action of Ang II. The protein kinase C (PKC) inhibitor H7 (10 microm, n = 9) also prevented the Ang II-induced inhibition of IA and the generation APs but not the depolarization nor the inhibition of M currents. Conversely, the PKC agonist phorbol 12-myristate 13-acetate mimicked the Ang II effects by triggering APs. The results indicate that Ang II may increase AP generation in sympathetic neurones by inducing a PKC-dependent inhibition of IA currents, and a PKC-independent depolarization through inhibition of M currents. The differential expression of various K+ channels and their sensitivity to phosphorylation by PKC may determine the degree of activation of sympathetic neurones and hence may influence the severity of the hypertensive response.