Chronotropic action of angiotensin II in neurons via protein kinase C and CaMKII

Angiotensin 11 (Ang 11) plays an important role in the central control of blood pressure and baroreflexes. These effects are initiated by stimulation of Ang 11 type I (AT(1)) receptor., on neurons within the hypothalamus and brain stein, and involve increasing the activity of noradrenergic, substance P, and glutamatergic pathways. The goal of this study is to investigate the intracellular signaling molecules, which are involved in mediating, the Ana II-induced increases in neuronal activity. Using neurons in primary culture from newborn rat hypothalamus and brain stem, we have previously determined that Ang 11 elicits an AT(1) receptor-mediated inhibition of delayed rectifier K+ current, a stimulation of Ca2+ current, and a consequent increase in firing rate. In the present study we have demonstrated that this chronotropic action of Ang 11 in neuronal cultures involves activation of Ca2+-dependent signaling molecules. The Ang II-induced increase in firing rate was abolished by inhibition of phospholipase C with U73122 (10 mumol/L), and was attenuated by the protein kinase C inhibitor calphostin C (10 mumol/L) or by the calcium/calmodulin-dependent kinase 11 (CaMKII) inhibitor KN-93 (10 mumol/L). A combination of calphostin C and KN-93 completely inhibited this Ang 11 action. These results indicate that the AT(1) receptor-mediated increase in neuronal firing rate involves activation of both PKC and CaMKII and suggest that these enzymes are potential targets for manipulating the central actions of Ang II.