Role of phosphatidylinositol 3-kinase in angiotensin II regulation of norepinephrine neuromodulation in brain neurons of the spontaneously hypertensive rat

Chronic stimulation of norepinephrine (NE) neuromodulation by angiotensin I I (Ang II) involves activation of the Ras-Raf-MAP kinase signal transductio n pathway in Wistar Kyoto (WKY) rat brain neurons. This pathway is only par tially responsible for this heightened action of Ang II in the spontaneousl y hypertensive rat (SHR) brain neurons. In this study, we demonstrate that the MAP kinase-independent signaling pathway in the SHR neuron involves act ivation of PI3-kinase and protein kinase B (PKB/Akt). Ang II stimulated PI3 -kinase activity in both WKY and SHR brain neurons and was accompanied by i ts translocation from the cytoplasmic to the nuclear compartment. Although the magnitude of stimulation by Ang II was comparable, the stimulation was more persistent in the SHR neuron compared with the WKY rat neuron. inhibit ion of PI3-kinase had no significant effect in the WKY rat neuron. However, it caused a 40-50% attenuation of the Ang II-induced increase in norepinep hrine transporter (NET) and tyrosine hydroxylase (TH) mRNAs and [H-3]-NE up take in the SHR neuron. In contrast, inhibition of MAP kinase completely at tenuated Ang II stimulation of NET and TH mRNA levels in the WKY rat neuron , whereas it caused only a 45% decrease in the SHR neuron. However, an addi tive attenuation was observed when both kinases of the SHR neurons were inh ibited. Ang II also stimulated PKB/Akt activity in both WKY and SHR neurons . This stimulation was 30% higher and lasted longer in the SHR neuron compa red with the WKY rat neuron. In conclusion, these observations demonstrate an exclusive involvement of PI3-kinase-PKB-dependent signaling pathway in a heightened NE neuromodulatory action of Ang II in the SHR neuron. Thus, th is study offers an excellent potential for the development of new therapies for the treatment of centrally mediated hypertension.