Rationale: Central angiotensin (Ang) II inhibits baroreflex and plays an important role in the pathogenesis of hypertension. However, the underlying molecular mechanisms are still not fully understood. Objective: Our objective in the present study was to characterize the signal transduction mechanism of phosphatidylinositol 3-kinase (PI3K) involvement in Ang II–induced stimulation of central neuronal activity in cultured neurons and Ang II–induced inhibition of baroreflex in spontaneously hypertensive rats (SHR) versus WKY rats. Methods and Results: Application of Ang II to neurons produced a 42% greater increase in neuronal firing in cells from the SHR than the WKY rat. Although the Ang II–mediated increase in firing rate was abolished entirely by the protein kinase (PK)C inhibitor GF109230 in the WKY, blockade of both PKC and PI3K activity was necessary in the SHR. This was associated with an increased ability of Ang II to stimulate NADPH oxidase–reactive oxygen species (ROS)–mediated signaling involving phosphorylation of the p47phox subunit of the NADPH oxidase and was dependent on the activation of PI3K in the SHR. Inhibition of PI3K resulted in the reduction of levels of p47phox phosphorylation, NADPH oxidase activity, ROS levels, and ultimately neuronal activity in cells from the SHR but not the WKY rat. In addition, in working heart–brainstem preparations, inhibition of PKC activity in the nucleus of the solitary tract in situ abolished the Ang II–mediated depression of cardiac and sympathetic baroreceptor reflex gain in the WKY. In contrast, PKC inhibition in the nucleus of the solitary tract of SHR only partially reduced the effect of Ang II on the baroreceptor reflex gain. Conclusions: These observations demonstrate that PI3K in the cardiovascular brainstem regions of the SHR may be selectively involved in Ang II–mediated signaling that includes a reduction in baroreceptor reflex function, presumably via a NADPH-ROS mediated pathway.
|Translated title of the contribution||Shift to an involvement of phosphatidylinositol 3-kinase in angiotensin II actions on nucleus tractus solitarii neurons of the spontaneously hypertensive rat|
|Pages (from-to)||1248 - 1255|
|Number of pages||8|
|Publication status||Published - 4 Dec 2009|