Differential role of kinases in brain stem of hypertensive and normotensive rats

Spontaneously hypertensive rats (SHR) are characterized by extreme elevatio ns of blood pressure. The genetic factors underlying this are yet to be ide ntified. Here we demonstrate, in vivo, that in SHR and normotensive Wistar- Kyoto rats (WKY), injection of the mitogen-activated protein kinase inhibit or PD 098,059 bilaterally into the rostral ventrolateral medulla (RVLM) dra matically lowers arterial pressure. PD 098,059 does not alter the responses evoked by microinjection of glutamate into the RVLM or brief apnea. Wortma nnin (phosphatidylinositol-3 kinase inhibitor) bilaterally into the RVLM ca uses a 35 +/-4% fall in arterial pressure in SHR but has no effect in WKY. Furthermore, wortmannin reduces the pressor response evoked by microinjecti on of angiotensin (Ang) II in the RVLM of SHR compared with WKY. The respon se to Ang II microinjection into the RVLM of WKY was unaffected by wortmann in. Simultaneous bilateral injections of PD 098,059 and wortmannin into the RVLM abolished the response to exogenous Ang II in the RVLM but did not af fect the response evoked by glutamate in either SHR or WKY. Thus, it appear s that PD 098,059- and/or wortmannin-sensitive mechanisms are not involved in the responses evoked by glutamate in the RVLM and that these kinase inhi bitors are not neurotoxic. We conclude that a PD 098,059-sensitive pathway in the RVLM of SHR and WKY tonically regulates arterial pressure and that a wortmannin-sensitive pathway in the RVLM is important in the maintenance o f hypertension in SHR. This may be related to a phosphatidylinositol-3 kina se-dependent mechanism involved in the action of Ang II on the Ang II type I receptor.