Defective Phosphatidylinositol 3-Kinase Signaling in Central Control of Cardiovascular Effects in the Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats

Abstract

Recently we have shown functional involvement of the phosphatidylinositol 3-kinase (PI3K)-Akt-nitric oxide synthase (NOS) signaling pathway in central control of cardiovascular effects in the nucleus tractus solitarii (NTS) of normotensive Wistar-Kyoto (WKY) rats. In this study we determined whether PI3K/Akt signaling was defective in spontaneously hypertensive rats (SHR). WKY rats and SHR were anesthetized with urethane. Mean blood pressure (MBP) and heart rate (HR) were monitored intra-arterially. Unilateral microinjection (60 nL) of insulin (100 IU/mL) into the NTS produced prominent depressor and bradycardic effects in 8- and 16-week-old normotensive WKY and 8-week-old SHR. However, no significant cardiovascular effects were found in 16-week-old SHR after insulin injection. Furthermore, pretreatment with PI3K inhibitor LY294002 and NOS inhibitor L-NAME into the NTS attenuated the cardiovascular response evoked by insulin in WKY and 8-week-old SHR but not in 16-week-old SHR. Unilateral microinjection of 1 mmol/L of PI(3,4,5)P(3) (phosphatidylinositol 3,4,5-triphosphate), a phospholipids second messenger produced by PI3K, into the NTS produced prominent depressor and bradycardic effects in 8- or 16-week-old WKY rats as well as 8-week-old SHR but not in 16-week-old SHR. Western blot analysis showed no significant increase in Akt phosphorylation in 8-week-old pre-hypertensive SHR after insulin injection. Similar results were also found in hypertensive 16-week-old SHR. Our results indicate that the Akt-independent signaling pathway is involved in NOS activation to regulate cardiovascular effects in the NTS of 8-week-old pre-hypertensive SHR. Both Akt-dependent and Akt-independent signaling pathways are defective in hypertensive 16-week-old SHR.