Abstract 1381: Ang II Induced Sympathetic Overactivity in the RVLM of Normal Rats Involves the PKC Pathway
It is well known that Ang II in the rostral ventrolateral medulla (RVLM)significantly increases arterial blood pressure and renal sympathetic nerve activity (RSNA). This effect of Ang II plays a critical role in the sympathetic overactivity in the chronic heart failure (CHF) state, a syndrome with markedly elevated endogenous Ang II. However, the intracellular signaling pathways mediating the sympathetic overactivity by Ang II in the RVLM are not completely clear. Evidences from other laboratories suggest that, in primarily cultured neurons, Ang II inhibits neuronal Ikv and then increases firing rate via protein kinase C (PKC) and calmodulin kinase II (CaMKII) pathways. In the present study we hypothesized that PKC mediates Ang II induced sympathetic overactivity in the RVLM. 32 anesthetized adult male Sprague-Dawley rats were used in this experiment. Rats were placed in a stereotaxic apparatus, microinjections into the RVLM were performed using a pressure injection system from a 3-barreled micropipette, and the RSNA, mean arterial pressure (MAP), and heart rate (HR) were recorded. Ang II (10 pmol in 50 nL) in RVLM induced sympathoexcitatory (ΔRSNA 67.6 ± 5.2%), pressor (ΔMAP: 19.7 ± 2.4 mmHg) and tachycardiac (ΔHR: 35.5 ± 2.2 bpm) responses, which were abolished by pretreatment with an AT1R blocker. Unilateral micoinjection of either the phospholipase C (PLC) inhibitor U73122 (10 pmol in 50 nL), the PKC inhibitor Calphostin (10 pmol in 50 nL), or the Calmodulin antagonist W-7 (10 pmol in 50 nL) into the RVLM decreased baseline RSNA, MAP and HR. Pretreatment with U73122, Calphostin, or W-7 in the RVLM partially blocked Ang II induced sympathoexcitation (U73122 ΔRSNA 29.2 ± 3.4%; Calphostin ΔRSNA 41.3 ± 3.5%; W-7 ΔRSNA 38.9 ± 3.5%) and pressor responses (U73122 ΔMAP: 6.5 ± 0.8 mmHg; Calphostin ΔMAP: 11.4 ± 1.5 mmHg; W-7 ΔMAP: 12.1 ± 1.6 mmHg). These results suggested that both PLC-PKC and PLC-CaMKII pathways exert a tonic effect in the maintenance of baseline sympathetic activity and these two pathways partially mediate the response to exogenous Ang II in the RVLM in normal rats. This pathway may play a role in sympatho-excitatory states such as hypertension and chronic heart failure state.