Abstract 1561: Ras/Raf/p38 MAPK/ERK Pathway is Activated in the Rostral Ventrolateral Medulla of Stroke-Prone Spontaneously Hypertensive Rats
The small G protein Ras activates small G protein Raf, and Raf causes neural apoptosis and cell proliferation through the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK). Previous reports suggested that microinjection of angiotensin II into the rostral ventrolateral medulla (RVLM), which regulates sympathetic nerve activity, induces the pressor response through the activation of p38 MAPK and ERK. However, the role of Ras an Raf in the RVLM on the regulation of sympathetic nerve activity has not been determined. We hypothesized that the Ras/Raf/p38 MAPK/ERK pathway in the RVLM is upregulated in stroke-prone spontaneously hypertensive rats (SHRSP), a hypertensive rat model with increased sympathetic nerve activity. In SHRSP (14–16 weeks old) and age-matched Wistar-Kyoto (WKY) rats, RVLM tissues were sampled using the punch-out technique. Systolic blood pressure, heart rate and 24 hours urinary norepipnephrine excretion, which is the marker of sympathetic nerve activity, were significantly higher in SHRSP than in WKY. The activity of both Ras (28±4%, n=8, p<0.01) and Raf (19±3, n=8, p<0.01), and the expression of phosphorylated p38 MAPK (33±5%, n=8, p<0.01) and ERK1/2 (36±4%, n=8, p<0.01) were significantly higher in SHRSP than in WKY. Microinjection of S-farnesylthiosalicylic acid, a Ras inhibitor, bilaterally into the RVLM decreased the mean blood pressure and heart rate in SHRSP (−28±4 mmHg and −44±6 bpm, n=5, p<0.01), but not in WKY. These results suggest that the Ras/Raf/p38 MAPK/ERK pathway in the RVLM is upregulated in SHRSP, and that this pathway might be involved in the pathogenesis of hypertension.