Role of Rostral Ventrolateral Medullary ERK / JNK /p38 MAPK Signaling in the Pressor Effects of Ethanol and Its Oxidative Product Acetaldehyde

Background We tested the hypothesis that alterations of the phosphorylation/dephosphorylation profile of mitogen‐activated protein kinases ( MAPK s) in the rostral ventrolateral medulla ( RVLM ) underlie the pressor response elicited by ethanol ( E t OH ) microinjection into the RVLM of spontaneously hypertensive rats ( SHR s). The studies were extended to determine whether acetaldehyde ( ACA ), the primary oxidative product of E t OH , replicates the molecular effects of E t OH within the RVLM and the consequent pressor response. Methods Effects of E t OH or ACA on blood pressure ( BP ) were evaluated in the absence or presence of selective JNK ( SP 600125), ERK ( PD 98059), p38 ( SB 203580), or ser/thr phosphatases (okadaic acid [ OKA ]) inhibitor. Results Intra‐ RVLM E t OH (10 μg/rat) or ACA (2 μg/rat) caused a similar ERK 2‐dependent pressor response because E t OH or ACA ‐evoked increases in BP and in RVLM p‐ ERK 2 level were abolished after pharmacologic inhibition of ERK phosphorylation. SP 600125 abrogated the pressor action of E t OH , but not ACA , thus implicating JNK in E t OH action on BP . Despite E t OH enhancement of p38 phosphorylation, pharmacological studies argued against a causal role for this kinase in E t OH ‐evoked pressor response. RVLM phosphatase catalytic activity was not influenced by E t OH or ACA . Interestingly, pharmacologic phosphatase inhibition ( OKA ), which increased RVLM p‐ ERK 2 and BP , abrogated the pressor effect of subsequently administered E t OH or ACA . Conclusions Enhancement of RVLM ERK 2 phosphorylation constitutes a major molecular mechanism for the pressor response elicited by intra‐ RVLM E t OH or its metabolite, ACA , in conscious SHR s. Further, RVLM kinases dephosphorylation does not contribute to intra‐ RVLM E t OH ‐ or ACA ‐evoked pressor response.