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 ( MAPKs) in the rostral ventrolateral medulla ( RVLM) underlie the pressor response elicited by ethanol ( Et OH) microinjection into the RVLM of spontaneously hypertensive rats ( SHRs). The studies were extended to determine whether acetaldehyde ( ACA), the primary oxidative product of Et OH, replicates the molecular effects of Et OH within the RVLM and the consequent pressor response. Methods Effects of Et OH or ACA on blood pressure ( BP) were evaluated in the absence or presence of selective JNK ( SP600125), ERK ( PD98059), p38 ( SB203580), or ser/thr phosphatases (okadaic acid [ OKA]) inhibitor. Results Intra- RVLM Et OH (10 μg/rat) or ACA (2 μg/rat) caused a similar ERK2-dependent pressor response because Et OH or ACA-evoked increases in BP and in RVLM p- ERK2 level were abolished after pharmacologic inhibition of ERK phosphorylation. SP600125 abrogated the pressor action of Et OH, but not ACA, thus implicating JNK in Et OH action on BP. Despite Et OH enhancement of p38 phosphorylation, pharmacological studies argued against a causal role for this kinase in Et OH-evoked pressor response. RVLM phosphatase catalytic activity was not influenced by Et OH or ACA. Interestingly, pharmacologic phosphatase inhibition ( OKA), which increased RVLM p- ERK2 and BP, abrogated the pressor effect of subsequently administered Et OH or ACA. Conclusions Enhancement of RVLM ERK2 phosphorylation constitutes a major molecular mechanism for the pressor response elicited by intra- RVLM Et OH or its metabolite, ACA, in conscious SHRs. Further, RVLM kinases dephosphorylation does not contribute to intra- RVLM Et OH- or ACA-evoked pressor response. [ABSTRACT FROM AUTHOR]