From the Department of Physiology, University of Florida, College of
Medicine, Gainesville, Fla.
Correspondence to Dr Mohan K. Raizada, Department of Physiology, University of Florida, PO Box 100274, JHMHC, 1600 SW Archer Rd, Gainesville, FL 32610. E-mail mraizada{at}phys.med.ufl.edu
Abstract—Angiotensin
II (Ang II), via its interaction with the angiotensin type
1 (AT1) receptor subtype, causes enhanced stimulation of
norepinephrine (NE) neuromodulation. This involves
increased transcription of NE transporter, tyrosine hydroxylase, and
dopamine ß-hydroxylase genes in Wistar-Kyoto rat (WKY) brain neurons.
AT1 receptor–mediated regulation of certain signaling
events (such as activation of the Ras-Raf-1–mitogen activated
protein (MAP) kinase signaling pathway, nuclear translocation of
transcription factors such as Fos and Jun, and the interactions of
these factors with AP-1 binding sites) is involved in this NE
neuromodulation (Lu et al. J Cell Biol.
1996;135:1609–1617). The aim of this study was to compare the signal
transduction mechanism of Ang II regulation of NE neuromodulation in
WKY and spontaneously hypertensive rat (SHR) brain neurons, in view of
the fact that AT1 receptor expression and Ang II
stimulation of NE neuromodulation are higher in SHR neurons compared
with WKY neurons. Despite this hyperactivity, Ang II stimulation of
Ras, Raf-1, and MAP kinase activities was comparable between the
neurons from WKY and SHR. Similarly, central injections of Ang II
caused a comparable stimulation of MAP kinase in the hypothalamic and
brain stem areas of adult WKY and SHR. Inhibition of MAP kinase by
either an MAP kinase kinase inhibitor (PD98059) or an MAP
kinase antisense oligonucleotide completely attenuated
the stimulatory effects of Ang II on [3H]-NE uptake, NE
transporter mRNA, and tyrosine hydroxylase mRNA levels in WKY neurons.
These treatments resulted in only 43% to 50% inhibition of
[3H]-NE uptake and NE transporter and tyrosine
hydroxylase mRNAs in SHR neurons. Thus, Ang II stimulation of NE
neuromodulation was completely blocked by MAP kinase inhibition in WKY
neurons and only partially blocked in the SHR neurons. These
observations suggest the presence of an additional signal transduction
pathway involved in NE neuromodulation in SHR neurons that is
independent of the MAP kinase pathway.
© 1998 American Heart Association, Inc.
Scientific Contributions
MAP Kinase–Independent Signaling in Angiotensin II Regulation of Neuromodulation in SHR Neurons
Key Words: angiotensin • intracellular signaling • MAP kinase • neurons • norepinephrine • rats, inbred SHR
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