INVESTIGADORES
GIRONACCI Mariela Mercedes
congresos y reuniones científicas
Título:
Neuromodulatory role for angiotensin-(1-7) on norepinephrine uptake in neurons from spontaneuosly hypertensive rats
Autor/es:
M. A. LOPEZ VERRILLI, M. RODRÍGUEZ FERMEPÍN, B. E. FERNANDEZ, M. M. GIRONACCI
Lugar:
Belo Horizonte, Brasil
Reunión:
Congreso; XVIIIth Scientific Sessions of the Inter-American Society of Hypertension; 2009
Resumen:
Introduction Hypothalamic norepinephrine (NE) release contributes
to arterial pressure regulation by altering sympathetic nervous system
activity. It has been suggested that the renin-angiotensin system may
counteract Ang II pressor effect by Ang-(1-7)
generation, an antihypertensive component of this system. We have determined
that, in contrast to Ang
II, Ang-(17)
reduces NE synthesis and release in isolated hypothalami from spontaneously
hypertensive rats (SHR) and in this way it may decrease sympathetic
activity. Objective Since Ang-(1-7)
decreases NE release and this effect may be correlated with an augmented NE
removal from the synaptic cleft, our aim was to investigate the effect of
Ang-(17) on neuronal NE uptake and norepinephrine transporter (NET) expression
at the central level. NET is responsible for the uptake of neuronally released
NE into presynaptic noradrenergic neurons, thus inactivating NE. Material and methods Neuronal 3H-NE
uptake was measured in isolated hypothalami from 3-month-old normotensive
controls (WKY) and SHR rats in the absence (basal) or presence of 0.1-1 μM
Ang-(1-7). NET expression was determined by western blot in primary neuronal
cultures from hypothalami of newborn WKY and SHR rats. Results No significant difference between basal neuronal NE uptake
from WKY and SHR hypothalami were observed. Ang-(1-7) (0.1-1 μM) did not modify
NE neuronal uptake in both strains There was no
significant difference in NET expression in hypothalamic neuronal cultures from
SHR compared to WKY. The addition of 0.1 μM
Ang-(1-7) to neuronal cultures from SHR hypothalami caused an increase in NET
expression after 3 and 5 h of incubation (40+7%
and 30+9%, respectively). To examine the receptor
subtypes involved in the stimulatory effect of Ang-(1-7) on NET expression,
specific Mas, AT1- and AT2-receptors antagonists were added. 1μM [D-Ala7]
Ang-(1-7), a Mas receptor antagonist, blocked the effect of Ang-(1-7),
suggesting the involvement of Mas receptor. Neither 1μM PD123319, an AT2 receptor
antagonist, nor 1μM losartan, an AT1 receptor antagonist, modified
the action of Ang-(1-7) on NET expression in SHR neuronal cultures. 1 μM
actinomycin-D or 0.5-1 μM cycloheximide, blocked the stimulatory effect of 0.1
μM Ang-(1-7) on NET expression, suggesting that Ang-(1-7) stimulates NET gene
transcription and translation. Conclusion
Our results showed that Ang-(1-7) does not evoke an acute effect on
neuronal NE uptake. Conversely, Ang-(1-7) induces a long-term effect by increasing
NET expression through stimulation of NET gene transcription and translation
and this effect is coupled to Mas receptor activation. Our study, together with
the fact that the peptide induces a decrease in NE synthesis and release,
supports a negative neuromodulatory role for Ang-(1-7) on central sympathetic
nervous activity.