Angiotensin-(1-7) and norepinephrine neuromodulation

MM GIRONACCI

Ouro Preto, Brasil

Conferencia; V International Symposium on Vasoactive Peptides; 2004

Among the functionally active metabolites of the renin-angiotensin system, angiotensin (Ang) (1-7) is considered the most pleitropic because it exerts effects that may be identical or opposite to those of Ang II. In addition, it has been suggested that Ang-(1-7) functions as an antihypertensive peptide within the cascade of the renin-angiotensin system. One of the physiological mechanisms of the hypertensive action of Ang II is the modulation of sympathetic activity and the regulation of cathecolamine metabolism. This means that at the cellular level, Ang II modulates the synthesis, uptake and release of these neurotransmitters in brain nuclei associated with the control of blood pressure. Ang-(1-7), in contrast to Ang II, exerts an inhibitory effect on central noradrenergic neurotransmission in normotensive rats. Since it has been suggested that the renin-angiotensin system possesses the ability to limit the pressor and proliferative actions of Ang II through Ang-(1-7) generation, particularly when Ang II activity is enhanced such us in hypertension, and that both Ang II and Ang-(1-7) exerts opposite effects on central sympathetic activity, our aim was to study Ang-(1-7) effect on norepinephrine (NE) release in hypothalami isolated from both coarcted hypertensive (CH) and spontaneously hypertensive rats (SHR). In hypothalami from CH rats, Ang-(1-7) not only diminished the K+-induced NE release but also blocked the Ang II-stimulated NE outflow through a nitric oxide-dependent mechanism. When levels of Ang II and Ang-(1-7) were measured in hypothalami from CH rats, we found that only Ang-(1-7) levels increased after the aortic coarctation, being its concentration equimolar to Ang II amounts. In addition, Ang-(1-7) inhibited the increased blood pressure caused by intrahypothalamic administration of Ang II in CH rats. In SHR, Ang-(1-7) inhibited the K+-induced NE release, being more potent than in normotensive rats. This inhibitory effect was a nitric oxide-mediated mechanism via the cGMP/PKG pathway, involving AT2-receptors and/or Ang(1-7) specific receptors and local bradykinin generation. Our results suggest that Ang-(1-7) may contribute to the regulation of blood pressure by modulating NE release at the central level.