Dataset Information

Renin activates PI3K-Akt-eNOS signalling through the angiotensin AT? and Mas receptors to modulate central blood pressure control in the nucleus tractus solitarii.

ABSTRACT:

Background and purpose

The renin-angiotensin system (RAS) is critical for the control of blood pressure by the CNS. Recently, direct renin inhibitors were approved as antihypertensive agents. However, the signalling mechanism of renin, which regulates blood pressure in the nucleus tractus solitarii (NTS) remains unclear. Here we have investigated the signalling pathways involved in renin-mediated blood pressure regulation, at the NTS.

Experimental approach

Depressor responses to renin microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and presence of the endothelial nitric oxide synthase (eNOS)-specific inhibitor, N(5)-(-iminoethyl)-L-ornithine, Akt inhibitor IV and LY294002, a PI3K inhibitor and GP antagonist-2A [G(q) inhibitor]. Lisinopril (angiotensin converting enzyme inhibitor), losartan, valsartan (angiotensin AT(1) receptor antagonists), D-Ala7-Ang-(1-7) (angiotensin-(1-7) receptor antagonist) were used to study the involvement of RAS on renin-induced depressor effects.

Key results

Microinjection of renin into the NTS produced a prominent depressor effect and increased NO production. Pretreatment with G(q) -PI3K-Akt-eNOS pathway-specific inhibitors significantly attenuated the depressor response evoked by renin. Immunoblotting and immunohistochemical studies further showed that inhibition of PI3K significantly blocked renin-induced eNOS-Ser ¹¹? and Akt-Ser??³ phosphorylation in situ. In addition, pre-treatment of the NTS with RAS inhibitors attenuated the vasodepressor effects evoked by renin. Microinjection of renin also increased Ras activation in the NTS.

Conclusions and implications

Taken together, these results suggest renin modulated blood pressure at the NTS by AT? and Mas receptor-mediated activation of G(q) and Ras to evoke PI3K-Akt-eNOS signalling.

SUBMITTER: Cheng WH

PROVIDER: S-EPMC3402768 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Publications

Renin activates PI3K-Akt-eNOS signalling through the angiotensin AT₁ and Mas receptors to modulate central blood pressure control in the nucleus tractus solitarii.

Cheng Wen-Han WH Lu Pei-Jung PJ Hsiao Michael M Hsiao Chun-Hui CH Ho Wen-Yu WY Cheng Pei-Wen PW Lin Chia-Te CT Hong Ling-Zong LZ Tseng Ching-Jiunn CJ

British journal of pharmacology 20120801 7

<h4>Background and purpose</h4>The renin-angiotensin system (RAS) is critical for the control of blood pressure by the CNS. Recently, direct renin inhibitors were approved as antihypertensive agents. However, the signalling mechanism of renin, which regulates blood pressure in the nucleus tractus solitarii (NTS) remains unclear. Here we have investigated the signalling pathways involved in renin-mediated blood pressure regulation, at the NTS.<h4>Experimental approach</h4>Depressor responses to r ...[more]

PMID: 22224457

Similar Datasets

Project description:AimIt is well-established that angiotensin II exerts a dampening effect on the baroreflex within the nucleus tractus solitarii (NTS), the principal brainstem site for termination of baroreceptor afferents and which is densely populated with gamma-aminobutyric acid (GABA)ergic neurons and nerve terminals. The present study was designed to investigate whether local release of GABA is involved in the effects mediated by local angiotensin II within the NTS.MethodsIn vivo microdialysis was used for measurement of extracellular glutamate and GABA levels and for infusion of angiotensin II within the NTS of conscious normotensive Wistar rats. The mean arterial pressure (MAP) and heart rate response to local infusion of angiotensin II were subsequently monitored with a pressure transducer under anesthesia. The angiotensin II type 1 receptor (AT1R) antagonist, candesartan, was used to assess whether responses were AT1R dependent and the nitric oxide (NO) synthase inhibitor, N(?)-nitro-L-arginine methyl ester (L-NAME), was used to assess the involvement of NO in the evoked responses by infusion of angiotensin II. The MAP and heart rate responses were monitored with a pressure transducer.ResultsLocal infusion into the NTS of angiotensin II induced a significant to ninefold significantly increase in extracellular GABA levels; as well as MAP was increased by 15 mmHg. These responses were both abolished by co-infusion of either, the angiotensin II type 1 receptor antagonist, candesartan, or the NO synthase inhibitor, L-NAME, demonstrating that the effect is not only AT1R dependent but also NO dependent. The pressor response to angiotensin II was reversed by co-infusion with the GABAA receptor antagonist, bicuculline. Local blockade of NO synthase decreased both, GABA and glutamate concentrations.ConclusionOur results suggest that the AT1R mediated hypertensive response to angiotensin II within the NTS in normotensive rats is GABA and NO dependent. Nitric oxide produced within the NTS tonically potentiates local GABA and glutamate release.