Dataset Information

Central and peripheral slow-pressor mechanisms contributing to Angiotensin II-salt hypertension in rats.

ABSTRACT:

Aims

High salt intake markedly enhances hypertension induced by angiotensin II (Ang II). We explored central and peripheral slow-pressor mechanisms which may be activated by Ang II and salt.

Methods and results

In protocol I, Wistar rats were infused subcutaneously with low-dose Ang II (150?ng/kg/min) and fed regular (0.4%) or high salt (2%) diet for 14?days. In protocol II, Ang II-high salt was combined with intracerebroventricular infusion of mineralocorticoid receptor (MR) blockers (eplerenone, spironolactone), epithelial sodium channel (ENaC) blocker (benzamil), angiotensin II type 1 receptor (AT1R) blocker (losartan) or vehicles. Ang II alone raised mean arterial pressure (MAP) ?10 mmHg, but Ang II-high salt increased MAP ?50 mmHg. Ang II-high salt elevated plasma corticosterone, aldosterone and endogenous ouabain but not Ang II alone. Both Ang II alone and Ang II-high salt increased mRNA and protein expression of CYP11B2 (aldosterone synthase gene) in the adrenal cortex but not of CYP11B1 (11-?-hydroxylase gene). In the aorta, Ang II-high salt increased sodium-calcium exchanger-1 (NCX1) protein. The Ang II-high salt induced increase in MAP was largely prevented by central infusion of MR blockers, benzamil or losartan. Central blockades significantly lowered plasma aldosterone and endogenous ouabain and markedly decreased Ang II-high salt induced CYP11B2 mRNA expression in the adrenal cortex and NCX1 protein in the aorta.

Conclusion

These results suggest that in Ang II-high salt hypertension, MR-ENaC-AT1R signalling in the brain increases circulating aldosterone and endogenous ouabain, and arterial NCX1. These factors can amplify blood pressure responses to centrally-induced sympatho-excitation and thereby contribute to severe hypertension.

SUBMITTER: Lu J

PROVIDER: S-EPMC5852508 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

Central and peripheral slow-pressor mechanisms contributing to Angiotensin II-salt hypertension in rats.

Lu Jiao J Wang Hong-Wei HW Ahmad Monir M Keshtkar-Jahromi Marzieh M Blaustein Mordecai P MP Hamlyn John M JM Leenen Frans H H FHH

Cardiovascular research 20180201 2

<h4>Aims</h4>High salt intake markedly enhances hypertension induced by angiotensin II (Ang II). We explored central and peripheral slow-pressor mechanisms which may be activated by Ang II and salt.<h4>Methods and results</h4>In protocol I, Wistar rats were infused subcutaneously with low-dose Ang II (150 ng/kg/min) and fed regular (0.4%) or high salt (2%) diet for 14 days. In protocol II, Ang II-high salt was combined with intracerebroventricular infusion of mineralocorticoid receptor (MR) bloc ...[more]

PMID: 29126194

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Project description:Hypertension alters cerebrovascular regulation and increases the brain's susceptibility to stroke and dementia. We investigated the temporal relationships between the arterial pressure (AP) elevation induced by "slow pressor" angiotensin II (ANG II) infusion, which recapitulates key features of human hypertension, and the resulting cerebrovascular dysfunction. Minipumps delivering saline or ANG II for 14 days were implanted subcutaneously in C57BL/6 mice (n = 5/group). Cerebral blood flow was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. With ANG II (600 ng · kg(-1) · min(-1)), AP started to rise after 9 days (P < 0.05 vs. saline), remained elevated at 11-17 days, and returned to baseline at 21 days (P > 0.05). ANG II attenuated the cerebral blood flow increase induced by neural activity (whisker stimulation) or endothelium-dependent vasodilators, an effect observed before the AP elevation (7 days), as well as after the hypertension subsided (21 days). Nonpressor doses of ANG II (200 ng · kg(-1) · min(-1)) induced cerebrovascular dysfunction and oxidative stress without elevating AP (P > 0.05 vs. saline), whereas phenylephrine elevated AP without inducing cerebrovascular effects. ANG II (600 ng · kg(-1) · min(-1)) augmented neocortical reactive oxygen species (ROS) with a time course similar to that of the cerebrovascular dysfunction. Neocortical application of the ROS scavenger manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin or the NADPH oxidase peptide inhibitor gp91ds-tat attenuated ROS and cerebrovascular dysfunction. We conclude that the alterations in neurovascular regulation induced by slow pressor ANG II develop before hypertension and persist beyond AP normalization but are not permanent. The findings unveil a striking susceptibility of cerebrovascular function to the deleterious effects of ANG II and raise the possibility that cerebrovascular dysregulation precedes the elevation in AP also in patients with ANG II-dependent hypertension.

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Dataset Information

Central and peripheral slow-pressor mechanisms contributing to Angiotensin II-salt hypertension in rats.

Aims

Methods and results

Conclusion

Publications

Central and peripheral slow-pressor mechanisms contributing to Angiotensin II-salt hypertension in rats.

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