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Sensitization of slow pressor angiotensin II (Ang II)-initiated hypertension: induction of sensitization by prior Ang II treatment.

ABSTRACT: Sensitization involving the central nervous system has been studied in many conditions but has received little attention in investigation of the pathogenesis of hypertension. Our experiments were initiated to determine whether angiotensin II (Ang II)-induced hypertension can be sensitized by prior Ang II treatment and the role of the brain renin-angiotensin-aldosterone system (RAAS) in this process. To demonstrate Ang II-induced sensitization, we used an experimental design of induction-delay-expression. Male rats were implanted for telemetered blood pressure (BP) recording. During induction (I), low doses of subcutaneous or intracerebroventricular Ang II were delivered for 1 week, and then the rats were rested for 1 week (delay [D]) to ensure that any exogenous Ang II was metabolized. After this, a second higher dose of Ang II was given subcutaneously for 2 weeks (expression [E]). During I and D, the low doses of Ang II had no sustained effects on BP. However, during E, the Ang II-induced BP increase was greater in the groups that had received low doses of Ang II during I in comparison to the group receiving saline during I. Central angiotensin type 1 receptor antagonist delivery blocked this sensitization. Brain tissue collected at the end of D and E showed increased mRNA expression of several RAAS components in key forebrain regions of sensitized rats. Fos-related antigen-like immunoreactivity was also increased at the end of E in the sensitized forebrain. These results indicate that subpressor doses of Ang II act on the brain to sensitize the hypertensive response to subsequent Ang II and that sensitization is associated with altered expression of RAAS components in forebrain cardiovascular control structures.

SUBMITTER: Xue B

PROVIDER: S-EPMC3296679 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Sensitization of slow pressor angiotensin II (Ang II)-initiated hypertension: induction of sensitization by prior Ang II treatment.

Xue Baojian B Zhang Zhongming Z Johnson Ralph F RF Johnson Alan Kim AK

Hypertension (Dallas, Tex. : 1979) 20120103 2

Sensitization involving the central nervous system has been studied in many conditions but has received little attention in investigation of the pathogenesis of hypertension. Our experiments were initiated to determine whether angiotensin II (Ang II)-induced hypertension can be sensitized by prior Ang II treatment and the role of the brain renin-angiotensin-aldosterone system (RAAS) in this process. To demonstrate Ang II-induced sensitization, we used an experimental design of induction-delay-ex ...[more]

PMID: 22215719

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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.

Dataset Information

Sensitization of slow pressor angiotensin II (Ang II)-initiated hypertension: induction of sensitization by prior Ang II treatment.

Publications

Sensitization of slow pressor angiotensin II (Ang II)-initiated hypertension: induction of sensitization by prior Ang II treatment.

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