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Enalapril attenuates the exaggerated sympathetic response to physical stress in prenatally programmed hypertensive rats.

ABSTRACT: Adulthood hypertension can be prenatally programmed by maternal dietary protein deprivation. We have shown that the sympathetically mediated pressor response to physical stress is exaggerated in prenatally programmed hypertensive (PPH) rats. The mechanisms underlying this abnormal responsiveness remain undetermined. The renin-angiotensin system is known to affect sympathetic nerve activity. Therefore, the purpose of this study was to determine whether inhibition of the renin-angiotensin system attenuates the enhanced sympathetic and pressor responses to physical stress in PPH rats. Changes in renal sympathetic nerve activity and blood pressure in response to hindlimb contraction, hindlimb stretch, and hindlimb intra-arterial capsaicin administration were assessed in control and PPH rats treated (from age 3 weeks) with either vehicle or the angiotensin-converting enzyme inhibitor enalapril. Conscious resting systolic arterial pressure was significantly greater in PPH rats (142±5 mm?Hg) than in control (128±2 mm?Hg) after vehicle treatment (P<0.05). Resting systolic pressure was reduced by enalapril treatment in PPH rats (125±2 mm?Hg) but had no effect in control (128±2 mm?Hg). The pressor and renal sympathetic responses to muscle contraction and stretch were significantly higher in decerebrate PPH rats than in decerebrate control in vehicle-treated groups. Responses to capsaicin were variable. Enalapril significantly attenuated the enhanced contraction-induced elevations in mean pressure (vehicle, 45±6 mm?Hg; enalapril, 21±3 mm?Hg) and renal sympathetic activity (vehicle, 175±22%; enalapril, 89±23%) in PPH rats. Its effects were similar on responses to stretch in PPH rats but were equivocal during capsaicin administration. The results suggest that the renin-angiotensin system contributes to the enhancement of the renal sympathetic and pressor responses to physical stress in PPH rats.

SUBMITTER: Mizuno M

PROVIDER: S-EPMC3891399 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Enalapril attenuates the exaggerated sympathetic response to physical stress in prenatally programmed hypertensive rats.

Mizuno Masaki M Lozano German G Siddique Khurrum K Baum Michel M Smith Scott A SA

Hypertension (Dallas, Tex. : 1979) 20131104 2

Adulthood hypertension can be prenatally programmed by maternal dietary protein deprivation. We have shown that the sympathetically mediated pressor response to physical stress is exaggerated in prenatally programmed hypertensive (PPH) rats. The mechanisms underlying this abnormal responsiveness remain undetermined. The renin-angiotensin system is known to affect sympathetic nerve activity. Therefore, the purpose of this study was to determine whether inhibition of the renin-angiotensin system a ...[more]

PMID: 24191284

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Project description:The stroke-prone spontaneously hypertensive rat (SHRSP) is known to have exaggerated sympathetic nerve activity to various types of stress, which might contribute to the pathogenesis of severe hypertension and stroke observed in this strain. Previously, by using a congenic strain (called SPwch1.72) constructed between SHRSP and the normotensive Wistar-Kyoto rat (WKY), we showed that a 1.8-Mbp fragment on chromosome 1 (Chr1) of SHRSP harbored the responsible gene(s) for the exaggerated sympathetic response to stress. To further narrow down the candidate region, in this study, another congenic strain (SPwch1.71) harboring a smaller fragment on Chr1 including two functional candidate genes, Phox2a and Ship2, was generated. Sympathetic response to cold and restraint stress was compared among SHRSP, SPwch1.71, SPwch1.72 and WKY by three different methods (urinary norepinephrine excretion, blood pressure measurement by the telemetry system and the power spectral analysis on heart rate variability). The results indicated that the response in SPwch1.71 did not significantly differ from that in SHRSP, excluding Phox2a and Ship2 from the candidate genes. As the stress response in SPwch1.72 was significantly less than that in SHRSP, it was concluded that the 1.2-Mbp congenic region covered by SPwch1.72 (and not by SPwch1.71) was responsible for the sympathetic stress response. The sequence analysis of 12 potential candidate genes in this region in WKY/Izm and SHRSP/Izm identified a nonsense mutation in the stromal interaction molecule 1 (Stim1) gene of SHRSP/Izm which was shared among 4 substrains of SHRSP. A western blot analysis confirmed a truncated form of STIM1 in SHRSP/Izm. In addition, the analysis revealed that the protein level of STIM1 in the brainstem of SHRSP/Izm was significantly lower when compared with WKY/Izm. Our results suggested that Stim1 is a strong candidate gene responsible for the exaggerated sympathetic response to stress in SHRSP.

Project description:Hypertensive cerebropathy is a pathological condition associated with cerebral edema and disruption of the blood-brain barrier. However, the molecular pathways leading to this condition remains obscure. We hypothesize that MMP-9 inhibition can help reducing blood pressure and endothelial disruption associated with hypertensive cerebropathy. Dahl salt-sensitive (Dahl/SS) and Lewis rats were fed with high-salt diet for 6 weeks and then treated without and with GM6001 (MMP inhibitor). Treatment of GM6001 (1.2 mg/kg body weight) was administered through intraperitoneal injections on alternate days for 4 weeks. GM6001 non-administered groups were given vehicle (0.9% NaCl in water) treatment as control. Blood pressure was measured by tail-cuff method. The brain tissues were analyzed for oxidative/nitrosative stress, vascular MMP-9 expression, and tight junction proteins (TJPs). GM6001 treatment significantly reduced mean blood pressure in Dahl/SS rats which was significantly higher in vehicle-treated Dahl/SS rats. MMP-9 expression and activity was also considerably reduced in GM6001-treated Dahl/SS rats, which was otherwise notably increased in vehicle-treated Dahl/SS rats. Similarly MMP-9 expression in cerebral vessels of GM6001-treated Dahl/SS rats was also alleviated, as devised by immunohistochemistry analysis. Oxidative/nitrosative stress was significantly higher in vehicle-treated Dahl/SS rats as determined by biochemical estimations of malondialdehyde, nitrite, reactive oxygen species, and glutathione levels. RT-PCR and immunohistochemistry analysis further confirmed considerable alterations of TJPs in hypertensive rats. Interestingly, GM6001 treatment significantly ameliorated oxidative/nitrosative stress and TJPs, which suggest restoration of vascular integrity in Dahl/SS rats. These findings determined that pharmacological inhibition of MMP-9 in hypertensive Dahl-SS rats attenuate high blood pressure and hypertension-associated cerebrovascular pathology.

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Enalapril attenuates the exaggerated sympathetic response to physical stress in prenatally programmed hypertensive rats.

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Enalapril attenuates the exaggerated sympathetic response to physical stress in prenatally programmed hypertensive rats.

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