Abstract 157: MAP Kinase Phosphatase-1 Inhibitor Injection into the Solitary Tract Nucleus Impairs Cardiovagal Baroreflex Function in Transgenic ASrAOGEN Rats

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Hypotensive transgenic ASrAOGEN rats (AS) with low brain angiotensinogen resulting from glial overexpression of an antisense oligonucleotide to angiotensinogen, have enhanced baroreflex sensitivity (BRS) relative to hypertensive transgenic (mRen2)27 rats (mRen) that overexpress the murine Ren2 gene or normotensive Sprague Dawley rats (SD). The AS rats exhibit elevated protein expression and activity (less phosphorylated-ERK) of the MAP Kinase Phosphatase-1 [MKP-1], a negative regulator of MAP Kinase signaling in the brain dorsal medulla compared with either mRen or SD rats at 26 wks of age. To determine if MKP-1 plays a role in maintenance of BRS, we gave acute bilateral microinjections of an irreversible MKP-1 inhibitor {2,3-bis-[(2-Hydroxyethyl)thiol]-1,4-naphthoquinone, NSC 95397; 200 nM/120 nL} into the solitary tract nucleus (NTS), an important site in the dorsal medulla for modulation of BRS in urethane/chloralose anesthetized AS, mRen and SD rats at 21 wks of age. The MKP-1 inhibitor impaired the BRS for bradycardia in response to increases in pressure by 48 % at 10 min (1.01 ± 0.16 baseline vs. 0.49 ± 0.1 msec/mm Hg at 10 min), 56 % at 60 min and 64 % at 120 min in the AS rats (p = 0.02, n = 8), but not in the mRen or SD rats. In addition, NSC 95397 reduced resting pressure (91 ± 3 at baseline vs. 79 ± 3 at 60 min vs. 80 ± 3 mm Hg at 120 min) in the SD rats, with a similar trend in the other strains, without effects on resting heart rate in any strain. Thus, up-regulated expression of MKP-1 contributes to the higher resting BRS function in AS rats. AS animals are spared age-related declines in BRS and they maintain higher expression of MKP-1 protein in the dorsal medulla vs. either mRen or SD rats (AS: 1.6 ± 0.2, mRen: 0.8 ± 0.1, SD: 1 ± 0.1 arbitary units; p = 0.01, n = 6 per group) at 66 wks of age. Thus, higher MKP-1 may be involved the preservation of BRS in older AS rats, suggesting the phosphatase be a novel therapeutic target to improve BRS function in aging and hypertension.

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