{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:39:42Z","timestamp":1791175182097,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2013,10,1]],"date-time":"2013-10-01T00:00:00Z","timestamp":1380585600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2013,10]]},"abstract":"Background and Purpose<\/jats:title>Clinical studies indicate that statins have a BP<\/jats:styled-content>\u2010lowering effect in hypercholesterolemic individuals with hypertension. Specifically, statins modulate BP<\/jats:styled-content> through the up\u2010regulation of endothelial NOS (eNOS<\/jats:styled-content>) activation in the brain. However, the signalling mechanisms through which statins enhance eNOS<\/jats:styled-content> activation remain unclear. Therefore, we examined the possible signalling pathways involved in statin\u2010mediated BP<\/jats:styled-content> regulation in the nucleus tractus solitarii (NTS<\/jats:styled-content>).<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>To investigate the involvement of Ras and other signalling pathways in simvastatin\u2010induced effects on BP, BP<\/jats:styled-content> and renal sympathetic nerve activity (RSNA<\/jats:styled-content>) were determined in spontaneously hypertensive rats (SHRs<\/jats:styled-content>) before and after i.c.v. administration of simvastatin in the absence and presence of a Ras\u2010specific inhibitor (farnesyl thiosalicylic acid, FTS<\/jats:styled-content>), a geranylgeranyltransferase inhibitor (GGTI<\/jats:styled-content>\u20102133), a PI3K inhibitor (LY<\/jats:styled-content>294002) or a MAPK<\/jats:styled-content>\u2010ERK<\/jats:styled-content> kinase (MEK<\/jats:styled-content>) inhibitor (PD<\/jats:styled-content>98059).<\/jats:p><\/jats:sec>Key Results<\/jats:title>FTS<\/jats:styled-content> significantly attenuated the decrease in BP<\/jats:styled-content> and increased NO evoked by simvastatin and reversed the decrease in basal RSNA<\/jats:styled-content> induced by simvastatin. Immunoblotting and pharmacological studies showed that inhibition of Ras activity by FTS<\/jats:styled-content> significantly abolished simvastatin\u2010induced phosphorylation of ERK<\/jats:styled-content>1\/2, ribosomal protein S6 kinase (RSK<\/jats:styled-content>), A<\/jats:styled-content>kt and decreased eNOS<\/jats:styled-content> phosphorylation. Likewise, administration of A<\/jats:styled-content>kt and ERK<\/jats:styled-content>1\/2 signalling inhibitors, LY294002 and PD98059, attenuated the reduction in BP<\/jats:styled-content> evoked by simvastatin. Furthermore, i.c.v. simvastatin decreased Rac1 activation and the number of ROS<\/jats:styled-content>\u2010positive cells in the NTS<\/jats:styled-content>.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>Simvastatin modulates central BP control in the NTS of SHRs by increasing Ras\u2010mediated activation of the PI3K\u2010Akt and ERK1\/2\u2010RSK signalling pathways, which then up\u2010regulates eNOS activation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12317","type":"journal-article","created":{"date-parts":[[2013,8,14]],"date-time":"2013-08-14T14:25:34Z","timestamp":1376490334000},"page":"847-858","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Simvastatin induces a central hypotensive effect via Ras\u2010mediated signalling to cause eNOS<\/scp> up\u2010regulation"],"prefix":"10.1111","volume":"170","author":[{"given":"Wen\u2010Han","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Medical Education and Research Kaohsiung Veterans General Hospital Kaohsiung Taiwan"},{"name":"Institute of Clinical Medicine National Yang\u2010Ming University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Yu","family":"Ho","sequence":"additional","affiliation":[{"name":"Division of General Internal Medicine Department of Internal Medicine Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Taiwan"},{"name":"Department of Internal Medicine, Faculty of Medicine, College of Medicine Kaohsiung Medical University Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien\u2010Feng","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences National Sun Yat\u2010sen University Kaohsiung 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