Antisense inhibition of the brain kallikrein-kinin system

Hypertension
P MadedduJ Chao

Abstract

We used antisense oligodeoxynucleotide (ODN) strategy, based on interference of information flow from gene to protein, to determine the role of kininogen and bradykinin B2 receptor genes in the pathogenesis of genetic hypertension in rats. Mean blood pressure of 9-week-old spontaneously hypertensive rats (SHR) increased 4 hours after acute intracerebroventricular injection of synthetic 18-mer antisense ODNs targeting the translation initiation codon of kininogen mRNA (from 164 +/- 5 to 181 +/- 4 mm Hg, P < .01) or bradykinin B2 receptor mRNA (from 161 +/- 5 to 185 +/- 8 mm Hg, P < .01) and then returned to basal levels within 24 hours. Prolonged vasopressor effects were observed after repeated injections of antisense ODN targeting kininogen mRNA. Antisense ODNs to kininogen and B2 receptor mRNAs increased blood pressure of normotensive Wistar-Kyoto rats only slightly compared with SHR (from 116 +/- 3 to 124 +/- 1 and from 116 +/- 2 to 126 +/- 4 mm Hg, respectively; P < .05). Cardiovascular responses were confirmed by the use of antisense ODNs targeted to bind to different non-overlapping regions of kininogen or B2 receptor mRNA. Microinjection of antisense ODN to B2 receptor mRNA into the nucleus tractus solitarii increased mea...Continue Reading

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Citations

Feb 2, 1999·Clinical Reviews in Allergy & Immunology·F Marceau, D R Bachvarov
Mar 29, 2007·Nature Clinical Practice. Nephrology·Paolo MadedduSamir El-Dahr
Apr 7, 1999·Antisense & Nucleic Acid Drug Development·A W Szklarczyk, L Kaczmarek
Dec 22, 1999·The Japanese Journal of Physiology·M MaedaM Nakai
Apr 2, 2003·Expert Opinion on Therapeutic Targets·John Howl, Sarah J Payne
Mar 26, 1998·Biochemical and Biophysical Research Communications·C WangJ Chao
Oct 24, 2000·The Journal of Comparative Neurology·E Y ChenJ H Kordower

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