ANTISENSE TO THYROTROPIN-RELEASING-HORMONE RECEPTOR REDUCES ARTERIAL BLOOD-PRESSURE IN SPONTANEOUSLY HYPERTENSIVE RATS

We report in the present study the effect of intrathecal treatment wit h antisense oligonucleotides complementary to thyrotropin releasing ho rmone (TRH) receptor mRNA on the presser response to intrathecal admin istration of TRH and on resting arterial blood pressure in Wistar-Kyot o (WKY) rats and spontaneously hypertensive rats (SKR). In 16-week-old male WKY rats, 18-base phosphodiester antisense or mismatch oligonucl eotides to TRH receptor mRNA (100 mu g per day) were injected intrathe cally for 3 days. Twenty-four hours after the last injection, the magn itude of the presser response to intrathecal TRH (10 mu g) was signifi cantly smaller in the antisense-treated group (n=7) compared with mism atch-treated controls (n=7) (change in mean arterial pressure, +20.3+/ -3.0 versus +32.6+/-2.5 mm Hg, P<.01). No differences were observed in the presser responses to injection of N-methyl-D-aspartic acid. Resti ng arterial blood pressure was unaffected by antisense treatment in WK Y rats. In separate experiments, 16-week-old male SHR were treated wit h antisense (n=7) or mismatch (n=6) oligonucleotides for 3 days. Mean resting arterial blood pressure was significantly reduced by treatment with antisense oligonucleotides (from 157+/-4.8 to 119+/-8.8 mmHg, P< .01): but no significant changes were observed in mismatch-treated ani mals. Our results suggest that the expression of TRH receptors in spin al sympathetic preganglionic neurons can be selectively reduced by int rathecal treatment with antisense oligonucleotides and that TRH projec tions to sympathetic preganglionic neurons play an important role in t he elevation of arterial blood pressure in SHR.