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 with antisense oligonucleotides complementary to thyrotropin releasing hormone (TRH) receptor mRNA on the presser response to intrathecal administration of TRH and on resting arterial blood pressure in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SKR). In 16-week-old male WKY rats, 18-base phosphodiester antisense or mismatch oligonucleotides to TRH receptor mRNA (100 mu g per day) were injected intrathecally for 3 days. Twenty-four hours after the last injection, the magnitude of the presser response to intrathecal TRH (10 mu g) was significantly smaller in the antisense-treated group (n=7) compared with mismatch-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. Resting arterial blood pressure was unaffected by antisense treatment in WKY rats. In separate experiments, 16-week-old male SHR were treated with 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 animals. Our results suggest that the expression of TRH receptors in spinal sympathetic preganglionic neurons can be selectively reduced by intrathecal treatment with antisense oligonucleotides and that TRH projections to sympathetic preganglionic neurons play an important role in the elevation of arterial blood pressure in SHR.