We report in the present study the effect of intrathecal treatment with 
antisense oligonucleotides complementary to thyrotropin releasing hormone (TRH) 
receptor mRNA on the pressor response to intrathecal administration of TRH and 
on resting arterial blood pressure in Wistar-Kyoto (WKY) rats and spontaneously 
hypertensive rats (SHR). In 16-week-old male WKY rats, 18-base phosphodiester 
antisense or mismatch oligonucleotides to TRH receptor mRNA (100 micrograms per 
day) were injected intrathecally for 3 days. Twenty-four hours after the last 
injection, the magnitude of the pressor response to intrathecal TRH (10 
micrograms) 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 pressor 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 mm Hg, 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.