Antisense inhibition of thyrotropin-releasing hormone reduces arterial blood pressure in spontaneously hypertensive rats.
Thyrotropin-releasing hormone (TRH) plays an important role in central cardiovascular regulation. Recently, we described that the TRH precursor gene overexpression induces hypertension in the normal rat. In addition, we published that spontaneously hypertensive rats (SHR) have central extrahypothalamic TRH hyperactivity with increased TRH synthesis and release and an elevated TRH receptor number. In the present study, we report that intracerebroventricular antisense (AS) treatment with a phosphorothioate oligonucleotide against the TRH precursor gene significantly diminished up to 72 hours and in a dose-dependent manner the increased diencephalic TRH content, whereas normalized systolic blood pressure (SABP) was present in the SHR compared with Wistar-Kyoto (WKY) rats. Although basal thyrotropin was higher in SHR compared with WKY rats and this difference disappeared after antisense treatment, no differences were observed in plasma T4 or T3 between strains with or without AS treatment, indicating that the effect of the AS on SABP was independent of the thyroid status. Because the encephalic renin-angiotensin system seems to be crucial in the development and/or maintenance of hypertension in SHR, we investigated the effect of antisense inhibition of TRH on that system and found that TRH antisense treatment significantly diminished the elevated diencephalic angiotensin II (Ang II) content in the SHR without any effect in control animals, suggesting that the Ang II system is involved in the TRH cardiovascular effects. To summarize, the central TRH system seems to be involved in the etiopathogenesis of hypertension in this model of essential hypertension.
Cardiología Molecular, Instituto de Investigaciones Médicas A. Lanari, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
S I
SI
García
A L
AL
Alvarez
P I
PI
Porto
V M
VM
Garfunkel
S
S
Finkielman
C J
CJ
Pirola
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D002552:Cerebral Ventricles / Q000378:metabolism; D016373:DNA, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012084:Renin-Angiotensin System / Q000502:physiology; D013963:Thyroid Hormones / Q000097:blood; D013973:Thyrotropin-Releasing Hormone / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D016373:DNA, Antisense; D016376:Oligonucleotides, Antisense; D013963:Thyroid Hormones; D000804:Angiotensin II; D013973:Thyrotropin-Releasing Hormone