In essential hypertension, a polygenic and multifactorial syndrome, several 
genes interact with the environment to produce high blood pressure. 
Thyrotropin-releasing hormone (TRH) plays an important role in central 
cardiovascular regulation. We have described that TRH overexpression induces 
hypertension in a normal rat, which was reversed by TRH antisense treatment. 
This treatment also reduces the central TRH hyperactivity in spontaneously 
hypertensive rats and normalizes blood pressure. Human TRH receptor (TRHR) 
belongs to the G protein-coupled seven-transmembrane domain receptor 
superfamily. Mutations of these receptors may result in constitutive activation. 
As it has been demonstrated that hypertensive patients have a blunted TSH 
response to TRH injection, suggesting a defect in the TRHR, we postulate that 
the TRHR gene is involved in human hypertension. We studied 2 independent 
populations from different geographic regions of our country: a sample of adult 
subjects from a referral clinic and a population-based sample of high school 
students. In search of molecular variants of TRHR, we disclosed that a 
polymorphic TG dinucleotide repeat (STR) at -68 bp and a novel single nucleotide 
polymorphism, a G-->C conversion at -221 located in the promoter of the TRHR are 
associated with essential hypertension. As STRs detected in gene promoters are 
potential Z-DNA-forming sequences and seem to affect gene expression, we studied 
the potentially different transcriptional activity of these TRHR promoter 
variants and found that the S/-221C allele has a higher affinity than does the 
L/G-221 allele to nuclear protein factor(s). Our findings support the hypothesis 
that the TRHR gene participates in the etiopathogenesis of essential 
hypertension.