Variability in phenylephrine response and essential hypertension: A searchfor human alpha(1B)-adrenergic receptor polymorphisms

Genetic polymorphisms in drug receptors, in particular adrenergic receptors , may contribute to intersubject differences in pharmacologic response. We tested patients and first-degree normotensive and hypertensive relatives of patients with essential hypertension and found substantial intersubject va riability in blood pressure response to infusion of the alpha(1)-adrenergic agonist phenylephrine. Because response to phenylephrine depends upon inte raction with alpha(1B)-adrenergic receptors, we tested whether polymorphism s in this receptor contribute to the variable responses. Accordingly, we de veloped a polymerase chain reaction-based method, generating four exon-span ning fragments, to identify polymorphisms in the coding sequence of the two exons of the human alpha(1B)-adrenergic receptor. We sequenced the entire coding sequence of exon 1 from 51 subjects and exon 2 from 16 of these 51 s ubjects. Compared with the published sequence for the alpha(1B)-adrenergic receptor, we found one amino acid addition in exon 2 at position 368 (Arg) and one substitution (Arg371Gly) in all subjects. We thus suggest we have d efined the correct coding sequence of the human alpha(1B) receptor. We foun d two "silent" polymorphisms in exon 1, one of which occurred in 3 of 51 su bjects. These polymorphisms were unrelated to blood pressure status or resp onse to phenylephrine. The 95% confidence intervals for expression of polym orphisms in exons 1 and 2 were 0 to 11%. Our data reveal that although phen ylephrine response varies in humans, frequent polymorphisms in the coding s equence of the human alpha(1B)-adrenergic receptor appear not to account fo r this variation or for the increased blood pressure in patients with essen tial hypertension.