Variability in Phenylephrine Response and Essential Hypertension: A Search for Human α1B-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 variability in blood pressure response to infusion of the α1-adrenergic agonist phenylephrine. Because response to phenylephrine depends upon interaction with α1B-adrenergic receptors, we tested whether polymorphisms in this receptor contribute to the variable responses. Accordingly, we developed a polymerase chain reaction-based method, generating four exon-spanning fragments, to identify polymorphisms in the coding sequence of the two exons of the human α1B-adrenergic receptor. We sequenced the entire coding sequence of exon 1 from 51 subjects and exon 2 from 16 of these 51 subjects. Compared with the published sequence for the α1B-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 defined the correct coding sequence of the human α1Breceptor. We found two “silent” polymorphisms in exon 1, one of which occurred in 3 of 51 subjects. These polymorphisms were unrelated to blood pressure status or response to phenylephrine. The 95% confidence intervals for expression of polymorphisms in exons 1 and 2 were 0 to 11%. Our data reveal that although phenylephrine response varies in humans, frequent polymorphisms in the coding sequence of the human α1B-adrenergic receptor appear not to account for this variation or for the increased blood pressure in patients with essential hypertension.