Vol. 291, Issue 2, 793-798, November 1999

Variability in Phenylephrine Response and Essential Hypertension: A Search for Human _1B-Adrenergic Receptor Polymorphisms¹

Rainer Büscher, Volker Herrmann, Kevin M. Ring, Mala T. Kailasam, Daniel T. O'Connor, Robert J. Parmer and Paul A. Insel

Departments of Pharmacology and Medicine, University of California-San Diego, La Jolla, California

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 ₁-adrenergic agonist phenylephrine. Because response to phenylephrine depends upon interaction with _1B-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 _1B-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 _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 defined the correct coding sequence of the human _1B receptor. 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 _1B-adrenergic receptor appear not to account for this variation or for the increased blood pressure in patients with essential hypertension.