beta2-Adrenoceptor gene variation and systemic vasodilatation during ganglionic blockade.
Regional infusions of beta(2)-adrenoceptor (ADRB2) agonist have generally shown that individuals homozygous for Gly16 produces greater vasodilatation than those homozygous for Arg16. Systemic infusions have shown an opposite effect on systemic vascular resistance (SVR), possibly confounded by baroreflexes or interactions between single nucleotide polymorphism (SNP) positions 16 and 27. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (Terb) during ganglionic blockade. Forty healthy young adults were recruited according to the double homozygous haplotypes: Arg16 + Gln27 (n = 13), the rare Gly16 + Gln27 (n = 6), and Gly16 + Glu27 (n = 21). Arterial pressure was measured by brachial arterial catheter, and cardiac output by acetylene breathing. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. Following baroreflex ablation with trimethaphan (3-7 mg min(1)), continuous phenylephrine was titrated to restore blood pressure to baseline. Terb was infused i.v. at 33 and 67 ng kg(1) min(1) for 15 min/dose. There was partial evidence to suggest a main effect of haplotype on the change in SVR (P = 0.06). For SNP position 16, the highest dose of Terb produced lower SVR in Gly16 (mean +/- s.e.m.: 7.5 +/- 0.4) vs. Arg16 (8.9 +/- 0.7 units; P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs. Arg16 (P = 0.05). We conclude that during ganglionic blockade, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16 + Glu27 homozygotes, with greater influence from Gly16, providing further evidence that ADRB2 gene variation influences vasodilatation.
Hesse
Christiane
C
Department of Anaesthesiology, Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Schroeder
Darrell R
DR
Nicholson
Wayne T
WT
Hart
Emma C
EC
Curry
Timothy B
TB
Penheiter
Alan R
AR
Turner
Stephen T
ST
Joyner
Michael J
MJ
Eisenach
John H
JH
D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D001340:Autonomic Nerve Block; D017704:Baroreflex / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology; D002302:Cardiac Output / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005260:Female; D005730:Ganglionic Blockers / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000502:physiology*; D013726:Terbutaline / Q000494:pharmacology; D014294:Trimethaphan / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics*; D055815:Young Adult
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D005730:Ganglionic Blockers; D018343:Receptors, Adrenergic, beta-2; D010656:Phenylephrine; D014294:Trimethaphan; D013726:Terbutaline