Effects of common polymorphisms in the alpha1A-, alpha2B-, beta1- and beta2-adrenoreceptors on haemodynamic responses to adrenaline.
Common naturally occurring polymorphisms have been identified in the coding regions of the alpha(1A)-, alpha(2B)-, beta(1)- and beta(2)-adrenoceptor (AR) genes [alpha(1A)-AR R492C, alpha(2B)-AR insertion/deletion (I/D), beta(1)-AR R389G, beta(2)-AR G16R and beta(2)-AR Q27E] and are associated with modified in vivo and in vitro functionality. We tested their possible effects on the haemodynamic responses to intravenous adrenaline (20, 40, 80 and 160 ng/kg of body weight per min; 5 min for each infusion rate) before and after beta-blockade (propranolol) in 16 young healthy men. We monitored changes in heart rate, blood pressure (BP), ECG, coronary flow velocity and plasma adrenaline and noradrenaline. The Cys/Cys (CC) genotype of the alpha(1A)-AR R492C polymorphism was associated with a longer ECG PR interval before and during the adrenaline infusions. The deletion/deletion (D/D) genotype of the alpha(2B)-AR I/D polymorphism was associated with blunted coronary blood flow increases during the adrenaline infusion before beta-blockade. The beta(1)-AR R389G polymorphism was not associated with modified responses to infused adrenaline. Subjects carrying the Gly/Gly (GG) genotype of the beta(2)-AR G16R polymorphism demonstrated increases in diastolic BP upon adrenaline infusion, whereas diastolic BP was decreased in the other genotype groups. These results suggest that, upon acute adrenaline infusion, the alpha(2B)-AR D/D genotype confers increased vasoconstriction and that the beta(2)-AR GG genotype confers reduced vasodilatation.
Snapir
Amir
A
Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4, Finland. snapir@utu.fi
Koskenvuo
Juha
J
Toikka
Jyri
J
Orho-Melander
Marju
M
Hinkka
Susanna
S
Saraste
Markku
M
Hartiala
Jaakko
J
Scheinin
Mika
M
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D004334:Drug Administration Schedule; D004452:Echocardiography; D004562:Electrocardiography / Q000187:drug effects; D004837:Epinephrine / Q000097:blood; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D016018:Least-Squares Analysis; D008297:Male; D015999:Multivariate Analysis; D009638:Norepinephrine / Q000097:blood; D011110:Polymorphism, Genetic; D011433:Propranolol / Q000494:pharmacology*; D011941:Receptors, Adrenergic / Q000235:genetics*; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics
D000319:Adrenergic beta-Antagonists; D011941:Receptors, Adrenergic; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D011433:Propranolol; D009638:Norepinephrine; D004837:Epinephrine