The preferential beta3-adrenoceptor agonist BRL 37344 increases force via beta1-/beta2-adrenoceptors and induces endothelial nitric oxide synthase via beta3-adrenoceptors in human atrial myocardium.
1 The present study investigated the effects of the preferential beta(3)-AR agonist BRL 37344 (BRL) on force of contraction (FOC), Ca(2+)-transient and eNOS-activity in human right atrial myocardium. 2 BRL concentration-dependently caused an increase in FOC that was paralleled by an increase in Ca(2+)-transient and a shortening of time to half peak relaxation (T0.5T). These effects were abolished in the presence of propranolol (0.3 micro M). 3 BRL acted as a competitive antagonist towards isoprenaline and in binding experiments it was shown to have a distinct affinity towards beta(1/2)-AR. 4 In immunohistochemical experiments BRL (10 micro M) increased detection of activated eNOS. This effect remained constant in the presence of propranolol (0.3 micro M). 5 BRL increased directly detected NO in DAF-staining experiments. This increase was significantly smaller in the presence of the NO-inhibitor L-NAME. 6 The inotropic effects of BRL were not changed in the presence of L-NMA. 7 These results suggest that the inotropic effects of BRL in human atrium are mediated via beta(1/2)-AR, whereas the increase of atrial eNOS-activity is due to beta(3)- adrenergic stimulation. This increase in eNOS-activity did not influence atrial myocardial contractility. In conclusion, this study shows that beta(3)-adrenergic stimulation is present in human atrium, but may not be functionally as significant as in the left ventricle.
Pott
C
C
Clinic III of Internal Medicine, Laboratory of Muscle Research and Molecular Cardiology, University of Cologne, Köln, Germany.
Brixius
K
K
Bundkirchen
A
A
Bölck
B
B
Bloch
W
W
Steinritz
D
D
Mehlhorn
U
U
Schwinger
R H G
RH
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000368:Aged; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005470:Fluorometry; D006325:Heart Atria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; C057368:BRL 37344; D011433:Propranolol; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D002118:Calcium