Human atrial β(1L)-adrenoceptor but not β₃-adrenoceptor activation increases force and Ca(2+) current at physiological temperature.
OBJECTIVE
It has been proposed that BRL37344, SR58611 and CGP12177 activate β₃-adrenoceptors in human atrium to increase contractility and L-type Ca(2+) current (I(Ca-L)). β₃-adrenoceptor agonists are potentially beneficial for the treatment of a variety of diseases but concomitant cardiostimulation would be potentially harmful. It has also been proposed that (-)-CGP12177 activates the low affinity binding site of the β₁-adrenoceptor in human atrium. We therefore used BRL37344, SR58611 and (-)-CGP12177 with selective β-adrenoceptor subtype antagonists to clarify cardiostimulant β-adrenoceptor subtypes in human atrium.


METHODS
Human right atrium was obtained from patients without heart failure undergoing coronary artery bypass or valve surgery. Cardiomyocytes were prepared to test BRL37344, SR58611 and CGP12177 effects on I(Ca-L). Contractile effects were determined on right atrial trabeculae.


RESULTS
BRL37344 increased force which was antagonized by blockade of β₁- and β₂-adrenoceptors but not by blockade of β₃-adrenoceptors with β₃-adrenoceptor-selective L-748,337 (1 µM). The β₃-adrenoceptor agonist SR58611 (1 nM-10 µM) did not affect atrial force. BRL37344 and SR58611 did not increase I(Ca-L) at 37°C, but did at 24°C which was prevented by L-748,337. (-)-CGP12177 increased force and I(Ca-L) at both 24°C and 37°C which was prevented by (-)-bupranolol (1-10 µM), but not L-748,337.


CONCLUSIONS
We conclude that the inotropic responses to BRL37344 are mediated through β₁- and β₂-adrenoceptors. The inotropic and I(Ca-L) responses to (-)-CGP12177 are mediated through the low affinity site β(1L)-adrenoceptor of the β₁-adrenoceptor. β₃-adrenoceptor-mediated increases in I(Ca-L) are restricted to low temperatures. Human atrial β₃-adrenoceptors do not change contractility and I(Ca-L) at physiological temperature.
Christ
Torsten
T
Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany.
Molenaar
Peter
P
Klenowski
Paul M
PM
Ravens
Ursula
U
Kaumann
Alberto J
AJ
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000368:Aged; D020517:Atrial Appendage / Q000166:cytology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004983:Ethanolamines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011412:Propanolamines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013696:Temperature; D013764:Tetrahydronaphthalenes / Q000037:antagonists & inhibitors / Q000494:pharmacology
C547787:ADRB1 protein, human; C553443:ADRB2 protein, human; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D020746:Calcium Channels, L-Type; D004983:Ethanolamines; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes; C057368:BRL 37344; C076252:amibegron; C033394:CGP 12177