Human atrial beta1L-adrenoceptor but not beta3-adrenoceptor activation increases force and Ca2+ current at physiological temperature
Christ, Torsten, Molenaar, Peter, Klenowski, Paul, Ravens, Ursula, & Kaumann, Alberto J. (2011) Human atrial beta1L-adrenoceptor but not beta3-adrenoceptor activation increases force and Ca2+ current at physiological temperature. British Journal of Pharmacology, 162(4), pp. 823-839.
BACKGROUND AND PURPOSE
It has been proposed that BRL37344, SR58611 and CGP12177 activate b3-adrenoceptors in human atrium to increase
contractility and L-type Ca2+ current (ICa-L). b3-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 b1-adrenoceptor in human atrium. We therefore used BRL37344, SR58611 and
(-)-CGP12177 with selective b-adrenoceptor subtype antagonists to clarify cardiostimulant b-adrenoceptor subtypes in
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 ICa-L. Contractile effects were
determined on right atrial trabeculae.
BRL37344 increased force which was antagonized by blockade of b1- and b2-adrenoceptors but not by blockade of
b3-adrenoceptors with b3-adrenoceptor-selective L-748,337 (1 mM). The b3-adrenoceptor agonist SR58611 (1 nM–10 mM) did
not affect atrial force. BRL37344 and SR58611 did not increase ICa-L at 37°C, but did at 24°C which was prevented by
L-748,337. (-)-CGP12177 increased force and ICa-L at both 24°C and 37°C which was prevented by (-)-bupranolol (1–10 mM),
but not L-748,337.
CONCLUSIONS AND IMPLICATIONS
We conclude that the inotropic responses to BRL37344 are mediated through b1- and b2-adrenoceptors. The inotropic and
ICa-L responses to (-)-CGP12177 are mediated through the low affinity site b1L-adrenoceptor of the b1-adrenoceptor.
b3-adrenoceptor-mediated increases in ICa-L are restricted to low temperatures. Human atrial b3-adrenoceptors do not change
contractility and ICa-L at physiological temperature.
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|Item Type:||Journal Article|
|Additional Information:||See link in Additional URL field for commentary on this article.|
|Keywords:||human heart, beta-adrenoceptors, beta1-adrenoceptors, beta1L-adrenoceptors, (-)-CGP 12177|
|Subjects:||Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PHARMACOLOGY AND PHARMACEUTICAL SCIENCES (111500)|
|Divisions:||Past > QUT Faculties & Divisions > Faculty of Science and Technology|
Current > Institutes > Institute of Health and Biomedical Innovation
Past > Schools > Pharmacy
|Copyright Owner:||Copyright 2011 Wiley|
|Deposited On:||27 Jan 2011 11:41|
|Last Modified:||11 Aug 2011 03:01|
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