Human atrial beta(1L)-adrenoceptor …

Christ, T., et al. (2011). "Human atrial beta(1L)-adrenoceptor but not beta(3)-adrenoceptor activation increases force and Ca2+ current at physiological temperature." British Journal of Pharmacology 162(4): 823-839.

BACKGROUND AND PURPOSE It has been proposed that BRL37344, SR58611 and CGP12177 activate beta(3)-adrenoceptors in human atrium to increase contractility and L-type Ca2+ current (ICa-L). beta(3)-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 beta(1)-adrenoceptor in human atrium. We therefore used BRL37344, SR58611 and (-)-CGP12177 with selective beta-adrenoceptor subtype antagonists to clarify cardiostimulant beta-adrenoceptor subtypes in human atrium. EXPERIMENTAL APPROACH 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. KEY RESULTS BRL37344 increased force which was antagonized by blockade of beta(1)- and beta(2)-adrenoceptors but not by blockade of beta(3)-adrenoceptors with beta(3)-adrenoceptor-selective L-748,337 (1 mu M). The beta(3)-adrenoceptor agonist SR58611 (1 nM-10 mu M) did not affect atrial force. BRL37344 and SR58611 did not increase ICa-L at 37 degrees C, but did at 24 degrees C which was prevented by L-748,337. (-)-CGP12177 increased force and ICa-L at both 24 degrees C and 37 degrees C which was prevented by (-)-bupranolol (1-10 mu M), but not L-748,337. CONCLUSIONS AND IMPLICATIONS We conclude that the inotropic responses to BRL37344 are mediated through beta(1)- and beta(2)-adrenoceptors. The inotropic and ICa-L responses to (-)-CGP12177 are mediated through the low affinity site beta(1L)-adrenoceptor of the beta(1)-adrenoceptor. beta(3)-adrenoceptor-mediated increases in ICa-L are restricted to low temperatures. Human atrial beta(3)-adrenoceptors do not change contractility and ICa-L at physiological temperature. LINKED ARTICLE This article is commented on by Michel et al., pp. 817-822 of this issue. To view this commentary visit http://dx.doi.org.ezproxy.library.uq.edu.au/10.1111/j.1476-5381.2010.01005.x.