Human atrial β(1L)-adrenoceptor but not β₃-adrenoceptor activation increases force and Ca(2+) current at physiological temperature.

background and purposeIt 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. 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 I(Ca-L). Contractile effects were determined on right atrial trabeculae. KEY

resultsBRL37344 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 AND IMPLICATIONS: 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.