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

Abstract

BACKGROUND AND PURPOSE:

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.

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 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 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.

• Authors: Torsten Christ, Peter Molenaar, Paul M Klenowski, Ursula Ravens, Alberto J Kaumann
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 162 Issue 4 Pg. 823-39 (Feb 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 20726983 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• ADRB1 protein, human
• ADRB2 protein, human
• Adrenergic beta-Agonists
• Adrenergic beta-Antagonists
• Calcium Channels, L-Type
• Ethanolamines
• Propanolamines
• Receptors, Adrenergic, beta-1
• Receptors, Adrenergic, beta-2
• Receptors, Adrenergic, beta-3
• Tetrahydronaphthalenes
• BRL 37344
• amibegron
• CGP 12177

Topics

• Adrenergic beta-Agonists (pharmacology)
• Adrenergic beta-Antagonists (pharmacology)
• Aged
• Atrial Appendage (cytology)
• Calcium Channels, L-Type (metabolism)
• Calcium Signaling (drug effects)
• Ethanolamines (antagonists & inhibitors, pharmacology)
• Female
• Humans
• In Vitro Techniques
• Kinetics
• Male
• Middle Aged
• Myocardial Contraction (drug effects)
• Myocytes, Cardiac (drug effects, metabolism)
• Propanolamines (antagonists & inhibitors, pharmacology)
• Receptors, Adrenergic, beta-1 (metabolism)
• Receptors, Adrenergic, beta-2 (metabolism)
• Receptors, Adrenergic, beta-3 (metabolism)
• Temperature
• Tetrahydronaphthalenes (antagonists & inhibitors, pharmacology)