The highs (B1H) and lows (B1L) of human heart B1-adrenoceptors (AR)
Molenaar, P., Klenowski, P., Semmler, A., Chee, K., Iconomou, M., Tugiono, N., Kiriazis, H., Xu, Qiang, Du, XJ., Ravens, U., Christ, T., & Kaumann, A. (2010) The highs (B1H) and lows (B1L) of human heart B1-adrenoceptors (AR). In Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists and Carney Symposium, 29-31 August 2010, Christchurch, New Zealand.
The 1AR has two binding sites which can be activated to cause cardiostimulation. The first, termed, 1HAR (high affinity site of 1AR) is activated by noradrenaline and adrenaline and is blocked by relatively low concentrations of β-blockers including carvedilol (Kaumann and Molenaar, 2008). The other, termed, 1LAR (low affinity site of 1AR) has lower affinity for noradrenaline and adrenaline and is activated by some β-blockers including CGP12177 and pindolol, at higher concentrations than those required to block the receptor (Kaumann and Molenaar, 2008). (-)-CGP12177 is a non-conventional partial agonist that causes modest and transient increases of contractile force in human atrial trabeculae (Kaumann and Molenaar, 2008). These effects are markedly increased and maintained by inhibition of phosphodiesterase PDE3. The stimulant effects of (-)-CGP12177 at human β1ARs was verified with recombinant receptors (Kaumann and Molenaar, 2008). However, in a recent report it was proposed that the positive inotropic effects of CGP12177 are mediated through 3ARs in human right atrium (Skeberdis et al 2008). This proposal was not consistent with the lack of blockade of (-)-CGP12177 inotropic effects or increases in L-type Ca2+ current (ICa-L ) by the β3AR blocker 1 μM LY748,337 (Christ et al, 2010). On the otherhand, (-)-CGP12177 increases in inotropic effects and ICa-L were blocked by (-)-bupranolol 1-10 μM (Christ et al, 2010). Chronic infusion of (-)-CGP 12177 (10 mg/Kg/24 hours) for four weeks in an aortic constriction mouse model of heart failure caused an increase in left ventricular wall thickness, fibrosis and inflammation-related left ventricular gene expression levels.
Christ T et al (2010) Br J Pharmacol, In press Kaumann A and Molenaar P (2008) Pharmacol Ther 118, 303-336 Skeberdis VA et al (2008) J Clin Invest, 118, 3219-3227
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|Item Type:||Conference Item (Keynote)|
|Keywords:||Human heart, beta-adrenoceptors, b1H-adrenoceptors, b1L-adrenoceptors|
|Subjects:||Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PHARMACOLOGY AND PHARMACEUTICAL SCIENCES (111500) > Basic Pharmacology (111501)|
|Divisions:||Past > QUT Faculties & Divisions > Faculty of Science and Technology|
Current > Institutes > Institute of Health and Biomedical Innovation
|Copyright Owner:||Copyright 2010 Please consult the authors.|
|Deposited On:||06 Sep 2010 10:22|
|Last Modified:||11 Aug 2011 04:28|
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