Functional evidence for a cyclic-AMP related mechanism of action of the beta(2)-adrenoceptor in human ventricular myocytes.
The human ventricle contains both beta(1)- and beta(1)-adrenoceptors (AR) and both have been shown to be present on a single myocyte. In animal ventricular myocardium there is evidence that beta(1)ARs increase cardiac contraction by non-cAMP-dependent mechanisms. We have used the anti-adrenergic effects of carbachol and the cAMP antagonist Rp -cAMPS to investigate the functional contribution of cAMP to beta(2)AR responses in human ventricular myocytes isolated from cardiac biopsies or explants. Concentration-response curves to isoproterenol (Iso) were constructed in the absence and presence of a beta(1)AR antagonist, CGP 207 12A (300 nmol/l) to determine the contribution of the beta(2)AR to contraction. The cells were rechallenged with sub-maximal dose of Iso under beta(2)AR-specific conditions and Rp -cAMPS (100-200 micromol/l) or carbachol (1-3 microm/l) added. Rp -cAMPS significantly decreased contraction amplitude (% shortening; Iso 7.1+/-0.7, Iso+Rp -cAMPS 3.5+/-0.5, n=7, P<0.001) though not completely to the baseline (2.2+/-0.6, n=7). Rechallenge with Iso alone reversed the effects of Rp -cAMPS, and subsequent addition of the beta(1)AR antagonist ICI 118,551 reduced the response to baseline (1.6+/-0.3, n=4) confirming beta(2)AR involvement. Similarly, carbachol decreased Iso-stimulated contraction from 7.5+/-1.2% to 3.2+/-0.9% (P<0.05, n=4), but not completely to basal levels (1.6+/-0.3%). These results provide functional evidence for a predominantly cAMP-mediated mechanism of contractile stimulation by beta(1)ARs in human ventricular myocardium, although a small contribution from a non-cAMP dependent pathway may occur.
Adamson
D L
DL
NHLI, Imperial College School of Medicine, Dovehouse Street, London, SW3 6LY. d.adamson@ic.ac.uk
Money-Kyrle
A R
AR
Harding
S E
SE
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism* / Q000502:physiology
D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D007093:Imidazoles; D018343:Receptors, Adrenergic, beta-2; D002217:Carbachol; C049763:CGP 20712A; D000242:Cyclic AMP; D007545:Isoproterenol