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. Copyright 2000 Academic Press.