Cantharidin attenuates the anti-β-adrenergic or anti-histaminergic or anti-serotoninergic effect of A1-adenosine receptor stimulation in the isolated human atrium

(R)-N⁶-Phenylisopropyladenosine (R-PIA), an agonist at A₁-adenosine receptors, per se leads to so-called "direct" negative inotropic effects (NIE) in mammalian atrium. These NIE in mammalian atrium are often accentuated in the presence of cAMP-increasing agonists acting through GTP-binding stimulatory proteins in the sarcolemma such as isoprenaline (via β-adrenoceptors), histamine (via H₂-histamine receptors) or serotonin (via 5-HT₄-serotonin receptors) so-called "indirect" effects. Cantharidin inhibits protein phosphatases 1 and 2A (PP1, PP2A). We hypothesized that cantharidin would attenuate this NIE of R-PIA because R-PIA activated the PPs, whereas isoprenaline, serotonin, and histamine most likely inhibit PPs. Thence, during open-heart surgery in patients suffering from severe coronary heart disease, trabeculae carneae from human right atrium (HAP) were studied. These HAPs were put into organ baths and electrically stimulated (1 Hz). For comparison, we investigated isolated electrically paced (1 Hz) left atrial preparations (LA) from wild type mice (WT) or from mice with cardiac overexpression of H₂-histamine receptors (H₂-TG) or mice with cardiac overexpression of the human 5-HT₄-serotonin receptors (5-HT₄-TG). R-PIA led to negative inotropic effects (NIE) in HAP and LA from WT in the presence of isoprenaline, which were lessened by cantharidin. Likewise, R-PIA diminished force of contraction (FOC) in HAP and in LA from H₂-TG excited by histamine, and also these NIE were made smaller by cantharidin. Similarly, R-PIA dampened FOC in HAP and in LA from 5-HT₄-TG aroused by serotonin, and these NIE were weakened by cantharidin. We hypothesize that A₁-adenosine receptors shrink the positive inotropic effects of β-adrenoceptors, H₂-histamine receptors, or 5-HT₄-serotonin receptors, in part, by activating PP1 and/or PP2A in the human atrium.