NEGATIVE INOTROPIC ACTION OF DENBUFYLLINE THROUGH INTERFERING WITH THE CALCIUM-CHANNEL INDEPENDENTLY OF ITS PDE-IV INHIBITORY ACTIVITY IN GUINEA-PIG VENTRICLE PAPILLARY-MUSCLES

The inotropic actions of xanthine derivatives with long alkyl chains w ere investigated in guinea pig ventricular papillary muscle. A potent and nonselective phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methy lxanthine, elicited a positive inotropy and inhibited the negative ino tropic effects of calcium channel inhibitors, as did a selective PDE I II inhibitor, amrinone, and these effects were canceled by a protein k inase inhibitor, romocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H -89). However, 1,3-di-n-butyl-7-(2'-oxopropyl)xanthine (denbufylline) and 1-n-butyl-3-n-propylxanthine (XT-044), which have potent and selec tive PDE IV-inhibitory activities, showed negative inotropic actions t hat became more potent in the presence of H-89. Denbufylline abolished the late restoration phase induced by ryanodine. This xanthine deriva tive attenuated the effects of both the calcium channel acting agents Bay K 8644 and verapamil, without interaction with caffeine and dihydr opyridine calcium channel inhibitors, and denbufylline had little dire ct influence on the specific binding of [H-3]azidopine and [H-3]desmet hoxyverapamil to cardiac membranes. A nonxanthine PDE IV inhibitor, Ro 20-1724, did not affect the inotropic actions of calcium channel inhi bitors, The attenuation by denbufylline or XT-044 of the negative inot ropic action of verapamil was not influenced by treatment with H-89. T hese results suggest that in the ventricular papillary muscle, these x anthine derivatives elicit negative inotropy by acting on a verapamil- sensitive site of the calcium channel without involving their PDE-inhi bitory activity.