Effects of several phosphodiesterase-inhibitors on guinea-pig myocardium

Abstract

1. The inotropic effects of (±)-isoprenaline and several phosphodiesterase (PDE)-inhibitors were studied in isometrically contracting guinea-pig papillary muscles driven at a rate of 0.2 Hz. The maximal positive inotropic effect of isoprenaline (ΔFc=2.2 g;n=7) corresponded to that of 1-methyl, 3-isobutylxanthine (IBMX) and theophylline (ΔFc=2.1 and 2.2 g, respectively;n=7 each). Papaverine produced only a slight increase in contractile force (ΔFc=0.38 g;n=7), which in some preparations was completely absent. 2. The positive inotropic effects of IBMX, theophylline, and papaverine were not due to release of noradrenaline from adrenergic nerve endings. Blockade of the β-adrenoceptors with 5×10−6 M (±)-propranolol did not prevent the positive inotropic effect of IMBX. 3. The relaxation time,t2, was shortened by isoprenaline (36 ms) more than by IBMX (28 ms) while the time to peak force,t1, was reduced by 12 ms by isoprenaline and by 24 ms by IBMX. Isoprenaline and IBMX abbreviated the total contraction time,t1+t2, to nearly the same extent (48 and 52 ms, respectively). Theopylline and papaverine prolongedt1+t2 by 68 and 30 ms, respectively, due to a lengthening oft2. 4. IBMX, theophylline, and papaverine shifted the isoprenaline concentration-effect curve to the left, decreasing the concentration of isoprenaline required to produce a half-maximal increase in the force of contraction from 1×10−8 M to 2×10−9 M for IBMX and papaverine and to 3.2×10−9 M for theophylline. IBMX enhanced the inotropic effect of dibutyryl cyclic AMP by a factor of 7. 5. Among several PDE-inhibitors, IBMX was found to mimic the effects of isoprenaline with regard to its maximum inotropic effect and its shortening oft1+t2. Isoprenaline-like effects of theophylline and papaverine were probably masked by the involvement of additional factors discussed in this study.