Positive inotropic effect of a stable analogue of PGI2 and of PGI2 on isolated guinea pig atria. Mechanism of action.

Fluoroprostacyclin (10,10-difluoro-13,14-dehydroprostacyclin) a stable analogue of PGI2, induced an increase of contractile tension and a positive chronotropic effect on spontaneously beating guinea-pig atria. The increase in contractile tension was proportional to the dose (10(-8) to 2.5 X 10(-7) M) and never exceeded 40% of absolute initial controls. The chronotropic positive effect was low (12 +/- 4%) and not dose-dependent. The positive inotropic effect was also evident on electrically driven atria and was greater at the slower rates of stimulation. Atria from guinea pigs pretreated with reserpine were still sensitive to fluoroprostacyclin, although to a lower degree. The use of appropriate agonists and antagonists excluded the possibility that beta and alpha receptors are involved in the positive inotropic effect of fluoroprostacyclin. PGI2 showed the same behavior as fluoro-PGI2. Prostacyclins were able to reverse the decrease of contractility induced by verapamil, nifedipine, tetrodotoxin and xylocaine. But the reversal by PGI2 was no longer evident when the atrial contractility was completely abolished by the presence of these drugs in high concentrations. The inotropic effect of prostacyclins was more evident when Ca2+ was reduced in the medium. These results demonstrate that the cardiostimulant effect of prostacyclins is not simply adrenergic in origin. A direct effect on ion movements, mainly dependent on Ca2+ transmembranes fluxes, may be largely responsible for their positive inotropic effect.