Cardiopharmacological profile of HOE 234, the new activator of ATP-sensitive K+ channels in the guinea pig heart.

The direct chronotropic and inotropic effects of HOE 234, the new activator of ATP sensitive K+ channels (KATP) were examined in isolated preparations of right ventricle papillary muscle and right atria from the guinea pig heart. HOE 234 (0.3-3 microM) produced concentration-dependent negative inotropic (IC50 = 0.5 +/- 0.1 microM) and chronotropic (IC50 = 0.56 +/- 0.08 microM) effects. These effects were significantly attenuated by glibenclamide, a selective blocker of KATP channels in the heart muscle, with pA2 = 6.6 for inotropic and 6.65 for chronotropic action of HOE 234. The results have shown that HOE 234 activates the KATP in the guinea pig papillary muscle as well as in the right atria with a high affinity. The onset of the negative inotropic and chronotropic effects was fast and similar in both preparations (5-7 min). However, the time needed for the recovery of the force of contraction was markedly longer (about 90 min) than that for the right atria to return to the control rate (about 40 min). The effects of HOE 234 compared to those of other known activators of KATP suggest its higher selectivity to myocardium.