Pretreatment with rimalkalim changes the adrenergic responsiveness of isolated guinea pig papillary muscle.

It has been proposed that the positive inotropic action of different drugs is influenced by the activation of ATP-sensitive K+ channels (K(ATP)). This hypothesis was tested by investigating the effects of rimalkalim ((3S,4R)-3-hydroxy-2,2-dimethyl-4-(oxo-1 pyrrolidinyl)-6-phenyl-sulfonylchroman hemihydrate (formerly HOE-234)) as activator of K(ATP) channels on the positive inotropic action of forskolin, L-phenylephrine hydrochloride and dibutyryl cyclic AMP (N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate). Experiments were performed with the isolated guinea-pig heart papillary muscle. The force of contraction (Fc), velocity of contraction (+dF/dt) and relaxation (-dF/dt), time to peak contraction (t(tp)) and duration of contractions at the level of 10% or more of their total amplitude (t(t10)) were measured. Pretreatment with 1 microM rimalkalim had no significant influence on the positive inotropic effects of dibutyryl cyclic AMP and L-phenylephrine in the presence of 1 microM metoprolol. However, the positive inotropic effects of L-phenylephrine in the absence of metoprolol were significantly attenuated after pretreatment with rimalkalim. The increase in force and velocity of contraction induced by forskolin was strongly enhanced under these conditions. Addition of 1 microM glibenclamide, an inhibitor of K(ATP) channels, to rimalkalim, prevented the above-mentioned changes in the positive inotropic effects of phenylephrine and forskolin obtained after pretreatment with rimalkalim. What is more, addition of 0.2 microM thapsigargin, a selective blocker of Ca2+-adenosinetriphosphatase of sarcoplasmic reticulum (Ca2+ ATP-ase), abolished the potentiation of the positive inotropic action of forskolin induced by pretreatment with rimalkalim. These results demonstrate that activation of K(ATP) channels by rimalkalim alters beta-adrenoceptors, but has no effect on alpha-adrenoceptor signalling pathways and enhances forskolin inotropic effects by a mechanism which probably involves Ca2+ ATP-ase.