Abstract
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 ((3 S,4 R)-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 ( N 6,2′- O-dibutyryladenosine 3′:5′-cyclic monophosphate). Experiments were performed with the isolated guinea-pig heart papillary muscle. The force of contraction ( F c), velocity of contraction (+d F/d t) and relaxation (−d F/d t), time to peak contraction ( t tp) and duration of contractions at the level of 10% or more of their total amplitude ( t t 10 ) were measured. Pretreatment with 1 μM rimalkalim had no significant influence on the positive inotropic effects of dibutyryl cyclic AMP and l-phenylephrine in the presence of 1 μM 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 μM 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 μM thapsigargin, a selective blocker of Ca 2+-adenosinetriphosphatase of sarcoplasmic reticulum (Ca 2+ 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 β-adrenoceptors, but has no effect on α-adrenoceptor signalling pathways and enhances forskolin inotropic effects by a mechanism which probably involves Ca 2+ ATP-ase.
Published Version
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