Studies on the Mechanism of the Positive Inotropic Effect of Piroximone in Cat Papillary Muscle

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Abstract
The mechanism of the inotropic effect of piroximone HC1 [MDL 19205A, 4-ethyl-1,3-dihydro-5-(4-pyridinylcarbonyl)-2H-imidozol-2-one HCl] was studied in the cat papillary muscle paced electrically in vitro. Piroximone produced a concentration-dependent positive inotropic effect accompanied by an increase in rate of contraction and rate of relaxation, but abbreviated time to peak tension and relaxation time. The positive inotropic effect produced by piroximone was antagonized by carbachol, 3 × 10−6M, whereas that produced by increasing calcium concentration was not affected by carbachol. In potassium chloride (22 mM) depolarized muscle, piroximone restored contractility, which was not affected by propranolol (10−6M) or by tetrodotoxin (2 × 10−5M), but was inhibited by nifedipine (10−7M). Piroximine also elevated tissue cyclic AMP (cAMP) content in the papillary muscle. Although nifedipine inhibited the restoration of contractility, it did so without altering the increase of cAMP produced by piroximone. These results suggest that piroximone causes an increase in calcium influx that is mediated by an increase in cAMP, and the results are consistent with the hypothesis that specific inhibition of the high affinity cAMP phosphodiesterase (PDE III) plays a role in the positive inotropic effect of piroximone.