Pharmacological analysis of the effects of Bay K 8644 and organic calcium antagonists on the mouse isolated distal colon

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Abstract
1 Bay K 8644 (10−8 to 10−6 m) induced concentration-related contractions of the longitudinal muscle of the mouse distal colon. The maximal responses were enhanced and the EC50 was lowered in the presence of tetrodotoxin (TTX; 1.5 × 10−7 m). The responses were not affected by atropine (10−7 m), mepyramine (2.5 × 10−7 m), methysergide (5 × 10−7 m), propranolol (10−6 m), phentolamine (10−6 m) or naloxone (4 × 10−7 m). By contrast, the contractile responses were inhibited by Ca2+ entry blockers (verapamil, nifedipine) and abolished in Ca2+-free EGTA solution. These observations indicate that the contractile effects of Bay K 8644 are dependent on its ability to promote Ca2+ influx. 2 At 10−4 m, Bay K 8644 provoked a slow relaxation of the preparation. Moreover, from 10−5 m, Bay K 8644 markedly reduced the contractile responses to ACh and K+ depolarization. These inhibitory effects were comparable with those produced by nifedipine. Such data suggest that, at high concentrations, Bay K 8644 could act in part as a dihydropyridine Ca2+ channel antagonist. 3 Bay K 8644 (10−9 m) preferentially enhanced, while nifedipine (10−10 to 10−8 m) as well as verapamil (3 × 10−9 to 10−6 m) preferentially inhibited, the tonic component of the contractile response evoked by K+ depolarizing solution. This may indicate that different populations of voltage-sensitive Ca2+ channels are involved in the biphasic response to K+ depolarization. 4 The biphasic contractile activity induced by ACh was barely enhanced by Bay K 8644 (10−9 m) and was less sensitive to Ca2+ entry blockers than the responses to KCl. These findings are discussed in terms of receptor-operated channels and mobilization of bound calcium.