Pharmacological analysis of the effects of Bay K 8644 and organic calcium antagonists on the mouse isolated distal colon.
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 x 10(-7) M). The responses were not affected by atropine (10(-7) M), mepyramine (2.5 x 10(-7) M), methysergide (5 x 10(-7) M), propranolol (10(-6) M), phentolamine (10(-6) M) or naloxone (4 x 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 x 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 (10-9M) 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.