Abstract
The effects of Ca 2+ channel antagonists and benzodiazepine receptor ligands against concentration-dependent contractions of rat urinary bladder induced by CaCl 2 (0.1–50 mM, in K +-depolarized tissues), KCl (1–100 mM) and acetylcholine (0.1 μM to 1 mM) were studied. Nifedipine (0.001–0.1 μM), verapamil (0.01–1 μM), diltiazem (0.01–1 μM), cinnarizine (1–100 μM), and trifluoperazine (1–100 μM) each produced a concentration-related inhibition of the log concentration-effect curve for CaCl 2. The rank order of potencies of these antagonists, measured as the IC 50 against Ca 2+ (25 mM)-induced contraction of depolarized bladder, was nifedipine (0.01 μM) > diltiazem (0.36 μM) ≈ verapamil (0.41 μM) ≥ cinnarizine (2.57 μM) > trifluoperazine (17.4 μM). These antagonists depressed KCl-induced contractions with an effectiveness and potency similar to that displayed against CaCl 2-induced contractions. Nifedipine, verapamil, and diltiazem but not cinnarizine and trifluoperazine had a preferential inhibitory effect on the contractions elicited by KCl when compared to those elicited by acetylcholine. Ro 5-4864, diazepam, midazolam and the non-benzodiazepine PK 11195, each at 1–100 μM, depressed CaCl 2- and KCl-induced contractions (IC 50 values in the micromolar range). Benzodiazepines and PK 11195, all at 100 μM, markedly depressed acetylcholine-induced contractions. Flumazenil was scarcely effective. Cinnarizine (100 μM) and trifluoperazine (100 μM), but not the other Ca 2+ channel antagonists and benzodiazepine receptor ligands tested, depressed Ca 2+ (20 μM)-evoked contractions of skinned bladder. It is concluded that the action of nifedipine, verapamil, and diltiazem is restricted to the plasmalemma whereas cinnarizine and trifluoperazine also act on the intracellular contractile apparatus. The inhibitory effects of micromolar concentrations of benzodiazepines appear to be related to an interaction with low-affinity sites functionally linked to L-type Ca 2+ channels but intracellular actions are present at high concentrations.
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