Inhibitory effects of AH 21–132 in guinea‐pig isolated ileum and taenia caeci

1 AH 21–132 is being investigated as a potential chemotherapeutic agent for bronchial asthma. The present experiments were designed to determine whether AH 21–132 shares the activity of theophylline as an antagonist at adenosine A 1 receptors and to assess its potency as a relaxant in intestinal smooth muscle. 2 In the transmurally‐stimulated guinea‐pig ileum, theophylline (1 m m ), but not AH 21–132 (1 and 10 μ m ), antagonized twitch depression induced by adenosine. Higher concentrations (100 μ m and 1 m m ) of AH 21–132 themselves had a depressant effect. Neither theophylline (1 m m ) nor AH 21–132 (1 and 10 μ m ) antagonized twitch depression induced by noradrenaline. 3 AH 21–132 (100 μ m and 1 m m ) depressed maximum contractions of ileum induced by both acetylcholine (ACh) and histamine. 4 In ileum treated with hyoscine (1 μ m ), AH 21–132 (>10 μ m ) caused a concentration‐dependent depression of the log concentration‐effect curve for potassium chloride. 5 Simultaneous extracellular electrophysiological and mechanical recording from taenia caeci showed that AH 21–132 (100 μ m ‐1 m m ) inhibited spontaneous tension waves and their associated bursts of electrical spike activity. 6 Intracellular electrophysiological recording from taenia caeci showed that the mechano‐inhibitory effect of 1 mM AH 21–132 was accompanied by abolition of spontaneous spike activity. Following spike abolition, the membrane potential assumed a value very close to that observed during periods of electrical quiescence prior to drug exposure. 7 AH 21–132 inhibited the activity of cyclic AMP‐dependent and cyclic GMP‐dependent phosphodiesterases derived from homogenates of ileal smooth muscle. The effective concentration ranges were 0.1–1000 μ m and 1–1000 μ m , respectively. Theophylline, too, inhibited these enzymes but in each case was less potent than AH 21–132. 8 It is concluded that AH 21–132 is devoid of antagonist activity at adenosine A 1 receptors which modulate ACh release from intramural cholinergic nerves in the ileum. At concentrations greater than 10 μ m , AH 21–132 has a relaxant effect on intestinal smooth muscle characterized by suppression of spontaneous action potentials but by minor change in resting membrane potential. AH 21–132 previously has been reported to depress the spontaneous tone of trachealis muscle with an EC 50 value of less than 10 μ m and the present experiments therefore show that this agent is much less potent in inhibiting intestinal muscle. This potency difference cannot be attributed to a tissue‐related difference in the potency of AH 21–132 as an inhibitor of cyclic AMP‐ or cyclic GMP‐dependent phosphodiesterases.