5‐Hydroxytryptamine receptors that facilitate excitatory neuromuscular transmission in the guinea‐pig isolated detrusor muscle

1 In isolated detrusor strips from the guinea‐pig urinary bladder, contractile responses to electrical field stimulation were mostly mediated by neurally released acetylcholine (ACh) and adenosine 5′‐triphosphate (ATP). 2 5‐Hydroxytryptamine (5‐HT) produced a concentration‐dependent increase in the amplitude of stimulated detrusor strip contractions. The 5‐HT concentration‐response curve showed a biphasic profile: the high potency phase was obtained at sub‐micromolar concentrations (10–300 nM), while the low potency phase in the range 1–30 μm. The maximum response of the first phase was 30% of the total 5‐HT response. 3 Like 5‐HT, the 5‐HT3 receptor agonist, 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT: 0.3–100 μm), the 5‐HT2 receptor agonist, (±)‐l‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI: 30 nM‐3 μm) and the 5‐HT4 receptor agonist, 5‐methoxytryptamine (5‐MeOT: 0.1–30 μm) potentiated, though with lower potency, detrusor contractions. The resulting concentration‐response curves were monophasic in nature. 2‐Methyl‐5‐HT had a maximum effect comparable to that of 5‐HT. By contrast, the maximal effects of DOI and 5‐MeOT were only 20% and 30% of that elicited by 30 μm 5‐HT, respectively. 4 The 5‐HT3 receptor antagonist, granisetron (0.3 μm) had no effect on the high potency phase, but caused a rightward parallel shift of the low potency phase of the 5‐HT curve (pKB = 7.3). Granisetron (0.3 μm) antagonized with comparable affinity (pKB= 7.1) 5‐HT‐induced responses after pharmacological isolation of 5‐HT3 receptors with the 5‐HT1/5‐HT2 receptor antagonist, methiothepin (0.3 μm) and the 5‐HT4 receptor antagonist, GR 125487 (30 nM). Granisetron (0.1, 0.3 and 1 μm) competitively antagonized the potentiating effect of 2‐methyl‐5‐HT with an estimated pA2 of 7.3. 5 Methiothepin (0.3 μm) and the 5‐HT2A receptor antagonist, ketanserin (0.3 μm) produced a slight inhibition of the first phase of the 5‐HT curve. In the presence of ketanserin, an equimolar concentration of methiothepin was ineffective in further reducing the effect of 5‐HT. Similarly, the 5‐HT4 receptor antagonist, GR 125487 (30 nM) slightly inhibited the first phase of the 5‐HT curve. Conversely, this phase was suppressed when detrusor strips were coincubated with ketanserin (or methiothepin) and GR 125487. 6 In a separate set of experiments, the interactions of 5‐HT with either the purinergic or cholinergic components of excitatory neuromuscular transmission were investigated. In the presence of hyo