Tachykinin antagonists and capsaicin‐induced contraction of the rat isolated urinary bladder: evidence for tachykinin‐mediated cotransmission

Abstract

1 The possible involvement of tachykinins (TKs) in the contraction produced by capsaicin in the rat isolated urinary bladder was addressed on the hypothesis that co-release of substance P (SP) and neurokinin A (NKA) occurs from sensory nerve terminals. 2 A low concentration of SP (30 nM) produced a rapid contraction which faded to baseline within 10min. A low concentration of NKA (10nM) produced a slowly developing contraction which was still evident at 10min. Capsaicin (1 pM) produced a rapid phasic response and a tonic response (late response to capsaicin). Co-administration of SP and NKA mimicked the response to capsaicin more than each TK alone. 3 Fading of the response to SP was not caused by receptor desensitization and was partially prevented by peptidase inhibitors.4 Spantide (3pM) selectively antagonized the SP-induced contraction while L-659,877 (3-lOpM) or MEN 10,376 (10-30pM) which are NK2 receptor selective antagonists selectively blocked the response to NKA.Co-administration of spantide and L-659,877 inhibited the response to both SP and NKA by an amount not greater than that produced by each antagonist alone. 5 Spantide selectively reduced the peak response to capsaicin, while leaving the late response unaffected.L-659,877 (3 pM) and MEN 10,376 (10pM) selectively inhibited the late response to capsaicin while, at higher concentrations, also reduced the peak response to capsaicin. Co-administration of spantide and L-659,877 reduced the peak response to capsaicin more than that produced by each antagonist alone. 6 Bombesin (10nM) produced a tonic contraction similar to that induced by NKA. The response to bombesin was not affected by spantide, L-659,877 or MEN 10,376. 7 P2. purinoceptor desensitization by repeated administration of a,fl-methylene ATP depressed the twitch response to electrical stimulation of postganglionic nerves but did not affect the peak or the late response to capsaicin. 8 We conclude that multiple TKs are coreleased by capsaicin in the rat bladder and mediate the capsaicin-induced contraction by activating both NKI and NK2 receptors. Endogenous TK with preferential affinity for the NK, receptor (putatively SP) are selectively involved in the peak response to capsaicin while endogenous TK with preferential affinity for the NK2 receptor (putatively NKA) are selectively involved in the late response to capsaicin and partly contribute to the peak response. These findings provide pharmacological evidence for tachykinin-mediated cotransmission in the rat urinary bladder. ATP is unlikely to be involved in the efferent function of capsaicin-sensitive sensory nerves in the rat bladder.

Mechanisms of neurokinin A‐ and substance P‐induced contractions in rat detrusor smooth muscle in vitro

“…Furthermore, in agreement with previous observations, these contractions were caused by a direct action on the muscle, as they were unaffected by tetrodotoxin [6,17]. Tachykinin-induced contractions were also unaffected by peptidase inhibitors, indicating little involvement of enzyme degradation in limiting the action of tachykinins in rat urinary bladder.…”

“…In the rat urinary bladder, the contractile responses to tachykinins are mediated via activation of NK 1 receptors by substance P and NK 2 receptors by neurokinin A [6,7] implying a duplication in tachykinergic signalling. Once released from afferent nerves, the activity of tachykinins at their receptors can be modulated by peptidases.…”

Hydrogen sulfide (H2S) stimulates capsaicin‐sensitive primary afferent neurons in the rat urinary bladder

“…H 2 S itself undergoes a complete tachyphylaxis, a second administration of this drug being totally ineffective; (2) preparations pretreated with H 2 S (30 mM-3 mM) become less responsive to capsaicin, showing that a (partial) cross-desensitization phenomenon occurs between the two drugs; (3) a combination of tachykinin NK 2 (nepadutant) and NK 1 (GR 82334) receptorselective antagonists, administered at concentrations producing strong, albeit selective, inhibition of responses mediated by these two receptors (Meini et al, 1994), completely prevents H 2 S-induced contractile effects. In a previous study (Maggi et al, 1991), we had shown that less potent and selective NK 1 and NK 2 antagonists (i.e. spantide and L 659877, respectively) are capable of strongly reducing the response to capsaicin in the rat urinary bladder.…”

“…The ability of capsaicin to produce smooth muscle excitatory and/or inhibitory effects by activating the local efferent function of capsaicin-sensitive sensory nerves has widely been investigated by our and other groups (Holzer, 1991;Maggi, 1995, for reviews). In particular, in the rat urinary bladder capsaicin produces excitatory motor responses that are mediated by tachykinins (mainly substance P, and neurokinin A) released from the activated sensory nerve terminals (Maggi et al, 1991). Tachykinins, in turn, stimulate tachykinin NK 1 and NK 2 receptors present on detrusor smooth muscle cells to produce the observed contractile response to capsaicin (Maggi et al, 1991).…”

“…In particular, in the rat urinary bladder capsaicin produces excitatory motor responses that are mediated by tachykinins (mainly substance P, and neurokinin A) released from the activated sensory nerve terminals (Maggi et al, 1991). Tachykinins, in turn, stimulate tachykinin NK 1 and NK 2 receptors present on detrusor smooth muscle cells to produce the observed contractile response to capsaicin (Maggi et al, 1991). One peculiar feature of capsaicin action is that the excitatory effects produced by this drug are followed by desensitization of sensory nerves, which become progressively less responsive to capsaicin itself and other activating stimuli (Maggi, 1995).…”