Tachykinin receptors in the guinea‐pig renal pelvis: activation by exogenous and endogenous tachykinins

Abstract

The contractile response to substance P, neurokinin A, selective agonists for the NK1, NK2 and NK3 tachykinin receptors and the activity of receptor‐selective antagonists has been investigated in circular muscle strips of the guinea‐pig isolated renal pelvis in the presence of indomethacin (3 μm). Neurokinin A was the most potent agonist tested, being about 32 times more potent than substance P. The action of both substance P and neurokinin A was enhanced by peptidase inhibitors (bestatin, captopril and thiorphan, 1 μm each). The selective NK2 receptor agonist [βAla8] neurokinin A (4–10), was slightly less potent and effective than neurokinin A itself. The selective NK1 receptor agonist [Sar9] substance P sulphone was effective at low (nm) concentrations but its maximal effect did not exceed 30% of maximal response to substance P or neurokinin A. The NK3‐selective agonist [MePhe7] neurokinin B was effective only at high (μm) concentrations. The pseudopeptide derivative of neurokinin A(4–10), MDL 28,564, displayed a clear‐cut agonist character, although it was less potent than neurokinin A. The responses to roughly equieffective (25–35% of maximal response) concentrations of [βAla8] neurokinin A (4–10), MDL 28,564 and [MePhe7] neurokinin B were antagonized to a similar extent by MEN 10,376 (3 μm), a selective NK2 tachykinin receptor antagonist, while the response to [Sar9] substance P sulphone was unchanged. The response to [Sar9] substance P sulphone was inhibited by the NK1 receptor‐selective antagonist, GR 82,334 (3 μm) while the response to [βAla8] neurokinin A (4–10) was unchanged.6 The selective NK2 receptor antagonists MEN 10,376, L 659,877 and R 396 antagonized competitively the response to [βAla8] neurokinin A (4–10) with the following rank order of potency (pA2 values in parentheses): MEN 10,376 (7.41) > L 659,877 (7.15) > R 396 (6.43). MEN 10,376 and L 659,877 also competitively antagonized the response to neurokinin A, although with lower potency as compared to the selective NK2 receptor agonist.7 MEN 10,376, L 659,877 and R 396 reduced in a concentration‐dependent manner the contractile response produced by electrical field stimulation (1 Hz, 100 V, 0.25 ms pulse width, trains of 10 s). The rank order of potency of NK2 receptor antagonists in blocking the response to electrical stimulation (MEN 10,376 > L 659,877 > R 396) closely mimicked their potency in antagonizing exogenous tachykinins.8 The inhibitory effect of MEN 10,376 toward responses produced by electrical field stimulation was significantly reduced when tested in the presence of peptidase inhibitors, which increased significantly the response to nerve stimulation.9 GR 82,334 (3 μm) did not significantly affect the response to nerve stimulation in untreated preparations and slightly reduced it in the presence of peptidase inhibitors.10 We conclude that both NK1 and NK2 receptors mediate the contractile effect of tachykinins in the circular muscle of the guinea‐pig renal pelvis and that the response ascribable to NK2 receptor stimulation is ...

Inhibition of tachykinin release from peripheral endings of sensory nerves by nociceptin, a novel opioid peptide

“…Discussion The positive inotropic effect produced by EFS in the guinea-pig isolated renal pelvis is determined through the release of tachykinins from the peripheral endings of capsaicin-sensitive primary afferent neurones, predominantly acting via postjunctional NK2 receptors (Maggi et al, 1992; and present findings). Opioids have been repeatedly shown to inhibit tachykinin release from both central and peripheral endings of these sensory neurones (Maggi, 1991): this effect is thought to mediate part of their analgesic action at spinal cord level and underlies the ability of opioids to suppress neurogenic inflammation in the peripheral nervous system.…”

“…With this aim we studied its effect on the contractile responses produced by electrical field stimulation (EFS) in the guinea-pig isolated renal pelvis which, as demonstrated previously (Maggi et al, 1992), are exclusively mediated by release of endogenous tachykinins from sensory nerves.…”

“…The kidneys and attached renal pelvis/ureter were quickly removed and placed in a Petri dish containing oxygenated Krebs solution for dissection of the renal pelvis: experiments were performed in the presence of 10 yM indomethacin, as described previously (Maggi et al, 1992). The mechanical activity of the whole renal pelvis was recorded isotonically, as described by Maggi et al (1992), under a resting load of 2 mN.…”

Expression and functional role of Rho‐kinase in rat urinary bladder smooth muscle

“…To characterize the effects of Y‐27632 on electrically‐evoked bladder contractions, experiments were carried out to compare the effects of Y‐27632 with muscarinic acetylcholine receptor blockade with atropine, NK 2 receptor blockade with MEN 10,376 (Maggi et al ., 1991a, b; 1992) or P2X receptor desensitization with α,β‐mATP.…”

Understanding the signaling and transmission of visceral nociceptive events

“…Neurokinin A, the mammalian tachykinin with the highest affinity for the NK2 receptor, is present in enteric neurons and in the peripheral terminals of extrinsic afferent fibers innervating the viscera (Holzer and Holzer-Petsche, 1997). Tachykinin NK2 receptors seem to have an important role in intestinal motility, especially under pathophysiological conditions of exaggerated motility (Holzer and Holzer-Petsche, 1997;Maggi et al, 1992). Antagonists for the tachykinin NK2 receptor reduce the behavioral responses evoked by rectal distension under normal conditions and the enhanced responses observed after stress or prolonged inflammation (Julia et al, 1994;Toulouse et al, 2000) as well as the activation of spinal neurons evoked by irritation of the lower urinary tract with acetic acid .…”