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

      Bju International

      drug effects, Urinary Bladder, pharmacology, Substance P, Rats, Wistar, Rats, Pyridines, Neurokinin A, Muscle, Smooth, Muscle Relaxants, Central, Muscle Contraction, Male, Animals, Amides

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          To investigate the mechanisms of neurokinin A- and substance P-induced contractions of rat urinary bladder smooth muscle, and to compare them with those of the muscarinic agonist carbachol. Rat urinary bladder strips were suspended under 1 g of tension in a physiological buffer at 37 degrees C, gassed with 95% O(2)/5% CO(2). Mechanical activity was recorded isometrically during exposure to neurokinin A and substance P. Both agents produced concentration-dependent contractions of smooth muscle strips which were unaffected by tetrodotoxin (1 micro mol/L), peptidase inhibitors (captopril, thiorphan and bestatin; 1 micro mol/L each) or piroxicam (10 micro mol/L). The rank order of potency of agonists was neurokinin A > substance P > carbachol. Contractile responses to neurokinin A and substance P, like the contractile responses to carbachol, were abolished in a nominally Ca(2+)-free medium and significantly reduced by nifedipine (1 micro mol/L). SKF-96365 (60 micro mol/L), an inhibitor of receptor-mediated Ca(2+) entry, abolished the nifedipine-resistant response to substance P and carbachol, and significantly attenuated the response to neurokinin A. Depleting intracellular Ca(2+) stores with thapsigargin (1 micro mol/L) significantly attenuated neurokinin A-induced contractions but had no effect on substance P- or carbachol- induced contractions. The Rho-kinase inhibitor, Y-27632 (10 micro mol/L), significantly reduced both phasic and tonic components of the contractile responses to neurokinin A, substance P and carbachol. The contractile responses induced by tachykinins in rat urinary bladder smooth muscle strips involve a direct action on smooth muscle and are not modulated by peptidases or prostanoids. Neurokinin A and substance P, like carbachol-induced contractions, depend on extracellular Ca(2+) influx largely through voltage-operated and partly through receptor-operated Ca(2+) channels. Intracellular Ca(2+) release contributes to the contractile response to neurokinin A but appears to have no involvement in substance P- and carbachol-induced contractions. Rho-kinase activation contributes to contractions induced by substance P, neurokinin A and carbachol.

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