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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Quinn
Teresa
T
Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University College Dublin, Ireland.
Collins
Colm
C
Baird
Alan W
AW
D000577:Amides / Q000494:pharmacology; D000818:Animals; D008297:Male; D009119:Muscle Contraction; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects*; D015288:Neurokinin A / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013373:Substance P / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects*
D000577:Amides; D009125:Muscle Relaxants, Central; D011725:Pyridines; C108830:Y 27632; D013373:Substance P; D015288:Neurokinin A