Pharmacological characterization of tachykinin-stimulated inositol phospholipid hydrolysis in peripheral tissues.
1. Tachykinin-stimulated inositol phospholipid hydrolysis was examined in slices of rat parotid gland, hamster urinary bladder and guinea-pig ileum longitudinal muscle. 2. In the presence of lithium, substance P and other naturally-occurring and synthetic tachykinins induced large, dose-dependent increases in [3H]-inositol monophosphate accumulation. 3. In slices of rat parotid gland, [pGlu6,L-Pro9]SP(6-11) was considerably more potent in stimulating inositol phospholipid hydrolysis than [pGlu6,D-Pro9]SP(6-11). 4. In contrast, in slices of hamster urinary bladder, [pGlu6,D-Pro9]SP(6-11) exhibited greater potency in evoking inositol phospholipid breakdown than [pGlu6,L-Pro9]SP(6-11). 5. The differential selectivity of these C-terminal fragments of substance P suggests that they may be useful tools for distinguishing between NK1 and NK2 receptors. 6. L-659,837 and L-659,874 antagonized eledoisin-stimulated inositol phospholipid hydrolysis in slices of hamster urinary bladder. Neither compound significantly reduced substance-P evoked inositol phospholipid breakdown in slices of rat parotid gland, or senktide-induced inositol phospholipid hydrolysis in slices of guinea-pig ileum. 7. L-659,837 and L-659,874 had no effect on the atropine-sensitive, carbachol-stimulated inositol phospholipid hydrolysis in slices of rat parotid gland. 8. These data further support the notion that L-659,837 and L-659,874 are potent and selective NK2 receptor antagonists.
Suman-Chauhan
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N
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
Guard
S
S
Williams
B J
BJ
Watling
K J
KJ
D000818:Animals; D006224:Cricetinae; D006168:Guinea Pigs; D006868:Hydrolysis; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D010306:Parotid Gland / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D015320:Tachykinins / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism
D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010716:Phosphatidylinositols; D015320:Tachykinins; C068459:L 659874; D013373:Substance P; C054725:septide; D011761:Pyrrolidonecarboxylic Acid