Functional difference between SP and NKA: relaxation of gastric muscle by SP is mediated by VIP and NO.
The mechanism of action of endogenous tachykinins [substance P (SP) and neurokinin A and B (NKA and NKB)] and of receptor-specific tachykinin analogues (SP methyl ester (SPME), [beta-Ala8]NKA-(4-10), and senktide) was examined in circular muscle of guinea pig stomach. Cross-desensitization studies confirmed that SPME and SP interacted with NK-1 receptors, [beta-Ala8]NKA-(4-10) and NKA with NK-2 receptors, and senktide and NKB with NK-3 receptors. NK-1 and NK-3-receptor agonists induced relaxation and stimulated vasoactive intestinal peptide (VIP) release and nitric oxide (NO) production: tetrodotoxin abolished VIP release, NO production, and relaxation, converting the response to NK-1-receptor agonists to contraction; the NO synthase inhibitor NG-nitro-L-arginine (L-NNA) abolished NO production, partly inhibited VIP release (56-64%, P < 0.01), and abolished relaxation; the VIP antagonist VIP-(10-28) partly inhibited NO production (73-74%, P < 0.001) and relaxation (56-58%, P < 0.01); and atropine augmented relaxation by 28-35% (P < 0.01). The pattern of inhibition implied that: 1) relaxation was mediated by VIP and NO; 2) VIP release was partly dependent on NO production, since it was strongly inhibited by L-NNA; and 3) NO was largely produced by the action of VIP on muscle cells, since it was strongly inhibited by VIP-(10-28). NK-2-receptor agonists elicited only contraction that was not affected by tetrodotoxin; these agonists also inhibited VIP release, NO production, and relaxation induced by NK-1- and NK-3-receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
Jin
J G
JG
Department of Medicine, Medical College of Virginia, Richmond 23298-0711.
Misra
S
S
Grider
J R
JR
Makhlouf
G M
GM
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015288:Neurokinin A / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine; D010446:Peptide Fragments / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology*; D015320:Tachykinins / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*
D010446:Peptide Fragments; D015320:Tachykinins; C054724:senktide; D019335:Nitroarginine; D009569:Nitric Oxide; D013373:Substance P; D014660:Vasoactive Intestinal Peptide; D013779:Tetrodotoxin; D015288:Neurokinin A; D001120:Arginine