In vivo evidence for tachykininergic transmission using a new NK-2 receptor-selective antagonist, MEN 10,376.
We have studied the effects of two newly developed tachykinin antagonists, MEN 10,207 and MEN 10,376, which are highly selective for NK-2 tachykinin receptors on tachykinin-induced contraction in the rat urinary bladder and guinea pig airways in vivo. MEN 10,207 exhibited antagonism only at doses which produced agonist effects. By contrast, MEN 10,376 was devoid of significant agonist activity at i.v. doses (1-3 mumol/kg) which selectively antagonized the effects of an NK-2 agonist [beta-Ala8]-neurokinin A(4-10) (bladder contraction in rats, bronchoconstriction in guinea pigs) without affecting the response to an NK-1 agonist [Sar9]-substance P sulfone (hypotension, salivation and bladder contraction in rats, bronchoconstriction in guinea pigs). At these NK-2-selective blocking doses, MEN 10,376: 1) did not affect urodynamic parameters at cystometry in normal rats but reduced amplitude of micturition contractions following induction of chemical (intravesical xylene) cystitis and 2) reduced by a maximum of 50% the noncholinergic bronchoconstrictor response to vagal nerve stimulation. These findings provide the first evidence for involvement of NK-2 receptors in physiological responses in the urinary and respiratory tracts.
Maggi
C A
CA
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Giuliani
S
S
Ballati
L
L
Lecci
A
A
Manzini
S
S
Patacchini
R
R
Renzetti
A R
AR
Rovero
P
P
Quartara
L
L
Giachetti
A
A
D000818:Animals; D001980:Bronchi / Q000294:innervation; D016084:Bronchoconstriction / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D009119:Muscle Contraction / Q000187:drug effects; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors* / Q000502:physiology; D018039:Receptors, Tachykinin; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects; D014630:Vagus Nerve / Q000502:physiology
D010446:Peptide Fragments; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; C054724:senktide; C063615:neurokinin A (4-10), Tyr(5)-Trp(6,8,9)-Arg(10)-; C069192:neurokinin A(4-10), Tyr(5)-Trp(6,8,9)-Lys(10)-; D013373:Substance P; D015288:Neurokinin A