Pharmacological profile of the novel mammalian tachykinin, hemokinin 1.
1. The effects of the novel mammalian tachykinin, hemokinin 1 (HEK-1), have been investigated by radioligand binding and functional in vitro and in vivo experiments. 2. Similar to SP (K(i)=0.13 nM), HEK-1 inhibited in a concentration-dependent manner and with high affinity [(3)H]-substance P (SP) binding to human NK(1) receptor (K(i)=0.175 nM) while its affinity for [(125)I]-neurokinin A (NKA) binding at human NK(2) receptor was markedly lower (K(i)=560 nM). 3. In isolated bioassays HEK-1 was a full agonist at tachykinin NK(1), NK(2) and NK(3) receptors. In the rat urinary bladder (RUB) HEK-1 was about 3 fold less potent than SP. In the rabbit pulmonary artery (RPA) HEK-1 and in the guinea-pig ileum (GPI), HEK-1 was about 500 fold less potent than NKA and NKB, respectively. 4. The responses to HEK-1 were antagonized by GR 82334 in RUB (pK(B)=5.6+/-0.07), by nepadutant in RPA (pK(B)=8.6+/-0.04) and by SR 142801 in GPI (pK(B)=9.0+/-0.2) with apparent affinities comparable to that measured against tachykinin NK(1), NK(2) and NK(3) receptor-selective agonists, respectively. 5. Intravenous HEK-1 produced dose-related decrease of blood pressure in anaesthetized guinea-pigs (ED(50)=0.1 nmol kg(-1)) and salivary secretion in anaesthetized rats (ED(50)=6 nmol kg(-1)) with potencies similar to that of SP. All these effects were blocked by the selective tachykinin NK(1) receptor antagonist, SR 140333. 6. We conclude that HEK-1 is a full agonist at tachykinin NK(1), NK(2) and NK(3) receptors, possesses a remarkable selectivity for NK(1) as compared to NK(2) or NK(3) receptors and acts in vivo experiments with potency similar to that of SP.
Bellucci
Francesca
F
Department of Pharmacology, Menarini Ricerche S.p.A., via Rismondo 12A, I-50131, Florence, Italy.
Carini
Francesca
F
Catalani
Claudio
C
Cucchi
Paola
P
Lecci
Alessandro
A
Meini
Stefania
S
Patacchini
Riccardo
R
Quartara
Laura
L
Ricci
Renzo
R
Tramontana
Manuela
M
Giuliani
Sandro
S
Maggi
Carlo Alberto
CA
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011498:Protein Precursors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000819:agonists* / Q000378:metabolism; D012463:Saliva / Q000378:metabolism; D012472:Salivation / Q000187:drug effects / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D015320:Tachykinins / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
D011498:Protein Precursors; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; C486037:TAC4 protein, human; D015320:Tachykinins