Long-lasting smooth-muscle relaxation by a novel PACAP analogue in human bronchi.
We compared the relaxant effect of original pituitary adenylate cyclase-activating peptide (PACAP)1-27 with that of a newly developed, synthetic PACAP1-27 analogue, [Arg15,20,21 Leu17]-PACAP-Gly-Lys-Arg-NH2, in human bronchi in vitro (n=4-5 in each group). Using precontraction by carbachol (0.1 microM), cumulative administration of PACAP1-27 and salbutamol caused concentration-dependent smooth muscle relaxation with similar potencies and maximum relaxant effects. Non-cumulative administration of the PACAP1-27 analogue and the original PACAP1-27 caused concentration-dependent relaxation with a similar maximum relaxant effect and potency as well. However, the onset and offset of action was markedly slower for the PACAP1-27 analogue than for the original PACAP1-27 (>90% versus <10% of peak relaxation remaining 5 h after administration). Peptidase inhibition by captopril (10 microM) and phosphoramidon (1 microM) significantly increased the maximum relaxant effect and duration of action of PACAP1-27 but not of the PACAP1-27 analogue, during the 3 h of observation in the human bronchi. We conclude that [Arg15,20,21 Leu17]-PACAP-Gly-Lys-Arg-NH2 produces significant concentration-dependent and sustained bronchial smooth muscle relaxation in vitro. The sustained relaxant effect is due, at least in part, to the synthetic PACAP1-27 analogue being less susceptible to cleavage by peptidases than the original peptide PACAP1-27.
Yoshihara
Shigemi
S
Department of Pediatrics, School Medicine, Dokkyo University, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan. shigemi@dokkyomed.ac.jp
Yamada
Yumi
Y
Abe
Toshio
T
Kashimoto
Kazuhisa
K
Lindén
Anders
A
Arisaka
Osamu
O
D000595:Amino Acid Sequence; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009414:Nerve Growth Factors / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D018377:Neurotransmitter Agents / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide
C495401:ADCYAP1 protein, human; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide