Long lasting smooth muscle relaxation by a novel PACAP analogue in guinea-pig and primate airways in vitro.
1. We compared the relaxant effect of pituitary adenylate cyclase activating peptide (PACAP) 1-27 with that of a newly developed PACAP 1-27 analogue, [Arg15,20,21Leu17]-PACAP-Gly-Lys-Arg-NH2, in the guinea-pig trachea and primate bronchi in vitro (n = 4-5). 2. In the guinea-pig trachea precontracted by a submaximally effective carbachol concentration (0.1 microM), cumulative administration of PACAP 1-27 and the beta 2-adrenoceptor agonist salbutamol (3 nM-3 microM) caused significant and concentration-dependent smooth muscle relaxation, with salbutamol being approximately one log-step more potent in this model. However, in primate bronchi precontracted by carbachol (0.1 microM), cumulative administration of PACAP 1-27 and salbutamol caused concentration-dependent smooth muscle relaxation with very similar potencies and maximum relaxant effects. 3. In the guinea-pig trachea, non-cumulative administration of the PACAP 1-27 analogue and the original PACAP 1-27 (0.3-3 microM) caused concentration-dependent relaxation with a very similar maximum relaxant effect and potency. However, the onset and offset of action was markedly slower for the PACAP 1-27 analogue than for the original PACAP 1-27 (< 90% versus < 10% of peak relaxation remaining 6 h after administration). Separate experiments confirmed that the PACAP 1-27 analogue also caused significant relaxation with slower onset and offset of action than did the original PACAP 1-27 in primate bronchi. 4. Peptidase inhibition by captopril (10 microM) and phosphoramidon (1 microM) significantly increased the maximum relaxant effect and duration of action of PACAP 1-27 but not of the PACAP 1-27 analogue, during the 3 h of observation in the guinea-pig trachea. 5. We conclude that [Arg15,20,21Leu17]-PACAP-Gly-Lys-Arg-NH2 produces significant, concentration-dependent and sustained airway smooth muscle relaxation in vitro. The sustained relaxant effect is due, at least in part, to the PACAP 1-27 analogue being less susceptible to cleavage by peptidases than the original peptide PACAP 1-27.
Yoshihara
S
S
Cardiovascular Research Institute, University of California San Francisco 94143-0130, USA.
Lindén
A
A
Kashimoto
K
K
Nagano
Y
Y
Ichimura
T
T
Nadel
J A
JA
D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D002216:Captopril / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D008252:Macaca fascicularis; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009479:Neuropeptides / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D006020:Glycopeptides; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D002216:Captopril; D000420:Albuterol; C008890:phosphoramidon