Bronchodilation by pituitary adenylate cyclase-activating peptide and related peptides.
Pituitary adenylate cyclase-activating peptide (PACAP) is present in nerves in the vicinity of bronchial and vascular smooth muscle in the airways. At least one endogenous form of PACAP, PACAP 1-27, has high affinity binding sites in the lung, probably including cholinergic nerve terminals, bronchial smooth muscle, epithelial and mononuclear inflammatory cells. The mechanism of action for PACAP 1-27 and 1-38 in vivo involves endogenous catecholamines, peptidases and nitric oxide, depending on tissue type. Intracellularly, cyclic adenosine monophosphate (cAMP) as well as calcium and sodium mobilization is probably involved. PACAP 1-27 and 1-38 inhibit airway smooth muscle tone in vitro and in vivo. The inhibitory effect of PACAP 1-38 is more sustained than that of PACAP 1-27, in vitro as well as in vivo. PACAP 1-38 also causes more sustained inhibition of bronchoconstriction after inhalation in vivo, than does vasoactive intestinal peptide (VIP). PACAP 1-27 given intravenously virtually abolishes allergen-induced bronchoconstriction in vivo. Novel synthetic analogues of PACAP 1-27 cause more sustained inhibition of airway smooth muscle tone in vitro and in vivo than do PACAP 1-27 or 1-38. Both PACAP 1-27 and 1-38 inhibit arterial smooth muscle tone but, administration of PACAP 1-27, 1-38 or a structural analogue of PACAP 1-27 in the airways, induces no cardiovascular side effects at doses inhibiting bronchoconstriction. PACAP 1-38 enhances phagocytosis in macrophages and inhibits the release of the pro-inflammatory cytokine interleukin-2 in lymphocytes, suggesting antiinflammatory effects. It is concluded that pituitary adenylate cyclase-activating peptide 1-27 and 1-38, or structurally related molecules, may be useful as bronchodilators but their effect on human bronchial smooth muscle and on human inflammatory cells is in need of evaluation.
Lindén
A
A
Lung Pharmacology Group, Dept of Respiratory Medicine & Allergology, Göteborg University, Gothenburg, Sweden.
Cardell
L O
LO
Yoshihara
S
S
Nadel
J A
JA
D000403:Airway Resistance / Q000502:physiology*; D001980:Bronchi / Q000294:innervation*; D016084:Bronchoconstriction / Q000502:physiology*; D010450:Endopeptidases / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology; D009129:Muscle Tonus / Q000502:physiology; D009130:Muscle, Smooth / Q000294:innervation*; D009479:Neuropeptides / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide
C495401:ADCYAP1 protein, human; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C108046:pituitary adenylate cyclase-activating-peptide (1-38), pig; D010450:Endopeptidases