Pharmacological Effects of Peptides on Tracheal Smooth Muscle

Abstract

Peptide and non-peptide agents were tested for their stimulatory or inhibitory effects on circular strips of guinea pig isolated tracheae. Substance P, eledoisin, physalaemin, neurotensin, angiotensin, histamine and carbachol were found to contract, while noradrena-line, dopamine, bradykinin, nucleotides (AMP, ADP, ATP) and prostaglandins (PGE_1; PGE₂, PGA₂) induced concentration-dependent relaxations of tracheae contracted with substance P or carbachol. Indomethacin (2.8 × 10^–6M) significantly potentiated the effect of substance P and blocked that of bradykinin. The contractions to substance P of tissues treated with indomethacin were not modified by atropine, methysergide, diphenhydramine, cimetidine, pro-pranolol, phentolamine, [Leu⁸]-AT₁₁, [Leu⁸]-des-Arg⁹-bradykinin, naloxone and baclofen. The order of potency of C-terminal fragments of substance P was: hexa(6–11) > hepta(5–11) > substance P > = octa(4–11). It is concluded that the guinea pig isolated trachea is a pharmacological preparation sensitive to numerous agents and useful for studying structure-activity relationship and the mechanism of cellular action of several peptides, particularly substance P.

Facilitation by tachykinins of neurotransmission in guinea‐pig pulmonary parasympathetic nerves

“…Previous studies (mostly with SP) have generally indicated that this effect is due to a direct action of the peptide(s) through receptors located on the trachealis muscle cells (Nilsson et al, 1977;Pernow, 1983). There is good evidence for this hypothesis, since the SP-induced contractions in human and guinea-pig isolated airway preparations are unaltered by atropine or mepyramine (Mizrahi et al, 1982;Lundberg et al, 1983), histamine antagonists, aadrenoceptor antagonists or f-adrenoceptor antagonists (Malo et al, 1986). However, there have also been at least two accounts of an effect of atropine on SP-induced contractions of airway-smooth muscle (Tanaka & Grunstein, 1984;Malo et al, 1986).…”

“…Addition of tachykinins to the organ bath caused slowly-developing, concentration-dependent in- (Mizrahi et al, 1982;Lundberg et al, 1983).…”

“…SP is present in afferent nerves in the airways of several species, including guinea-pigs and man (Nilsson et al, 1977;Lundberg et al, 1984;Polak & Bloom, 1986) and SP-immunoreactive neurones have been identified in the vagus nerve (Gamse et al, 1979). SP and other tachykinins have been shown to cause contraction of human and guinea-pig airways in vitro (Mizrahi et al, 1982;Lundberg et al, 1983) and in vivo (Andersson & Persson, 1977;Goel & Biggs, 1986). These responses are unaffected by atropine or mepyramine, and are probably due to a direct effect of the peptides on a specific sub-population of tachykinin receptors on the airway smooth muscle cells.…”

Purinergic Signaling in the Airways

“…Adenosine deaminase reduced the inhibitory response to adenosine and NANC inhibitory nerve stimulation in guinea pig trachea (Satchell, 1984b). ATP and adenosine caused relaxations of the guinea pig trachea, although adenosine was more potent than ATP (Farmer and Farrar, 1976;Mizrahi et al, 1982;Small, 1982), and Satchell (1984a) suggested that ATP acts on adenosine receptors after breakdown. However, in contradiction, Welford and Anderson (1988) later claimed that ATP itself can cause relaxation without being metabolized to adenosine.…”

Neutral endopeptidase-like enzyme controls the contractile activity of substance P in guinea pig lung.

“…Intravenous administration of substance P in guinea pigs causes acute bronchospasm, hypotension, and increases in vascular permeability (4). In vitro, substance P has also been shown to contract isolated guinea pig tracheal and lung parenchymal tissues in a muscle bath apparatus (6)(7)(8). Pharmacologic studies have shown that the contractile effects ofthe peptide are independent ofhistamine, catecholamines, and serotonin (5,6,8).…”