phosphoramidon and Cough

In this study we investigated the ability of aerosolized substance P to induce either cough or bronchoconstriction in guinea-pigs. We have also examined whether pre-treatment, by the inhaled route, of animals with a combination of the neutral endopeptidase inhibitor, phosphoramidon (10(-3) M), and the diaminopeptidase IV inhibitor, diprotin A (10(-3) M), enhances the airway response to substance P. Moreover, we also assessed whether aerosol pre-treatment of guinea-pigs with either substance P or bradykinin, at 10(-4) M, affects the citric acid-induced cough and/or bronchoconstriction. Challenge of guinea-pigs with substance P only at 10(-3) M resulted in significant bronchconstriction but only a weak and variable cough response (1.1+/-0.6; P>0.05). Pre-treatment of guinea-pigs with both phosphoramidon and diprotin A resulted in a small non-significant increase in the cough response (2.8+/-0.9 vs. 1.1+/-0.6; P>0.05) but significantly enhanced substance P-induced bronchoconstriction (P<0.05). Moreover, exposure of guinea-pigs to substance P (10(-4) M) prior to citric acid challenge (0.6 M) resulted in a significant (P<0.05) enhancement of the citric acid-induced bronchoconstriction but not the citric acid-induced cough (11.7+/-1.8 vs. 12.8+/-1.5; P>0.05). In contrast, exposure of guinea-pigs to bradykinin (10(-4) M) prior to the citric acid challenge resulted in a significant enhancement of the cough response (9.2+/-1.9 vs. 25.8+/-2.5; P<0.05) but not the bronchoconstriction (P>0.05). These data do not support a major peripheral role for substance P in the cough reflex, although bradykinin is able to sensitize the cough reflex. Furthermore, these data suggest that bronchoconstriction, induced by citric acid, is not responsible for the cough associated with this irritant.

Topics: Animals; Bradykinin; Bronchoconstriction; Citric Acid; Cough; Dose-Response Relationship, Drug; Glycopeptides; Guinea Pigs; Male; Oligopeptides; Protease Inhibitors; Reflex; Substance P; Time Factors

It has been suggested that bradykinin may play a role in stimulating cough in at least one pathological condition in humans. We have employed an animal model to investigate the possible role of this peptide in irritant-induced cough. The kinin antagonist Hoe 140 and codeine both produced dose-related inhibition of cough responses to inhalation of citric acid or bradykinin aerosols by conscious guinea pigs. The selective tissue kallikrein inhibitor CH694 inhibited cough caused by citric acid but not by bradykinin. Indomethacin pretreatment attenuated the responses to both stimuli as did phosphoramidon. It is concluded that cough produced by citric acid inhalation may be mediated, at least in part, by generation of kinins; secondary to this, a release of prostanoids also appears to participate in the response.

Topics: Administration, Inhalation; Animals; Bradykinin; Bradykinin Receptor Antagonists; Citric Acid; Codeine; Cough; Dipeptides; Dose-Response Relationship, Drug; Glycopeptides; Guinea Pigs; Indomethacin; Irritants; Kallikreins; Kinins; Male; Protease Inhibitors

We examined an endogenous substance causing cough in awake guinea pigs. An intraperitoneal injection of phosphoramidon, a selective inhibitor of neutral endopeptidase (E.C. 3.4.24.11), caused cough in a dose-dependent fashion for approximately 40 min. At a dose of 3 x 10(-3) mol/kg, phosphoramidon caused a total of 11.6 +/- 1.4 coughs in 40 min. Phosphoramidon (3 x 10(-3) mol/kg)-induced cough was significantly inhibited by systemic pretreatment with capsaicin (p < 0.01). Aerosols of FK 888 (1 min), a specific inhibitor of substance P (NK1) receptor, inhibited phosphoramidon (3 x 10(-3) mol/kg)-induced cough in a dose-dependent fashion with complete inhibition at a dose of 10(-5) M. Likewise, aerosols of FK 224 (10(-5) M; 1 min), another inhibitor of NK1 and NK2 receptors, or lidocaine (4%, 1 min) significantly inhibited phosphoramidon (3 x 10(-3) mol/kg)-induced cough (p < 0.01). Furthermore, aerosols of FK 888 (10(-5) M; 1 min) significantly inhibited cough induced by cigarette smoke in awake guinea pigs (p < 0.01). These results suggest that substance P released from sensory nerves in the airway may be an endogenous substance causing cough and the substance P antagonist may be the drug for treatment of cough in respiratory disease.

Topics: Aerosols; Animals; Capsaicin; Cough; Dipeptides; Dose-Response Relationship, Drug; Glycopeptides; Guinea Pigs; Indoles; Male; Neprilysin; Smoking; Substance P; Tachykinins

To study the roles of substance P and endogenous neutral endopeptidase in mediating cough, we measured cough responses in awake guinea pigs in response to exogenous substance P and capsaicin aerosols in the presence and absence of the neutral endopeptidase inhibitors leucine-thiorphan and phosphoramidon. Substance P stimulated cough in very low concentrations (10(-17)-10(-16) M). In a second study where the investigator did not know whether substance P or diluent alone was aerosolized, substance P (10(-16) M) caused cough. Leucine-thiorphan (10(-5) M) and phosphoramidon (10(-5) M) potentiated substance P-induced cough; NEP inhibitors also potentiated capsaicin-induced cough significantly. These findings suggest that substance P is a potent stimulator of cough responses, that capsaicin-induced cough is mediated by substance P or another similar neuropeptide, and that cough responses are modulated by endogenous neutral endopeptidase.

Topics: Animals; Capsaicin; Cough; Drug Synergism; Glycopeptides; Guinea Pigs; Male; Neprilysin; Substance P; Thiorphan