EFFECTS OF TACHYKININS AND CAPSAICIN ON THE MECHANICAL AND ELECTRICAL-ACTIVITY OF THE GUINEA-PIG ISOLATED TRACHEA

1 The effects of tachykinins and capsaicin were studied by means of in tracellular membrane potential and isometric tension recordings in the isolated trachea of the guinea-pig. 2 The basal membrane potential av eraged -51 mV, and most preparations demonstrated spontaneous slow wav es. Tetraethylammonium (TEA), a potassium channel blocker (8 x 10(-3) M), depolarized the membrane potential to -44 mV and induced a rhythmi c activity. 3 In control solution, substance P (10(-8)-10(-6) M), [Nle (10)]-neurokinin A(4-10) (10(-8)-10(-6) M) and capsaicin (10(-7)-10(-6 ) M) induced concentration-dependent depolarizations which were statis tically significant at the highest concentration tested (depolarizatio n by 10(-6) M: 8, 11 and 16 mV for the NK1 agonist, the NK2 agonist an d capsaicin, respectively). 4 In the presence of TEA (8 x 10(-3) M), t he three substances induced depolarizations which were statistically s ignificant at the highest concentration tested for substance P (10(-6) M) and at 10(-7) and 10(-6) M for both [Nle(10)]-neurokinin A(4-10) a nd capsaicin (depolarization by 10(-6) M: 11, 17 and 10 mV for substan ce P, [Nle(10)]neurokinin A(4-10) and capsaicin, respectively). 5 In t he presence or absence of tetraethylammonium, [MePhe(7)]-neurokinin B (10(-8)-10(-6) M) did not induce any significant changes in membrane p otential. 6 The depolarizing effects of substance P (10(-6) M) and [Nl e(10)]-neurokinin A(4-10) (10(-6) M) were blocked only by the specific antagonists for NK1 and NK2 receptors, SR 140333 (10(-7) M) and SR 48 968 (10(-7) M), respectively. The effects of capsaicin (10(-6) M) were partially inhibited by each antagonist and fully blocked by their com bination. 7 Substance P (10(-9) to 10(-4) M), [Nle(10)]-neurokinin A(4 -10) (10(-10) to 10(-5) M), [MePhe(7)]-neurokinin B and capsaicin (10( -7) to 10(-5) M) evoked concentration-dependent contractions. 8 The co ntractions to substance P were significantly inhibited by SR 140333 (1 0(-8) to 10(-6) M) but unaffected by SR 48968 (10(-8) to 10(-6) M). Fu rthermore, the response to [Nle(10)]-neurokinin A(4-10) was significan tly inhibited by SR 48968 and unaffected by SR 140333 at the same conc entrations. Although SR 48968 (10(-7) M) alone did not influence the e ffects of substance P, it potentiated the inhibitory effect of SR 1403 33 (10(-7) M). A similar synergetic effect of these two compounds was observed in the inhibition of the contractile response to [Nle(10)]-ne urokinin A(4-10). 9 Neither SR 140333 (10(-7) M) nor SR 48968 (10(-7) M) alone influenced the contractions to [MePhe(7)]-neurokinin B and ca psaicin. However, the combination of the two antagonists abolished the contractions to either peptide. 10 These results demonstrate that the stimulation of both NK1 and NK2 tachykinin-receptors induced contract ion and depolarization of the guinea-pig tracheal smooth muscle and th at both receptors were stimulated during the endogenous release of tac hykinins by capsaicin. There was no evidence for a major role of NK3 r eceptors in the contractile and electrical activity of the guinea-pig isolated trachea.