EP1 RECEPTOR BLOCKADE ATTENUATES BOTH SPONTANEOUS TONE AND PGE(2)-ELICITED CONTRACTION IN GUINEA-PIG TRACHEALIS

We assessed the effect of prostaglandin (PG) E-2 on tone of guinea pig tracheal smooth muscle (TSM) strips in vitro. In the presence of spon taneous tone [ST; i.e., no indomethacin (-Indo)], exogenous PGE(2) cau sed a significant relaxation of ST at concentrations >10(-6) M [to -12 7 +/- 40.8% electric field stimulation (EFS); P = 0.001 vs. baseline S TI and at concentrations <10(-6) M caused a variable change in contrac tile force (51.6 +/- 29.6% EFS; P = NS vs. baseline ST). In the absenc e of ST (i.e., + Indo) 10(-10) to 10(-7) M PGE(2) elicited contraction of TSM to 126.3 +/- 10.5% EFS (P = 0.001 vs. baseline) and no relaxat ion. Addition of prostanoid EP1 receptor antagonist (either AH-6809 or SC-19220) to Indo-treated TSM caused a substantial rightward shift an d attenuation of contraction in response to PGE(2) (55.9 +/- 16.8% EFS for 10(-5) MAH-6809; P = 0.007 vs. +Indo alone, and 80.5 +/- 12.7% EF S for 10(-5) M SC-19220, P = 0.03 vs. +Indo alone). We further assesse d the effect of EP1 and EP4 receptor antagonism on the ST of guinea pi g TSM strips. Concentration-response curves to the EP1 receptor-specif ic antagonists AH-6809 or SC-19220 and the EP4 receptor-specific antag onist AH-23848B were generated (10(-7) to 10(-5) M); AH-6809 caused re laxation of ST to 11.4 +/- 2.9% ST (P = 0.001 vs. initial ST) and SC-1 9220 caused relaxation to 31.0 +/- 12.7% ST (P = 0.02 vs. initial ST). However, AH-23848B did not significantly affect ST (to 60.9 +/- 7.7% ST; P = 0.07 vs. initial ST). Furthermore, AH-6809 specifically inhibi ted contraction elicited by the EP1 receptor agonist Iloprost but had no effect on contraction elicited by the EP3 receptor agonist Enprosti l. We demonstrate that in the presence of ST (-Indo), exogenous PGE(2) elicits a biphasic response in guinea pig TSM in which relaxation pre dominates. In the absence of ST (+Indo), exogenous PGE(2) elicits cont raction of guinea pig TSM strips that is inhibited by EP1 receptor-spe cific antagonism. Spontaneous tone of guinea pig TSM strips also is in hibited by EP1 receptor antagonism. Our data suggest that both PGE(2)- elicited contraction and ST of guinea pig TSM are mediated through act ivation of EP1 prostanoid receptors.