Relaxation of isolated guinea-pig trachea by apigenin, a constituent of celery, via inhibition of phosphodiesterase

Apigenin, was reported to have vasodilatory effects by inhibiting Ca2+ influx through both voltage- and receptor-operated calcium channels, but not by inhibiting cAMP- or cGMP-phosphodiesterases (PDEs) in rat thoracic aorta. However, apigenin was reported to inhibit PDE1, 2 and 3 in guinea-pig lung and heart. The aim of this study was to clarify that guinea-pig tracheal relaxation by apigenin whether via PDE inhibition.We isometrically recorded the tension of isolated guinea-pig tracheal segments on a polygraph. Antagonistic effects of apigenin against cumulative contractile agents or Ca2+ induced contractions of the trachealis in normal or isotonic high-K+, Ca2+-free Krebs solution, respectively. Effects of apigenin (15 and 30 μM) on the cumulative forskolin- and nitroprusside-induced relaxations to histamine (30 μM)-induced precontraction were performed. The inhibitory effects of 30-300 μM apigenin and 3-isobutyl-1-methylxanthine (IBMX, positive control) on the cAMP- and cGMP-PDEs were determined.Apigenin concentration-dependently but non-competitively inhibited cumulative histamine-, carbachol- or Ca2+-induced contractions in normal or in the depolarized (K+, 60 mM) trachealis, suggesting that Ca2+ influx through voltage-dependent calcium channels is inhibited. However, apigenin (15-30 μM) parallel leftward shifted the concentration-response curves of forskolin and nitroprusside, and significantly increased the pD2 values of these two cyclase activators. Both apigenin and IBMX, a reference drug, concentration (10-300 μM)-dependently and significantly, but non-selectively inhibited the activities of cAMP- and cGMP-PDEs in the trachealis. In conclusion, the relaxant effect of apigenin may be due to inhibition of both enzyme activities and reduction of intracellular Ca2+ by inhibiting Ca2+ influx in the trachealis.