Dual inhibitory action of ATP on adrenergic neuroeffector transmission in rabbit pulmonary artery.

The aim of this study was to determine whether the inhibitory action of ATP on sympathetic neuroeffector transmission in the isolated pulmonary artery is due to ATP itself or one of its dephosphorylated breakdown products, ADP, AMP or adenosine. Furthermore, the mechanism of the inhibitory action was investigated. ATP (10(-6)-3 X 10(-4) M), the degradation-resistant ATP-analogue, beta, gamma-methylene-5'-triphosphate (10(-5)-3 X 10(-4) M), ADP (10(-6)-3 X 10(-4) M), AMP (10(-5)-3 X 10(-4) M), adenosine (10(-5)-3 X 10(-4) M) and 2-chloroadenosine (10(-7)-3 X 10(-4) M) reduced the contractions evoked by field-stimulation. This was also the case for prostaglandin E2 (3 X 10(-9)-3 X 10(-7) M), while prostaglandin F2 alpha (1.4 X 10(-8) M) slightly augmented the neurogenic response. The time course of the inhibitory effect of purinergic compounds on the stimulation evoked contractions was studied. In the case of ATP and ADP the inhibition was biphasic: an initial marked block (1 min. after drug addition) which in the continued presence of either compound recovered partially 10 min. later and then remained almost constant for another 90 min. The other purinergic agents caused a monophasic reduction. In the presence of indomethacin (5 X 10(-5) M), ATP and ADP also reduced the neurogenic contractions in a monophasic manner. Indomethacin did not alter the beta, gamma-methylene-5'-triphosphate-induced inhibition. Dilazep (3 X 10(-6) M) plus deoxycoformycin (3.6 X 10(-6) M), augmented the inhibitory effect of ATP. In contrast, theophylline (5 X 10(-5) M) did not alter the effect of ATP. The inhibitory effect of ATP (10(-4) M) on stimulation-evoked contractions was inversely proportional to the extracellular Ca2+ concentration (0.3-5.2 mM) and to frequency of stimulation (3-15 Hz). These results suggest that ATP initially causes a presynaptic inhibition of noradrenaline release evoked by field-stimulation. This phase I block is probably mainly due to an ADP-mediated short-lasting release of prostaglandins of the E type. The continuous inhibition (phase II) is probably due to ATP and its metabolites, possibly mainly adenosine. The phase II inhibition may possibly involve a decreased entry of Ca2+ into adrenergic nerve terminals during depolarization.