Interaction of acetylcholine and endothelin-1 in the modulation of pulmonary arterial pressure

Objective: The study was designed to investigate the effects of acetylcholi ne (ACh) on pulmonary circulation with special regard to mediators that cou ld be involved in the mediation of ACh-induced effects. ACh has been report ed to induce either vasodilation or vasoconstriction in the pulmonary circu lation of different species. Design: Prospective experimental study in rabbits. Setting: Experimental laboratory in a university teaching hospital. Subjects: Sixty-six adult rabbits of either sex. Interventions: The experiments were performed on 66 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer soluti on. ACh was injected in various concentrations after pulmonary artery preco nstriction and in untreated lungs. Measurements and Main Results: Pulmonary arterial pressure (PAP) and lung w eight gain were monitored continuously. Perfusate samples were taken interm ittently to determine endothelin-1 (ET-1), thromboxane A(2) (TXA(2)), and p rostacyclin (PGI(2)) concentrations. ACh in final dosages from 10(-5) to 10 (-2) M (n = 6 each) was injected into the pulmonary artery of lungs treated with U46619 to induce pulmonary arterial hypertension or was injected into untreated lungs. To analyze the potential mechanisms of action, ACh (10(-5 ) M) was administered in additional experiments after pretreatment with eit her ET, receptor antagonist BQ123 (10(-6) M; n = 6) or the cyclooxygenase i nhibitor diclofenac (10 mug/mL; n = 6). In preconstricted pulmonary vessels , ACh (10(-3) and 10(-2) M) initially induced a PAP rise for 10 mins follow ed by a sustained decrease. In untreated lungs, ACh induced an immediate do se-dependent increase in PAP, requiring as long as 30 mins to return to pre drug levels. Simultaneously, significantly elevated TXA(2) and PGI(2) level s were observed. Furthermore, ET-1 was detected in the perfusate, which was free from ET-1 before ACh administration. Pretreatment with BQ123 reduced substantially the ACh (10(-5) M)-induced PAP increase and the release of TX A(2) and PGI(2). At 5 mins, the PAP maximum was reduced from 18.5 +/- 3.2 m m Hg to 9.9 +/- 0.65 mm Hg by BQ123 pretreatment (p < .01). An inhibition o f PAP increase was also observed after diclofenac pretreatment (11.6 +/- 0. 4 mm Hg at 5 mins; p < .05). Inhibitory effects at 5 mins were significantl y more pronounced in the BQ123 group compared with the diclofenac group. Conclusions: The effects of ACh on the pulmonary circulation of isolated ra bbit lungs depend an ACh concentration and the basal tone of the arterial v asculature. In lungs with a normal pulmonary vascular resistance, ACh admin istration causes vasoconstriction via the release of ET-1 and TXA(2), where as vasodilation is induced in preconstricted pulmonary vessels.