Effects of bradykinin and indomethacin on cyclic GMP and cyclic AMP in lung slices

Abstract

Bradykinin, 1-100 mug/ml, produced a rapid rise in the concentration of 3':5'-guanosine monophosphate (cyclic GMP) and 3':5'-adenosine monophosphate (cyclic AMP) in slices of guinea pig lung. Concentrations of both nucleotides reached a maximum in about 2 min, then declined to a basal levels in 6-12 min. The transient nature of the effect was presumbaly due to the rapid destruction of bradykinin as evidenced by (1) reaccumulation of nucleotides when bradykinin was added a second time, and (2) potentiation of the bradykinin effects by pyroGlu-Lys-Trp-Ala-Pro, a peptide that inhibits inactivation of bradykinin by kininase. It has been reported elsewhere that histamine, prostaglandins E(1) and E(2), and beta-adrenergic stimulation can cause accumulation of cyclic AMP in lung slices without affecting cyclic GMP concentration, whereas acetylcholine increases the concentrations of both cyclic GMP and cyclic AMP. Thus it was possible that the effects of bradykinin were indirect, i.e., secondary to release of one or more of these compounds. Promethazine (an antihistamine), propranolol (a beta-adrenergic blocking agent) and atropine (an anticholinergic agent) did not alter basal cyclic nucleotide concentrations or the effects of bradykinin. Two inhibitors of prostaglandin synthesis, indomethacin and aspirin, which alone were without effect, in the presence of bradykinin completely prevented the rise in cyclic AMP but did not interfere with cyclic GMP accumulation. Similarly, the effect of acetylcholine on cyclic AMP was abolished by indomethacin while that on cyclic GMP was unaltered. We suggest that in lung and probably in other tissues, bradykinin, acetylcholine, and perhaps other stimuli enhance the synthesis and release of prostaglandins as one of the consequences of their effects on cyclic GMP metabolism.