BRONCHODILATOR AND PRE-PROTECTIVE EFFECTS OF URODILATIN IN BOVINE BRONCHI IN-VITRO - COMPARISON WITH ATRIAL-NATRIURETIC-PEPTIDE

1 This study examined the activity and mechanisms of action of urodila tin in bovine bronchi. For comparison, the ability of urodilatin to ev oke bronchodilatation or protect against subsequent challenge was comp ared to that of the closely related peptide alpha-human atrial natriur etic peptide (ANP). 2 Urodilatin reversed methacholine-evoked contract ion in a concentration-dependent manner in bovine bronchi. In the abse nce of any attempt to prevent degradation by neutral endopeptidases, u rodilatin was more potent than ANP in this tissue. 3 The bronchodilato r properties of urodilatin were significantly augmented by the neutral endopeptidase inhibitor, phsophoramidon (3.68 x 10(-5) M). This provi des evidence for at least partial degradation of urodilatin by neutral endopeptidases. With phosphoramidon present, urodilatin and ANP were equipotent. 4 In the presence of phosphoramidon (3.68 x 10(-5) M), pre -incubation with urodilatin(10(-6) M) had a protective effect against subsequent methacholine-induced contraction. This action of urodilatin was quantitatively similar to that of ANP in the presence of this end opeptidase inhibitor. 5 The actions of urodilatin appear to involve AT P-sensitive K+ channels since tolbutamide (10(-6)-10(-5) M) significan tly attenuated the relaxations induced by this peptide. 6 Small conduc tance Ca2+-activated K+ channels seem likewise to be implicated in the actions of urodilatin since blockade of these channels with apamin (1 0(-7)-10(-6) M) resulted in a marked attenuation of urodilatin-evoked responses.7 The presence of charybdotoxin (10(-9) M-10(-7) M) had no s ignificant effect on subsequent responses to urodilatin suggesting tha t large conductance Ca2+-activated K+ channels are not involved in the relaxations evoked by this peptide. 8 In the presence of phosphoramid on (3.68 x 10(-5) M), urodilatin (10(-6) M) evoked elevation of cyclic GMP levels within bovine bronchial tissue. Levels of cyclic GMP incre ased significantly within 5-10 s in response to this peptide and prece ded the initiation of relaxant responses. Maximum increases in cyclic GMP levels were reached within 5 min; the time required for maximal re laxation evoked by this peptide. 9 In conclusion, urodilatin, like ANP reversed and protected against, subsequent methacholine-induced bronc hoconstriction; an action enhanced by the presence of phosphoramidon ( 3.68 x 10(-5) M). Associated with these actions of urodilatin was a ri se in cyclic GMP levels as well as the opening of ATP-sensitive K+ and small conductance Ca2+-activated K+ channels.