Natriuretic peptide-induced relaxation of myometrium from the pregnant guinea pig is not mediated by guanylate cyclase activation

We tested both relaxation and cGMP generation by atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) in oxytocin-stimulated myometrium fro m near-term pregnant guinea pigs to investigate the ability and mechanism o f natriuretic peptides to inhibit myometrial contractility. Myometrial stri ps were contracted by 10(-8) M oxytocin, and relaxation to the cumulative a ddition (10(-9)-10(-6) M) of the natriuretic peptides measured. Maximal rel axation to BNP was significantly greater than to ANP (52 versus 32% respect ively; p < 0.05), whereas CNP failed to produce relaxation. However, the in crease in cGMP produced by BNP (10(-7) M) was significantly less than that produced by ANP (10(-7) M) (4.5 versus 7.0 times basal; p < 0.05); CNP did not increase myometrial cGMP. Anantin, a competitive blocker of the guanyla te cyclase A receptor, significantly reduced the increase in cGMP produced by ANP and BNP, but had no effect on relaxation induced by either peptide. Rp-8-Br-cGMP, an inhibitor of the cGMP-dependent protein kinase, did not al ter BNP-induced relaxation. The atrial natriuretic peptide-fragment 4-23 am ide, a natriuretic peptide clearance receptor agonist, failed to inhibit ox ytocin-stimulated myometrial contraction. We conclude that natriuretic pept ide induced relaxation of oxytocin-stimulated myometrium from the pregnant guinea pig is not mediated by either guanylate cyclase A or B activation, i s independent of the cGMP pathway, and does not involve clearance receptor activation. Our results suggest that natriuretic peptide-induced relaxation of pregnant myometrium is mediated via a novel mechanism.