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 from near-term pregnant guinea pigs to investigate the ability and mechanism of natriuretic peptides to inhibit myometrial contractility. Myometrial strips were contracted by 10(-8) M oxytocin, and relaxation to the cumulative addition (10(-9)-10(-6) M) of the natriuretic peptides measured. Maximal relaxation to BNP was significantly greater than to ANP (52 versus 32% respectively; p < 0.05), whereas CNP failed to produce relaxation. However, the increase 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 guanylate 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 alter BNP-induced relaxation. The atrial natriuretic peptide-fragment 4-23 amide, a natriuretic peptide clearance receptor agonist, failed to inhibit oxytocin-stimulated myometrial contraction. We conclude that natriuretic peptide induced relaxation of oxytocin-stimulated myometrium from the pregnant guinea pig is not mediated by either guanylate cyclase A or B activation, is 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.
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Bressler Research Building, 655 W. Baltimore St., Baltimore, MD 21201, USA.
J A
JA
Carvajal
K
K
Aguan
L P
LP
Thompson
I A
IA
Buhimschi
C P
CP
Weiner
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology*; D006168:Guinea Pigs; D009126:Muscle Relaxation / Q000187:drug effects; D009215:Myometrium / Q000187:drug effects* / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology*; D010121:Oxytocin / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D014590:Uterine Contraction / Q000187:drug effects*
D010456:Peptides, Cyclic; D020097:Natriuretic Peptide, Brain; C068090:anantin; C016276:8-bromocyclic GMP; D010121:Oxytocin; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D006152:Cyclic GMP