ABSTRACT. Sodium nitroprusside (SNP), a nonreceptor mediated stimulant of soluble guanylate cyclase, and atrial natriuretic factor, a receptor-dependent stimulator of particulate guanylate cyclase, mediate relaxation responses by increasing intracellular cGMP. This in vitro study was designed to compare the ontogeny of relaxation responses to S N P and atrial natriuretic factor in the guinea pig thoracic aorta. Aortic rings from fetuses at 55-60 d gestation (term = 68 d), 1-to 3-d-old newborn, and 12-wk-old adult Hartley guinea pigs were mounted in an organ bath, bathed in Kreb's solution, and connected to a force-displacement transducer to measure isometric tension. Relaxation responses to S N P and atriopeptin 111 were studied with the vessels at optimal resting tension and after preconstriction with an ECs5 concentration of norepinephrine. SNP-mediated relaxation showed a significant increase in sensitivity with development among the three age groups (p < 0.05). Methylene blue, an inhibitor of soluble guanylate cyclase, produced no inhibition of relaxation to S N P in fetal aortae, significantly decreased responses along the straight portion of the concentration-response curve in newborn aortae ( p < 0.05), and significantly shifted the concentration-response curve to the right ( p < 0.05) in adult aortae; but did not prevent vessels from relaxing almost 100% in any age group. However, atriopeptin IIImediated responses were similar in the three age groups and were unaffected by methylene blue. These results suggest that I) sensitivity to S N P increases with age from fetal through adult life; 2) relaxation mediated by atriopeptin I11 is similar during development; 3) methylene blue does not affect S N P mediated relaxation in fetuses but progressively decreases sensitivity to S N P in newborns and adults; and 4) methylene blue does not affect atriopeptin 111-mediated relaxation in any age group. APIII, atriopeptin I11 NE, norepinephrine MB, methylene blue cGMP is an intracellular mediator of relaxation in vascular smooth muscle (1-3). cGMP production in the vascular smooth muscle occurs by direct stimulation of soluble guanylate cyclase by agents such as nitrites, nitrates, and endothelium-derived relaxing factor (3) or by receptor dependent stimulation of particulate guanylate cyclase by ANF (4).ANF can be secreted by the fetal mammalian heart (5) resulting in measurable plasma levels of ANF in sheep ( 6 4 , rats (5), and humans (9). Furthermore, it has been demonstrated that the ANF hormonal system is functional during fetal life (5,9). Recent studies suggest that the hemodynamic response to ANF may evolve during maturation (6). Although it is known that isolated vessels located centrally consistently relax in the presence of ANF (lo), little is known regarding the ontogeny of ANF-mediated vascular relaxation from fetal into adult life.However, increasing attention is now focused on the role of cGMP-mediated processes in regulation of vascular tone (3) and this interest has extended to the ontogeny of these...