Ductus arteriosus: involvement of a sarcolemmal cytochrome P-450 in O₂ constriction?

Abstract

Our previous studies implicate a cytochrome P-450-based mechanism in the constrictor response of the ductus arteriosus to oxygen. The present experiments were conducted on saponin-skinned strips of ductal muscle from mature fetal lambs to determine the location, sarcolemmal versus intracellular, of this cytochrome and to obtain a better insight into the sequence of events underlying the action of oxygen. Skinned preparations contracted to free Ca2+ over the range between 0.1 and 5-10 microM (pCa 7 to 5). In contrast, oxygen (PO2, 608-690 Torr; 1 Torr = 133.3 Pa) had no significant effect, both in the absence and presence of 10 microM calcium. Carbon monoxide, tested as pure CO or a CO-O2 mixture (ratio 0.28), did not relax preparations maximally contracted with calcium. These findings indicate that oxygen exerts its effect on the plasma membrane of ductus muscle cells and that a membrane-bound cytochrome P-450 mechanism likely functions as the signal transducer for oxygen in the formation of a constrictor agent.

Tissue hypoxia inhibits prostaglandin and nitric oxide production and prevents ductus arteriosus reopening

“…6). The exact mechanisms that mediate this response are still unknown (14,17). Oxygen causes membrane depolarization, which, in turn, is associated with a rise in smooth muscle intracellular calcium (33).…”

Mechanisms Regulating the Ductus Arteriosus

“…A cytochrome P 450 hemoprotein, that is located in the plasma membrane of the vascular smooth muscle cells, appears to act as a receptor for the oxygen-induced events in the ductus [24,25] . Oxygen inhibits K + channels [26,27] .…”

Cimetidine-associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonism

“…The purpose for CYP3A expression in this spatiotemporal distribution is unclear. The data of Coceani and colleagues provide strong evidence that a hemoprotein in the CYP3A family of enzymes endows the ductus with a fundamental mechanism for oxygen-sensing [4–6, 32, 33]. In this regard, we observed that the term gestation DA was more susceptible than the preterm DA to cimetidine-induced relaxation, corresponding to maturation-related changes in DA sensitivity to oxygen.…”

“…CO-induced relaxation was completely reversed by monochromatic light at 450nm wavelength, implicating the actions of a hemoprotein in the CYP family [4, 5]. Additional evidence suggested that the CYP moiety was localized in the DA smooth muscle since endothelium-stripped vessels were equally relaxed by CO and required an intact plasma membrane [4, 5, 33]. Subsequent electron microscopy studies showed immunoreactive localization of CYP3A enzymes in the plasma membrane and sarcoplasmic reticulum of cultured DA smooth muscle cells [32].…”