Oxygen and cyclic nucleotides in human umbilical artery.

Abstract

In the human umbilical artery 02 has a direct contractile effect and is also required for induction of contraction by several other agents. Agonists that cause contraction (bradykinin, histamine, and serotonin) cause accumulation of guanosine 3':5'-monophosphate (cGMP) without altering adenosine 3':5'-monophosphate (cAMP). They appear to act through two different mechanisms: one Ca++-dependent, the other Ca++-inhibited. 02 increased the cGMP content of the artery in a Ca++-dependent manner without affecting the cAMP content. Inhibitors of oxidative phosphorylation (oligomycin and 2,4-dinitrophenol) did not diminish this effect of 02.02 was required for demonstration of the Ca++-dependent accumulation of cGMP in response to bradykinin, histamine, and ionophore A23187. The effect of the phosphodiesterase inhibitor 3-isobutyl-1-methyl xanthine on basal cGMP content and on the bradykinin-induced accumulation was also dependent on the presence of 02. Methylene blue and sodium ascorbate caused cGMP accumulation in 02-deprived arteries. Their effects were not diminished in Ca++-depleted arteries and, in fact, seemed to be inhibited when 2.7 mM Ca++ was present in the medium. The effects of these agents and of serotonin on cGMP, which were inhibited by Ca++, were also inhibited by 02. These non Ca++-, non 02-dependent agents (methylene blue, ascorbate, and serotonin) did not, however, permit demonstration of the effects of the Ca++-and Ordependent agonists on Ordeprived arteries. It appears that there are in the umbilical artery (and probably in other tissues also) at least two separate mechanisms for control of cGMP synthesis that are influenced differently by Ca++-and 02-linked processes.There is considerable evidence that in human umbilical artery an increase in 02 tension induces contraction and a decrease leads to relaxation (1-3). Humoral agents that cause contraction of the artery in vitro induce accumulation of guanosine 3':5'-monophosphate (cGMP) and those that initiate relaxation cause accumulation of adenosine 3':5'-monophosphate (cAMP) (4). Regulation of cGMP content appears to be effected through two distinct mechanisms: one that requires Ca and one that is inhibited by Ca++ (5). In the experiments reported here the effects of 02 on cyclic nucleotide metabolism in human umbilical artery were investigated. It was found that 02 caused accumulation of cGMP in a Ca++-dependent manner, without affecting the cAMP content of the artery. Further, agonists that required Ca++ in order to bring about an increase in cGMP content also required 02, whereas the effects of the agonists that were inhibited by Ca++ were also inhibited by 02-METHODS AND MATERIALS Human umbilical cords from full-term deliveries, obtained within 30 min of delivery, were dissected and prepared for incubation as previously described (4). For these procedures Hanks' medium without Ca++ and Mg++ was used at room were randomly assigned to 25 ml Erlenmeyer flasks containing 4 ml of medium as indicated in specific experiments.The complete medi...

Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations

“…However, other effects of oxidizing and reducing agents on native and activated guanylate cyclase cannot be excluded. These effects of redox agents upon the formation and/or activity of nitric oxide may explain several reports that oxygen, H202, methylene blue, and ascorbate have altered cyclic GMP accumulation and/or guanylate cyclase activity (24,25).…”

Activation of guanylate cyclase by superoxide dismutase and hydroxyl radical: a physiological regulator of guanosine 3',5'-monophosphate formation.

“…In some cell-free systems, guanylate cyclase is activated by H202 (32), arachidonic acid, prostaglandin endoperoxide, and other fatty acids (37,43,44). Oxygen tension and ascorbic acid also influence cyclic GMP levelsin tissues (45). The formation or utilization of superoxide ion is involved in thromboxane and prostaglandin formation (46), peroxidation of membranes (30,47), reduction of oxygen by flavin enzymes (48), autooxidation of hemoglobin (49), phagocytosis and lysosomal enzyme release from leukocytes (50), and other processes.…”

Oxidant and redox signaling in vascular oxygen sensing mechanisms: basic concepts, current controversies, and potential importance of cytosolic NADPH

“…A cellular signaling system regulated by PO 2 and by multiple cellular redox systems and ROS is sGC. It has been known for ϳ30 yr that cellular cGMP levels appear to be controlled by PO 2 (22). This enzyme can be directly regulated (57) through a heme group that binds nitric oxide and CO in its ferrous (Fe 2ϩ ) oxidation state (23), mechanisms described above for stimulation by peroxide, and there are superoxide and thiol redox-dependent mechanisms inhibiting rates of cGMP production.…”