prostaglandin-d2 and Hypertension--Pulmonary

The characteristic arteriopathy of primary pulmonary hypertension (PPH) with attendant endothelial dysfunction provides an opportunity for enhanced cellular activation in the lung. Data from many laboratories support the concept of altered eicosanoid metabolism in PPH. Rigorously quantitative measurements of the excretion of metabolites of thromboxane A2 and prostacyclin support persistent platelet activation and inadequate endothelial response in patients with PPH. Recent studies measuring excretion of prostaglandin D2 metabolites suggest that additional cell sources, such as activated tissue macrophages, may also play a role in the observed elevation in thromboxane excretion and possibly in the pathogenesis of the vascular remodeling. Additional research examining in vivo cell activation in patients receiving therapy with long-term infusion of prostacyclin may further our understanding of the pathogenesis of PPH.

Topics: Animals; Eicosanoids; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Macrophage Activation; Prostaglandin D2; Pulmonary Artery; Thromboxanes

It is clear that prostaglandins and related compounds are important in the physiology and pathophysiology of the perinatal pulmonary circulation. This article focuses on what is known about prostaglandin-related compounds (PRC) in the pulmonary circulation of the developing and newly born mammal. Also included is a discussion of the effects of PRC on the ductus arteriosus and on the systemic circulation.

Topics: Animals; Animals, Newborn; Arachidonic Acids; Blood Pressure; Epoprostenol; Female; Fetus; Humans; Hydroxyeicosatetraenoic Acids; Hypertension, Pulmonary; Infant, Newborn; Lung; Persistent Fetal Circulation Syndrome; Pregnancy; Prostaglandin Antagonists; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; Pulmonary Circulation; Sheep; SRS-A; Thromboxanes; Vascular Resistance; Vasoconstriction

This 15-year-old disease has been clearly described anatomically. Some understanding of possible in utero predisposing conditions has emerged from clinical and animal studies. However, we have very little understanding of the cellular processes that trigger and/or prolong the abnormal medial smooth muscle hypertrophy underlying the condition. Empiric observation has resulted in the development of hyperventilation as a fairly successful treatment modality, although the underlying mechanism of this salubrious effect is unknown. Drugs, a major focus of clinical and laboratory investigations, sometimes are marginally successful (and sometimes are utter failures). Translated into the neonatal intensive care unit, the disease is more frequently accurately diagnosed than in the past, but it remains frustratingly difficult to manage, and thus far is impossible to prevent. The research foundations laid in the past decade provide impetus for accelerated search into the fundamental cellular and biochemical derangements that cause persistent pulmonary hypertension. It is to be hoped that the next decade will yield major advances in both mechanistic understanding and in treatment.

Topics: Acetylcholine; Calcium; Catecholamines; Epoprostenol; Homeostasis; Humans; Hypertension, Pulmonary; Infant, Newborn; Muscle Contraction; Muscle, Smooth, Vascular; Nifedipine; Nitroglycerin; Nitroprusside; Oxygen; Persistent Fetal Circulation Syndrome; Prostaglandin D2; Prostaglandins D; Pulmonary Artery; Pulmonary Veins; Tolazoline; Verapamil

TXA(2) (thromboxane A(2)) is a lipid mediator believed to be produced primarily by platelets in normal subjects, although macrophages are capable of synthesis. There is increased production of TXA(2) in patients with primary pulmonary hypertension (PPH), which may reflect augmented production by macrophages. The objective of this study was to determine if macrophages are activated in PPH and whether they contribute to the increased production of TXA(2).. Case control.. University hospital.. We measured the urinary metabolites of three mediators that predominantly derive from different cell types in vivo: (1) TX-M (platelets and macrophages), a TXA(2) metabolite; (2) prostaglandin D(2) (PGD(2)) metabolite (PGD-M); and (3) N-methylhistamine (mast cells), a histamine metabolite, in 12 patients with PPH and 11 normal subjects.. The mean (+/- SEM) excretion of both TX-M and PGD-M at baseline was increased in PPH patients, compared to normal subjects (460 +/- 50 pg/mg creatinine vs 236 +/- 16 pg/mg creatinine [p = 0.0006], and 1,390 +/- 221 pg/mg creatinine vs 637 +/- 65 pg/mg creatinine [p = 0.005], respectively). N-methylhistamine excretion was not increased compared to normal subjects. There was a poor correlation between excretion of TX-M and PGD-M (r = 0.36) and between excretion of PGD-M and methylhistamine (r = 0.09) in individual patients.. In patients with PPH, increased levels of PGD-M, without increased synthesis of N-methylhistamine, suggest that macrophages are activated. The lack of correlation between urinary metabolite levels of TXA(2) and PGD(2) implies that macrophages do not contribute substantially to elevated TXA(2) production in patients with PPH. They may, however, have a role in the pathogenesis and/or maintenance of PPH, which warrants further investigation.

Topics: Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Female; Humans; Hypertension, Pulmonary; Macrophage Activation; Macrophages; Male; Methylhistamines; Middle Aged; Prostaglandin D2; Prostaglandins D; Thromboxane A2

After antenatal induction of diaphragmatic hernias in fetal lambs, prostaglandins D2, E1, and I2 were compared to tolazoline, or isoprenaline, for the treatment of pulmonary hypertension. When rendered hypoxic, these, and normal lambs, showed an increase in pulmonary artery pressure, a decrease in systemic pressure, and a decrease in pulmonary blood flow. All of the drugs altered that response, but to different degrees. None of the drugs tested was consistently successful in reversing the adverse affects of hypoxia, but prostaglandin D2 came closest to the ideal vasodilator, decreasing the pulmonary artery pressure in all seven hypoxic lambs having a diaphragmatic hernia. There was a concomitant increase in pulmonary blood flow in six; in the remaining lamb the decrease in blood flow induced by the hypoxia was arrested. At the same time, there was an increase in systemic artery pressure in three, the decrease was arrested in two, but the decrease continued in the other two. Isoprenaline was a more effective drug than tolazoline, producing an increase in pulmonary blood flow in five of the seven lambs, with minor decreases in systemic pressure in five. Tolazoline improved blood flow in three of six lambs (not all lambs survived the full study), with a marked decrease in systemic pressure in four of them. Prostaglandin D2 seems to be a useful drug for the treatment of patients having diaphragmatic hernias and pulmonary hypertension, and warrants further study. Isoprenaline was the most effective of the readily available drugs tested in this animal model.

Topics: Animals; Blood Flow Velocity; Blood Pressure; Disease Models, Animal; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Isoproterenol; Prostaglandin D2; Pulmonary Artery; Sheep; Tolazoline

Infusions of group B streptococci cause pulmonary hypertension in several neonatal animal models. A continuous infusion of prostaglandin D2 reduced the magnitude of this pulmonary hypertensive response; indomethacin completely blocked the response. Prostaglandin D2 or cyclooxygenase inhibitors may be important therapeutic agents for infants with group B streptococcal sepsis who manifest pulmonary hypertension.

Topics: Animals; Animals, Newborn; Blood Pressure; Hemodynamics; Hypertension, Pulmonary; Indomethacin; Prostaglandin D2; Prostaglandins D; Pulmonary Circulation; Sheep; Streptococcal Infections; Streptococcus agalactiae; Vascular Resistance