Desvíos de los Indicadores

In 1975 Hamberg, Svesson, and Samuelsson⁶⁴ discovered an agent derived from endothelium that caused vasodilatation and inhibited platelet aggregation, it was called PGI2

or Prostacyclin.

Arachidonic Acid

Phospholipase A2

Membrane Phospholipids

Figure 6: Transformation of Released Arachidonate to Prostagladin and Prostacylin in Endothelial Cells as catalysed by Cyclooxygenase Enzymes⁶⁴.

Synthesis of PGI2

Exposure to stimuli increases intracellular calcium levels, which in turn activates phospholipases such as A2 and C. The phospholipases catalyse formation of free arachidonate from membrane phospholipids. Oxygenation and cyclization of free arachidonate are catalysed by a microsomal enzyme known as PGH synthase-1 , also known as cyclooxygenase. A cyclic endoperoxidase PGG2, then forms and is reduced to PGH2 via peroxidase activity in COX-1. The major and most important COX-1 product of endothelial cells is prostacyclin, (PGI2) which is catalysed by the isomerase PGI-synthase. With a half-life of 3 minutes, PGI2 undergoes chemical hydrolysis to 6-keto-PGF.

Activities of PGI2

Activity of PGI2 as a muscle relaxant can be demonstrated following infusion of the parent molecule. The inhibitory action of PGI2 is due to an interaction with its receptor on vascular smooth muscle cells and platelets. The biochemical effects of PGI2 are mediated mainly through G proteins and result in an increase in intra-platelet concentration of cyclic AMP, that leads to abolition of shape change, absence of platelet secretion and impaired binding of Von Willebrands factor and fibrinogen to the platelet surface.

PGI2 also inhibits platelet adhesion to sub endothelium. Decreased PGI2 production has been described in thrombotic thrombocytopenic purpura. It has not been possible to use Prostacyclin as therapeutic agents because of side effects, such as diarrhoea.

Prostanoids in Urine from Healthy Human Subjects.

Wennmalm, Benthin, Granstrom, et al⁶⁵ investigated the excretion of 2,3-dinor metabolites of thromboxane A2 and Prostacyclin, in urine of healthy subjects. They wanted to find a

possible diurnal variation in urinary thromboxane metabolite (TX-M) and prostacyclin metabolite (PGI-M) excretion and how the urinary levels in single samples reflect their respective 24h excretion rates.

Their study involved measuring the Tx-M, PGI-M and creatinine levels in consecutive portions of urine collected during 24h in 15 healthy non-smoking subjects.

They found out that the total 24h excretion of Tx-M, 31ng) and PGI-M (223+/-31ng) in men did not differ from women, Tx-M (215+/-44ng) and PGI-M (127+/- 29ng).

Neither the excretion of Tx-M nor that of PGI-M displayed any significant diurnal variation.

The excretion of Tx-M in a 3h period and the Tx-M/ creatinine ratio in a urinary sample accurately reflected the 24h excretion of Tx-M. (Correlation coefficient ranges 0.74-0.94 and 0.74-0.86, respectively.)

Likewise the excretion of PGI-M and the PGI-M /creatinine ratio in urine were accurate measures of 24h excretion of PGI-M, (correlation coefficient ranges 0.76 and 0.94 and 0.72 and 0.83 respectively.

Simple concentrations of these metabolites were poor indices of their respective 24h excretion.

Inflammatory Cytokines and Prostanoid Levels in Sickle Cell Diseases Graido-Gonzalez, Doherty, Bergreen et al⁶⁶, studied the relationship between the inflammatory cytokines and prostanoids especially prostaglandin E2 in Sickle cell disease.

They investigated the plasma levels of Endothelin-1, (ET-1 ) a potent vasoconstrictor and pro inflammatory agonist that has been shown to be elevated in sickle celldisease⁶⁶, and pro inflammatory cytokines (tumor necrosisfactor [TNF ], interleukin-1 [IL-1 ], IL-6, and

IL-8) , anti inflammatorycytokines (IL-10), and counter-regulatory prostaglandin E2 (PGE2) in asymptomatic sickle cell disease and during and after painful crisis.

In the study⁴⁵, thirteen adult homozygous sickle cell patients, had blood drawn at routine outpatient visits to confirm priorpublished results indicating high baseline levels of ET-1,⁶⁶ giving a mean ET-1 level of 35 pg/mL with a range of 0 to 151pg/mL (n = 13). Additional blood samples were obtained from a group of 11 comparably aged African-American consenting volunteers, who were documented tobe negative for sickle or C hemoglobin.

These samples served asage- and race-matched healthy controls. Bloodwas drawn from 13 consecutive consenting adult patients (20 to50 years of age) with known homozygous sickle cell disease presenting in acute pain crisis without infection or other concurrent medicalillness.

In the hospital, they were placed on intravenous hydration with 5% dextrose and 0.45 N saline and received boluses of morphine. Blood wascollected for this study on admission and each morning for 3 daysthereafter. The post crisis specimenfrom each patient was drawn at post hospitalization visit to the clinic, at a time ranging from 1 to 3 weeks.

Commercially available enzyme-linked immunosorbent assay (ELISA) kits were used to determine plasma ET-1 , PGE2 and TNF , IL-1 , IL-6, IL-8,and IL-10).

Plasma ET-1 levels were found to be significantly elevated relative to healthy controls (0.535 ± 0.508 pg/mL) in both patients in acutepain crisis (130.9 ± 23.1 pg/mL; P = .0002) and those at post crisisfollow-up (23.69 ± 9.52 pg/mL; P = .04) interpreted as their baseline symptom-free levels. Post crisis levels decreased significantlyfrom levels drawn in crisis for all patients (P = .0001).

Plasma PGE2 levels were also significantly elevated in crisis (316 ± 33.9 pg/mL; P < .001) relative to healthy controls andpost crisis patients (670.9 ± 61.0 pg/mL; P = .003)Similar to the pattern observed with respect to ET-1 levels, PGE2 levels in crisis were elevated compared with healthy controlsand decreased post crisis (P = .048). Neither the levels of ET-1nor those of PGE2 varied significantly during the crisis sampling period

Plasma levels of TNF , IL-1 , IL-6, IL-8, and IL-10 were not different between healthy controls and sickle cell patients (P< .05), although a trend was observed in which TNF and IL-10remained higher than controls during and after crisis. No differencewas observed between the levels in crisis and those of the samepatients at post crisis follow-up (P > .05).

In the study⁶⁶, the plasma levels of ET-1 and PGE2 were elevated in 13 adult sickle cell patients in crisis compared with aged-matchedAfrican-American controls and with their own levels on asymptomaticfollow-up. Whereas TNF , IL-1 , IL-6, and IL-8 were only variablyincreased, there were high levels of counter regulatory PGE2 andIL-10.

They therefore concluded that endothelin could contribute to both theprolonged vasospasm and to inflammation in acute painful sicklecell crisis and that endothelin antagonist strategies might haveutility in the treatment of this complex disorder.