6-keto Prostaglandin F1 Alpha Levels Research Articles

Synergistic action of famotidine and chlorpheniramine on acetic acid-induced chronic gastric ulcer in rats

To assess the synergistic action of famotidine (FMD) and chlorpheniramine (CPA) on acetic acid-induced chronic gastric ulcer in rats. Chronic gastric lesions were induced in male Sprague-Dawley (SD) rats by serosal application of the acetic acid. Forty SD rats were randomly divided into blank group (n = 8), control group (n = 8), FMD group (n = 8), CPA group (n = 8), and FMD+CPA group (n = 8). Each group was given intraperitoneally (i.p.) 0.5 mL/100 g distilled water, 9 g/L NaCl saline, 4 mg/kg FMD, 10 mg/kg CPA, 4 mg/kg FMD+10 mg/kg CPA, respectively, daily for 10 d. On d 10, ulcer area was determined by planimetry. The level of myeloperoxidase (MPO) in the liver homogenization was determined by biochemical methods and the plasma levels of 6-ketoprostaglandin F1 alpha (6-keto-PGF(1a)) and IL-8 were determined by radioimmunoassay. The synergistic effects of FMD+CPA group on the lesion, IL-8, 6-keto-PGF(1a) and MPO were confirmed. The effect of FMD+CPA group was significantly different as compared to the control and FMD groups. The lesion (mm(2)) was reduced from 40.18+/-2.6 in control group to 6.83+/-2.97 in PMD+CPA group, P<0.01, and from 32.9+/-3.27 in FMD group to 6.83+/-2.97 in PMD+CPA group, P<0.01. The plasma levels of IL-8 decreased from 0.69+/-0.11 ng/L in control group to 0.4+/-0.04 ng/L in PMD+CPA group, P<0.01, and from 0.51+/-0.08 ng/L in FMD group to 0.4+/-0.04 ng/L in PMD+CPA group, P<0.05. The level of 6-keto-PGF(1a) increased from 7.55+/-1.65 ng/L in control group to 16.62+/-0.97 ng/L in PMD+CPA group, P<0.01, and from 13.15+/-1.48 ng/L in FMD group to 16.62+/-0.97 ng/L in PMD+CPA group, P<0.05. The levels of MPO in the liver homogenate decreased from 9.12+/-2.05 u/L in control group to 4.33+/-0.95 u/L in PMD+CPA group, P<0.01, and from 8.3+/-1.29 u/L in FMD group to 4.33+/-0.95 u/L, P<0.01. The synergistic action of FMD and CPA on acetic acid-induced chronic gastric ulcer in rats decreases the incidence of ulcer and also enhances the healing of ulcer.

Early endothelial dysfunction following renal mass reduction in rats.

Endothelial dysfunction has been previously described in severely hypertensive rats with renal mass reduction (RMR) receiving large dietary Na loads. Because hypertension and Na loading reduce endothelium-dependent vasodilation, the effect of renal failure per se is unclear. Responses to acetylcholine in noradrenaline-contracted isolated perfused mesenteric arteries were studied. Vessels were obtained from RMR rats kept on a normal diet, 3 and 10 days after surgery, and the results were compared with those from sham-operated rats (SN). The role of three putative mediators of endothelium-dependent vasodilation was assessed using: L-NAME (10(-4) mol L(-1)); indomethacin (INDO, 10(-5) mol L(-1)); and a mixture of charybdotoxin and apamin (C/A, both 10(-7) mol L(-1)), inhibitors of Ca-activated K-channels to mediate the effects of endothelium-derived hyperpolarizing factor (EDHF). Response to acetylcholine but not that to nitroprusside (endothelium-independent) was decreased in RMR. L-NAME reduced further acetylcholine relaxations in SN but not in RMR. By contrary, INDO decreased acetylcholine vasodilation in RMR but had no effect in SN. C/A had similar effects in the SN and RMR rats. The levels of 6-keto prostaglandin F1alpha were elevated in the urine of the RMR rats and were perfusate from the RMR vessels. Endothelial dysfunction occurs early after RMR, even when systolic blood pressure is only minimally elevated and Na intake is normal. This alteration may be because of decreased availability of nitric oxide, partially compensated by increased prostacyclin production.

Eicosanoids and inflammatory cells in frostbitten tissue: prostacyclin, thromboxane, polymorphonuclear leukocytes, and mast cells.

The pathophysiology of cold injury is still controversial. An inflammatory process has been implicated as the underlying mechanism and certain anti-inflammatory substances such as ibuprofen and acetylsalicylic acid have been used in the clinical treatment of frostbite injury. It has been postulated that the progressive ischemic necrosis is secondary to excessive thromboxane A2 production, which upsets the normal balance between prostacyclin (prostaglandin I2) and thromboxane A2. It was aimed to clarify the pathophysiology of cold injury in this study. Twenty-one New Zealand White rabbits, each weighing 1.2 to 2.9 kg, were divided into control (n = 10) and frostbitten (n = 11) groups the randomly. The rabbit ears in the frostbitten group were subjected to cold injury, and the levels of thromboxane A2 (as thromboxane B2) and of prostaglandin I2 (as 6-keto-prostaglandin F1alpha) and the number of inflammatory cells (polymorphonuclear leukocytes and mast cells) were measured in normal and frostbitten skin of rabbit ears. The levels of 6-keto prostaglandin F1alpha and thromboxane B2, the stable metabolites of prostaglandin I2 and thromboxane A2, respectively, were increased in a statistically significant way (p < 0.002) by frostbite injury; however, thromboxane B2 increased more than 6-keto prostaglandin F1alpha. Polymorphonuclear leukocytes and mast cells, absent in normal skin, were present in the frostbitten skin. There was a statistically significant (p < 0.01) correlation between the time a rabbit ear was maintained at below -10 degrees C and skin survival and between the weights of rabbits and skin survival (p < 0.024). All these findings suggest that inflammation is involved in frostbite injury; a decrease in prostaglandin I2/thromboxane A2 ratio could be one of the factors leading to necrosis; the bigger the animal, the better its ability to counter frostbite.

Immunosuppressive therapy for recurrent aborters with positive antiphospholipid antibodies and alteration of 6ketoPGF1 alpha/TXB2 ratio.

Twelve women (13 pregnancies) with antiphospholipid antibodies (APA) who had suffered from two or more recurrent spontaneous abortions or fetal deaths and had successful pregnancy outcomes after immunosuppressive therapy were studied. APA titers were determined by enzyme-linked immunosorbent assay against cardiolipin, phosphatidyl serine and phosphatidyl inositol. Plasma levels of 6ketoprostaglandin F1 alpha (6ketoPGF1 alpha) and thromboxane B2 (TXB2) were determined by radioimmunoassay. All of the 13 pregnancies resulted in term delivery. None of the 13 patients suffered from pregnancy-induced hypertension, and only one showed intrauterine growth retardation. A significant decrease of APA titer was observed after immunosuppressive therapy. The 6ketoPGF1 alpha/TXB2 ratios before the therapy, after it and at the 1st, 2nd and 3rd trimesters of pregnancy were 0.62 +/- 0.398, 0.88 +/- 0.106, 0.84 +/- 0.550, 1.25 +/- 0.834 and 0.67 +/- 0.413, respectively. The ratio at the 2nd trimester was significantly higher than that before the therapy (P < 0.05, paired t-test, n = 9). The results indicate that the immunosuppressive therapy affected the physiological balance between thromboxane A2 and prostacyclin, and improved clinical symptoms such as recurrent fetal wastage.

Lung mechanics and pulmonary but not systemic vascular responses to ET-1 are Tx and infusion rate dependent

The role of cyclooxygenase metabolites formation in the systemic and pulmonary vascular and airway responses to different intravenous infusion rates of endothelin-1 (ET-1) was investigated in eight barbiturate-anesthetized mechanically ventilated adult sheep. ET-1 (20, 200, and 400 pmol/kg) was infused into the femoral vein over either 1, 10, or 180 s before and after pretreatment with indomethacin (1.5 mg/kg i.v.). ET-1 infusion produced a dose-dependent systemic vasoconstriction that was similar with all three infusion rates. In contrast, the pulmonary vascular and airways responses to ET-1 were not only dose dependent but also infusion rate dependent so that consistent effects on the pulmonary vasculature and airways were observed only when the peptide was injected over 1 s. At the highest dosage and at the fastest rate of administration, ET-1 produced a fivefold rise in pulmonary vascular resistance, a twofold rise in airway resistance, and a 45% decrease in dynamic pulmonary compliance, whereas no changes were observed when the peptide was injected over 180 s. Plasma levels of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) increased 20-fold when ET-1 was administered over 1 s but only 5-fold when it was administered over 180 s. Thromboxane B2 (TxB2) increased 5-fold when ET-1 was administered over 1 s and did not increase when ET-1 was given over 180 s. Plasma TxB2 levels were linearly correlated with pulmonary vascular or airway resistance during the bolus ET-1 infusion. Pretreatment with indomethacin completely prevented the ET-1-induced rise in TxB2 and 6-keto-PGF1 alpha and blocked pulmonary vaso- and bronchoconstriction observed, whereas it enhanced systemic vasoconstriction. These results demonstrate that in adult sheep intravenous ET-1 produces pulmonary vaso- and bronchoconstriction that is infusion rate dependent and is associated with the rate-dependent production of thromboxane. In contrast, the increase in systemic vascular tone elicited by ET-1 is not affected by its rate of infusion and does not depend on the secondary generation of cyclooxygenase metabolites.

The mechanism of coronary collateral vasoconstriction in response to cyclooxygenase blockade.

The present study was performed to examine the mechanism by which cyclooxygenase blockade produces vasoconstriction in well-developed coronary collateral vessels. Eight dogs were studied 4 to 6 months after occlusion of the left anterior descending coronary artery (LAD) had been performed to stimulate collateral vessel growth. At the time of study, the LAD was cannulated at the site of occlusion for measurement of retrograde blood flow as an index of collateral blood flow. Levels of 6-ketoprostaglandin F1 alpha were 32 +/- 13% higher in blood diverted from the collateral-dependent LAD than in aortic blood (P < .05); the increase in this stable product of prostacyclin metabolism indicated production of prostacyclin across the coronary collateral system. Administration of arachidonic acid into the left main coronary artery to reach collateral vessels entering the LAD resulted in a 21 +/- 6% increase in retrograde flow (P < .01), demonstrating cyclooxygenase activity with production of vasodilator prostaglandins in the collateral system. Ibuprofen (10 mg/kg IV) caused a 55 +/- 7% decrease in retrograde flow (P < .03), suggesting that cyclooxygenase blockade inhibited tonic production of vasodilator prostaglandins in the collateral system. In contrast, neither thromboxane synthase inhibition with dazmegrel nor thromboxane receptor blockade with SQ 30741 caused a significant change in collateral flow, thus failing to support thromboxane-induced collateral constriction. After cyclooxygenase blockade, prostacyclin infused into the left main coronary artery was able to restore retrograde flow to the preibuprofen level.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostacyclin is required for t-PA release after venous occlusion.

The role of vascular cyclooxygenase pathway on tissue-type plasminogen activator (t-PA) release after venous occlusion was studied in anesthetized rats. After the inferior vena cava was clamped for 30 min, fibrinolytic activity increased from 143.7 +/- 14.5 to 209.5 +/- 10.3 mm2 (mean +/- SE, P < 0.002). This increase was prevented by aspirin at high (100 mg/kg i.v.) but not at low doses (1 mg/kg i.v.). Dazoxiben (10 mg/kg i.v.), an inhibitor of thromboxane synthase, was ineffective on the fibrinolytic response. Both the basal levels of 6-ketoprostaglandin F1 alpha and its increase after venous occlusion were suppressed by 100 mg/kg aspirin administration (from 0.64 +/- 0.2 to 0.05 +/- 0.002 ng/ml before occlusion, P < 0.001; and from 1.08 +/- 0.2 to 0.06 +/- 0.002 ng/kg after occlusion, P < 0.001), whereas they were both unaffected by aspirin at low doses (from 0.53 +/- 0.06 before to 1.20 +/- 0.08 ng/ml after stasis). Moreover, iloprost, a stable analogue of prostacyclin, reversed the aspirin inhibitory effects on fibrinolytic activity by restoring t-PA vascular release after venous stasis. Our results provide experimental evidence that an intact cyclooxygenase pathway in vascular wall is required for the fibrinolytic activity increase after venous occlusion in rats.

Effect of cyclooxygenase blockade on gas exchange and hemodynamics in Pseudomonas pneumonia.

Acute bilateral Pseudomonas aeruginosa pneumonia was induced in 10 anesthetized dogs, after which five dogs received intravenous indomethacin (2 mg/kg) (indomethacin group), whereas five others were infused with saline (2 ml/kg) (control group). Plasma levels of 6-ketoprostaglandin F1 alpha(6-keto-PGF1 alpha) and thromboxane B2 (TxB2), stable metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), respectively, were measured by radioimmunoassay. Although TxB2 levels were not different before and after inoculation in either group, 6-keto-PGF1 alpha levels increased from their base-line value in each animal as pneumonia developed (indomethacin group: less than 100 to 330 +/- 90 pg/ml; control group: less than 100 to 630 +/- 300 pg/ml). Both prostaglandins fell to less than 100 pg/ml in each dog after indomethacin infusion, whereas they remained elevated in the control group after infusion of normal saline. Perfusion of consolidated lung regions (Qp/QT), measured with radioactive microspheres and expressed as a percent of total pulmonary blood flow, was dramatically reduced after indomethacin (35 +/- 3 to 16 +/- 1%) with consequent improvement in pulmonary shunt (Qs/QT: 30 +/- 8 to 18 +/- 6%) and arterial O2 tension (PaO2: 123 +/- 25 to 274 +/- 77 Torr). These parameters remained unchanged or deteriorated further in the control group after infusion of saline. Three additional dogs with Pseudomonas pneumonia were studied in which the indomethacin-induced reduction in Qp/QT was substantially but not completely reversed by intravenous infusion of PGI2.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial effects of U-63 557A a thromboxane synthetase inhibitor, in an ovine model of pregnancy-induced hypertension

Pregnancy-induced hypertension was induced in five ewes (gestational day 135; term 150 days) by 72 hours of food deprivation. Maternal arterial pressure, uterine blood flow, platelet function, renal function, and plasma levels of 6-ketoprostaglandin F1 alpha and thromboxane B2 were measured before and during hypertension and after three intravenous injections of U-63,557A; sodium 5-(3'-pyridinylmethyl) benzofuran-2-carboxylate, monohydrate (30 mg/kg every 8 hours). Blood pressure increased (p less than 0.03), and returned to normal after U-63,557A. Left uterine artery blood flow increased after U-63,557A (p less than 0.03). Creatinine clearance decreased during hypertension (p less than 0.03) and increased after U-63,557A. Urine protein increased during hypertension (p less than 0.03) and decreased after treatment. Platelet count dropped during hypertension (p less than 0.03) and was elevated after treatment. Collagen lag phase decreased during hypertension (p less than 0.03) and increased after treatment. After U-63,557A, 6-ketoprostaglandin F1 alpha levels were higher (p less than 0.04) than baseline or hypertensive values. Administration of a thromboxane synthetase inhibitor caused resolution of hemodynamic, renal, and coagulation dysfunctions that occurred in ovine pregnancy-induced hypertension.

Human Atrial Natriuretic Peptide

The effects of human alpha-natriuretic peptide (alpha-ANP) were investigated in seven patients with severe congestive heart failure by incremental bolus injections and by a continuous infusion for 30 min. alpha-ANP was measured in plasma before and after administration. We found a significant inverse correlation between basal levels of alpha-ANP and cardiac output. The administration of alpha-ANP resulted in a fall of peripheral vascular resistance, an increase in cardiac output, a relatively small decrease in blood pressure, and almost no change in pulmonary arterial pressure. alpha-ANP inhibits aldosterone and cortisol secretion and enhances diuresis and urinary sodium and potassium excretion. Plasma adrenocorticotropic hormone was reduced in two of the patients after the continuous infusion. Plasma renin concentration, norepinephrine, vasopressin, and plasma levels of 6-keto prostaglandin F1-alpha and prostaglandin E2 were unchanged. A small but significant decrease of serum potassium was observed.

Relation of prostanoids to strength of hypoxic vasoconstriction in dogs with lobar atelectasis.

In dogs with acute lobar atelectasis, meclofenamate administration decreases shunt fraction uniformly and moderately without abolishing the wide variation of strength of hypoxic vasoconstriction and resultant variability of shunt fraction (J. Appl. Physiol. 54: 284-289, 1983). To further assess the role of prostanoids, we measured prostanoid metabolites as well as shunt fraction and pressor response to alveolar hypoxia. In six intact anesthetized dogs with acute left lower lobe atelectasis, shunt fraction during normoxia was measured with SF6. Levels of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 in arterial, mixed venous, and left lower lobe venous blood were measured with the double antibody radioimmunoassay technique. Ten percent O2 was administered to assess pressor response. Twenty-one percent O2 was restarted, meclofenamate was administered, and measurements were repeated 30 min later. Atelectasis did not elevate levels of prostanoid metabolites. 6-Keto-PGF1 alpha averaged 88 +/- 65 pg/ml prior to atelectasis and 81 +/- 73 pg/ml after atelectasis (F = 0.7, P = NS). Likewise, thromboxane B2 values were normal. No transpulmonary concentration differences were found. 6-Keto-PGF1 alpha did not correlate with shunt values, which ranged from 14 to 35% (mean 21%). Meclofenamate effectively blocked cyclooxygenase, as demonstrated by decreases in prostanoid metabolite levels. It seems likely that in dogs with acute atelectasis prostacyclin localized in the pulmonary vasculature decreases strength of hypoxic vasoconstriction modestly and uniformly without raising blood levels of prostacyclin metabolite.

Failure of myocardial ischemia to increase pulmonary microvascular permeability in dogs.

Increased extravascular lung water has been reported following periods of myocardial ischemia. To determine whether increased pulmonary microvascular permeability was produced by ischemia, total protein lymph-to-plasma concentration ratios (CL/CP) were obtained at mechanically increased left atrial pressures (Pla) before and after ligation of the left anterior descending coronary artery in dogs. Pulmonary and systemic vascular pressures and cardiac output were monitored and lymph flow was measured from an afferent tracheobronchial lymphatic. Osmotic reflection coefficients (sigma) for total protein were estimated using CL/CP = 1-sigma at high filtration rates, and permeability-surface area (PSf) products were fit to the data. The postischemic lung lymph data best fit average values of sigma = 0.68 and PSf = 0.073 ml X min-1 X 100 g-1 wet weight. There were no significant differences in lymph protein or water clearances between the pre- and postischemic increased Pla states or for myocardial ischemia compared with control values for the experimental preparation. Levels of 6-ketoprostaglandin F1 alpha, a degradation product of prostacyclin, increased by 10- to 14-fold above preischemic values in pulmonary lymph, and there was a significant increase in pulmonary vascular resistance during ischemia. Extravascular lung water was not increased above that attributed to the increased Pla alone. These data indicate no significant increase in pulmonary microvascular permeability to plasma proteins during myocardial ischemia.