6-ketoprostaglandin-f1-alpha and Hyperemia

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cardiovascular Physiological Phenomena; Cardiovascular System; Cyclooxygenase Inhibitors; Dinoprostone; Epoprostenol; Female; Humans; Hyperemia; Indomethacin; Kidney; Microsomes; Muscle, Smooth, Vascular; Nicotine; Pregnancy; Prostaglandins; Prostaglandins E; Smoking; Umbilical Arteries

During skeletal muscle contractions, the concentration of ATP increases in muscle interstitial fluid as measured by microdialysis probes. This increase is associated with the magnitude of blood flow, suggesting that interstitial ATP may be important for contraction-induced vasodilation. However, interstitial ATP has solely been described to induce vasoconstriction in skeletal muscle. To examine whether interstitial ATP induces vasodilation in skeletal muscle and to what extent this vasoactive effect is mediated by formation of nitric oxide (NO) and prostanoids, three different experimental models were studied. The rat gluteus maximus skeletal muscle model was used to study changes in local skeletal muscle hemodynamics. Superfused ATP at concentrations found during muscle contractions (1-10 μM) increased blood flow by up to 400%. In this model, the underlying mechanism was also examined by inhibition of NO and prostanoid formation. Inhibition of these systems abolished the vasodilator effect of ATP. Cell-culture experiments verified ATP-induced formation of NO and prostacyclin in rat skeletal muscle microvascular endothelial cells, and ATP-induced formation of NO in rat skeletal muscle cells. To confirm these findings in humans, ATP was infused into skeletal muscle interstitium of healthy subjects via microdialysis probes and found to increase muscle interstitial concentrations of NO and prostacyclin by ~60% and ~40%, respectively. Collectively, these data suggest that a physiologically relevant elevation in interstitial ATP concentrations increases muscle blood flow, indicating that the contraction-induced increase in skeletal muscle interstitial [ATP] is important for exercise hyperemia. The vasodilator effect of ATP application is mediated by NO and prostanoid formation.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Triphosphate; Adult; Animals; Blood Flow Velocity; Cells, Cultured; Erythrocytes; Female; Fluorescent Dyes; Humans; Hyperemia; Injections; Male; Microdialysis; Middle Aged; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Tonus; Muscle, Skeletal; Nitrates; Nitrites; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Vasodilation

Taking into consideration age-related changes in endothelium, the ability of endothelium to produce vasoactive substances has been studied in healthy subjects of various age. Under experimental conditions, the activity of constitutive and inducible NO-synthase has been studied as well. The clinical part of the study involved investigation of 38 healthy subjects aged 60-79. The study has been designed to investigate vasomotor function of the endothelium, the levels of endothelin-1, NO2, prostacyclin, thromboxan, the level of adhesive molecules and inhibitor of tissue plasminogen activator. The levels of endothelial and inducible NO-synthases in tissues of the myocardium and the aorta has been investigated in healthy rats of various age. The data obtained show a decrease in the production of relaxation factors: NO and prostacyclin with aging. An important mechanism of deterioration of NO-synthesizing function of the endothelium is a decrease in endothelial NOS activity. The synthesis of endothelial vasoconstricting agents increased with ageing. This in combination with decreased production of vasodilating substances results in deterioration of defence properties of the endothelium. The increase in titer of adhesive molecules and inhibitors of tissue plasminogen activator testifies to age-dependent deterioration of anti-inflammatory and antithrombotic activities of the endothelium.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aging; Animals; Aorta; Biological Factors; Blood Flow Velocity; Cell Adhesion Molecules; Endothelin-1; Endothelium, Vascular; Erythrocytes; Forearm; Humans; Hyperemia; Laser-Doppler Flowmetry; Middle Aged; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Rats; Thromboxane B2

Clinical studies have shown that low doses of aspirin (<300 mg/day) inhibit thromboxane A2 production and platelet aggregation but preserve prostacyclin synthesis. In contrast, high doses of aspirin (>1,000 mg/day) suppress the synthesis of both eicosanoids. Because the consequences of aspirin administration have never been investigated on coronary vasomotor tone in vivo, we investigated the effects of low and high doses of aspirin on systemic and coronary hemodynamics under basal conditions and after myocardial reactive hyperemia in conscious dogs. Dogs were instrumented with a Doppler flow probe and a hydraulic occluder. Coronary blood flow was measured in the conscious state at baseline and during myocardial reactive hyperemia after 10, 20, and 30 s of coronary occlusion. Thromboxane B2 serum concentrations, an index of platelet aggregation, decreased by >90% after long-term i.v. administration of aspirin, 100 mg/day for 7 days (low dose). Neither systemic and coronary hemodynamics nor reactive hyperemia were affected by the drug. After combined administration of this low dose of aspirin and of the nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine (L-NNA, 30 mg/kg/day/7 days), reactive hyperemia decreased to the same extent as when L-NNA was administered alone. After administration of a unique high-dose aspirin (1,000 mg, i.v.), myocardial reactive hyperemia was markedly reduced, and this effect was still observed after previous blockade of NOS and cyclooxygenase by L-NNA and diclofenac, respectively. Thus long-term treatment with a low antiaggregant dose of aspirin does not alter the ability of coronary vessels to dilate during myocardial reactive hyperemia in conscious dogs. In contrast, short-term administration of a high antiinflammatory dose of aspirin severely blunts myocardial reactive hyperemia through a mechanism that is independent of both cyclooxygenase and nitric oxide metabolic pathways.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Bradykinin; Coronary Disease; Coronary Vessels; Cyclooxygenase Inhibitors; Diclofenac; Dogs; Dose-Response Relationship, Drug; Hyperemia; Male; Myocardium; Nitric Oxide Synthase; Nitroarginine; Salicylic Acid; Thromboxane B2; Time Factors

Previously, it has been observed that methionine enkephalin and leucine enkephalin contribute to hypoxia-induced pial artery dilation in the newborn pig. It has also been observed that the cyclooxygenase inhibitor indomethacin attenuates hypoxic hyperemia in piglets. The present study was designed to determine the relationship between opioids and prostaglandins in hypoxia-induced pial artery dilation. Newborn pigs equipped with closed cranial windows were used to measure pial artery diameter and collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids and prostaglandins. Hypoxia-induced artery vasodilation was mildly attenuated during moderate hypoxia (PaCO2 approximately 35 mm Hg), while this response was blunted during severe hypoxia (PaO2 approximately 25 mm Hg) by indomethacin, 5 mg/kg iv (23% +/- 1 % vs 18% +/- 1% and 33% +/- 2% vs 21% +/- 2% for moderate and severe hypoxia in the absence and presence of indomethacin, respectively). Hypoxic dilation was accompanied by increased CSF prostaglandin E2 (PGE2) concentration (1260 +/- 37 vs 1734 +/- 67 and 1256 +/- 33 vs 2859 +/- 189 pg/ml for moderate and severe hypoxia, respectively). Similar changes in CSF 6 keto PGF1alpha concentration during hypoxia were also observed. Topical PGE2 (10,100 ng/ml) increased CSF methionine enkephalin (874 +/- 35, 1290 +/- 44, and 1791 +/- 143 pg/ml for control, 10 and 100 ng/ml PGE2 respectively). Similar increases in CSF methionine enkephalin concentration were observed for topical PGI2. Additionally, these two prostaglandins also increased CSF leucine enkephalin concentration. Furthermore, while indomethacin had no effect on the release of CSF methionine enkephalin during moderate hypoxia, it attenuated the release of this opioid during severe hypoxia (786 +/- 27 and 2633 +/- 74 vs 781 +/- 51 and 2467 +/- 52; 926 +/- 15 and 3489 +/- 156 vs 898 +/- 11 and 2314 +/- 124 pg/ml for control and moderate/severe hypoxia before and after indomethacin, respectively). Similar effects of indomethacin on hypoxic release of leucine enkephalin were also observed. These data indicate that prostaglandins contribute to hypoxic pial dilation. Additionally, these data show that prostaglandins release the opioids methionine enkephalin and leucine enkephalin. Finally, these data suggest that elevated prostaglandin concentrations during severe hypoxia release opioids which in turn contribute to hypoxic pial dilation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Arterioles; Blood Pressure; Carbon Dioxide; Cerebrovascular Circulation; Cyclooxygenase Inhibitors; Dinoprostone; Enkephalin, Leucine; Enkephalin, Methionine; Female; Hyperemia; Hypoxia, Brain; Indomethacin; Male; Oxygen; Partial Pressure; Pia Mater; Skin Window Technique; Swine; Vasodilation

In the perfused guinea-pig heart reactive hyperaemia (RH) after occlusion of coronary flow (1-60 s) was inhibited by 100-60% with NG-nitro-L-arginine (100 microM) and to a lesser extent (by 35%) after 8-phenyltheophylline (10 microM), but not by indomethacin (5 microM). Inhibition of adenosine deaminase by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) (5 microM) not only increased the concentration of adenosine in the coronary perfusate, but also prolonged the duration of RH. RH induced cardiac generation of prostacyclin, nitric oxide and adenosine as indicated by the appearance of 6-keto-PGF1 alpha, cyclic GMP, adenosine, inosine, hypoxanthine, xanthine and urate in the perfusate. Only NO and adenosine, but not prostacyclin, were responsible for RH. RH after short-term (1-10 s) coronary occlusion was mediated by NO, whereas adenosine and NO maintained RH that followed after longer (20 s-10 min) periods of cardiac ischaemia. Prostacyclin never participated in the mediation of RH.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine; Animals; Coronary Circulation; Cyclic GMP; Cyclooxygenase Inhibitors; Electrocardiography; Endothelins; Epoprostenol; Guinea Pigs; Hyperemia; In Vitro Techniques; Indomethacin; Myocardial Ischemia; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Perfusion; Prostaglandin Antagonists; Purinergic P1 Receptor Antagonists; Purines; Theophylline

This study was undertaken to examine the role of prostaglandins and histamine in the hyperemic response to gastric mucosal damage followed by H+ back-diffusion. Cat stomachs were exposed to 2 mol/liter NaCl for 10 min followed by luminal perfusion at pH 1. Hypertonic saline caused extensive (microscopic) damage to the surface epithelium, increased gastric mucosal blood flow, and increased release of histamine, PGE2, and 6-keto PGF1 alpha (prostacyclin) into portal venous blood. The effect of indomethacin and histamine blockers (H1 + H2) on the hyperemic response to acid back-diffusion was related to the depth of the mucosal injury and the region of the stomach. In the corpus, indomethacin enhanced mucosal injury. In areas with superficial damage, the hyperemia was inhibited by indomethacin and antihistamines and eliminated by the combination of both. In corpus areas with indomethacin-induced deep lesions, the blood flow was very high, and this hyperemia was partly inhibited by antihistamines. In the antrum the hyperemic response was reduced by antihistamines. Indomethacin increased the release of histamine into portal venous blood (baseline recordings) and reduced basal gastric mucosal blood flow.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Astemizole; Cats; Dinoprostone; Gastric Acid; Gastric Mucosa; Histamine; Histamine H2 Antagonists; Hyperemia; Indomethacin; Male; Prostaglandins; Regional Blood Flow; Saline Solution, Hypertonic; Triazoles

Endogenous prostaglandins and injury-induced hyperemia are important defense mechanisms in the gastric mucosa. In the rat stomach, we tested the hypotheses that an ulcer-promoting dose of intravenous nicotine 1) reduces ex vivo prostaglandin generation and 2) aggravates mucosal lesions by impairing injury-induced hyperemia. Anesthetized rats were given intravenous control or 4 or 40 micrograms.kg-1.min-1 nicotine infusion. In study 1, ex vivo generation of prostaglandin E2 and 6-ketoprostaglandin F1 alpha (stable metabolite of prostacyclin) was determined by vortexing the mucosal tissue, followed by radioimmunoassay. No significant difference in prostaglandin generation was found between the control and experimental groups. In study 2, intravenous nicotine (40 micrograms.kg-1.min-1) produced a significant rise (19 +/- 3%) in mean blood pressure and completely abolished the gastric hyperemia produced by intragastric saline (2 M). The extent of the associated gastric mucosal injury was significantly increased (from 5.3 +/- 0.8 to 17.4 +/- 5.2% of the corpus mucosa), while the maximum depth of the largest lesions was not affected by intravenous nicotine. The data confirm that the gastric hyperemia associated with gastric mucosal exposure to hypertonic saline plays an important role in limiting the extent of gastric mucosal damage. We conclude that in the rat stomach 1) an ulcer-promoting dose of intravenous nicotine does not significantly inhibit cyclooxygenase activity, and 2) the same does of intravenous nicotine exacerbates hypertonic saline-induced gastric mucosal injury by a mechanism that involves inhibition of injury-induced hyperemia.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Dinoprostone; Gastric Mucosa; Hydrogen; Hyperemia; Injections, Intravenous; Male; Nicotine; Rats; Rats, Inbred Strains; Sodium Chloride

A role for prostacyclin (PGI2) as a mediator of estrogen-induced increases in uterine blood volume (UBV) was investigated by measuring uterine tissue levels of 6-keto-prostaglandin F1 alpha (6-keto-PGF 1 alpha), and testing estrogen responses in rats pretreated with the PGI2 synthesis inhibitor, tranylcypromine (TCP). Uterine 6-keto-PGF1 alpha content was determined by radioimmunoassay of tissue extracts purified through the use of high-performance liquid chromatography (HPLC). Estrogen treatment of castrate rats resulted in a significant increase of uterine 6-keto-PGF 1 alpha was compared to saline treated controls (9.3 ng/uterine horn vs 6.7 ng/uterine horn, p=0.01). Pretreatment with TCP (20 mg/kg) markedly reduced the uterine content of 6-keto-PGF 1 alpha (2.5 ng/uterine horn). The typical 50% increase in UBV observed after estrogen was unaffected by tranylcypromine pretreatment. It was concluded that the increased PGI2 synthesis, as indicated by elevated levels of 6-keto-PGF1 alpha, may function as an amplifying mechanism for the uterine vasodilation-induced by estrogen in castrate rats, but that production of this prostanoid is not essential for the estrogen response.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Estrogens; Female; Hyperemia; Prostaglandin Antagonists; Rabbits; Radioimmunoassay; Rats; Rats, Inbred Strains; Tranylcypromine; Uterus

We studied post-occlusive reactive hyperaemia using ecg-triggered mercury strain-gauge plethysmography in eight normal subjects treated with incremental doses of aspirin (27.5-1200 mg). The reactive hyperaemic response was measured in the finger (predominantly skin blood flow) and the calf (predominantly muscle). Concentrations of TXB2 and 6-oxo-PGF1 alpha were measured in venous effluent blood from the hand by RIA, following arterial occlusion. Levels of TXB2 were significantly higher at 0-10 and 60-70 seconds (p less than 0.01), and 90-100 seconds (p less than 0.05) following release of occlusion compared to pre-occlusion values. However there was no significant change in concentrations of 6-oxo-PGF1 alpha and therefore by this method release of prostacyclin during reactive hyperaemia in the hand. Aspirin had no influence on finger or calf reactive hyperaemia 90 minutes after dosing, despite marked inhibition of platelet MDA production (75% after 110 mg, maximal inhibition after 1200 mg). These data provide no support for the hypothesis that prostacyclin is involved in the determination of the post-occlusive reactive hyperaemic response in the finger and calf in man.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Blood Platelets; Epoprostenol; Humans; Hyperemia; Male; Prostaglandins; Thromboxane B2

Circulating basal levels of prostanoids were measured in non-insulin dependent diabetics (NIDDs) who showed chlorpropamide alcohol flushing (CPAF), with and without diabetic complications, and in non-diabetic controls. Prostanoids were also measured during CPAF in those diabetics in whom CPAF is or is not blocked by indomethacin and also in CPAF-negative patients. There was no significant difference in circulating prostanoids between diabetics with and without severe vascular disease. The level of prostaglandin F, however, was significantly higher in the diabetic than in the non-diabetic subjects (mean +/- SEM PGFM 521 +/- 23 v. 414 +/- 18 pmol/l respectively P less than 0.01). In the group in whom CPAF could be blocked by indomethacin there was a significant rise in thromboxane during CPAF when compared with basal values (mean +/- SEM 905 +/- 48 v. 688 +/- 46 pmol/l respectively P less than 0.01) which was abolished by prior administration of indomethacin. There was no significant rise in prostacyclin or PGF. The group in which CPAF could not be blocked by indomethacin and the CPAF negative group showed no rise in any of the prostanoids measured. These findings support the concept of at least two different groups of CPAF positive NIDDs, one in which prostanoids are involved in CPAF and one in which they are not. It is the group in which prostanoids are involved in CPAF who seem to be highly protected against vascular disease.

Topics: 6-Ketoprostaglandin F1 alpha; Alcoholic Beverages; Chlorpropamide; Diabetes Mellitus; Face; Female; Humans; Hyperemia; Indomethacin; Male; Middle Aged; Prostaglandins; Prostaglandins F; Thromboxane B2