6-ketoprostaglandin-f1-alpha and Hypercapnia

To study the effect of Safflower injection (a compound of Chinese Traditional medicine) on pulmonary hypertension in rat during chronic hypoxia and hypercapnia.. Sprague-Dawley rats were randomly divided into normal control group (A), hypoxic hypercapnic group (B), hypoxic hypercapnia + Safflower injection group (C). The concentration of TXB2 and 6-keto-PGF18 in plasma and in lung homogenate were detected by the radioimmunoassay.. (1) mPAP, weight ratio of right ventricle (RV) to left ventricle plus septum (LV + S) were much higher in rats of hypoxic hypercapnic group than those of control group. Differences of mCAP among the three groups were not significant. (2) The concentration of TXB2 and the ratio of TXB2/6-keto-PGF1a were significantly higher in rats of B group than those of A and C group. (3) The results examined by light microscopy showed that WA/TA (vessel wall area/total area), SMC (the density of medial smooth muscle cell) and PAMT (the thickness of medial smooth cell layer) were significantly higher in rats of B group than those of A and C group. (4) The results examined by electron microscopy showed proliferation of medial smooth muscle cells and collagen fibers of pulmonary arterioles in rats of B group, and Safflower injection could reverse the changes mentioned above.. Safflower injection may inhibit hypoxic hypercapnia pulmonary hypertension and pulmonary vessel remodeling by decreasing the ratio of TXB2/6-keto-PGF1a.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Carthamus tinctorius; Drugs, Chinese Herbal; Hypercapnia; Hypertension, Pulmonary; Hypoxia; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Thromboxane B2

To study the effect of aspirin on chronic hypoxia and hypercapnic pulmonary hypertension.. SD rats were randomly divided into normal control group (A), hypoxic hypercapnic group (B), hypoxic hypercapnia + aspirin group (C). The concentration of TXB2 and 6-keto-PGF1alpha in plasma and in lung were detected by the technique of radioimmunology.. (1) mPAP was significantly higher in B group than those of A and C group. Differences of mCAP were not significant in three groups. (2) Light microscopy showed that WA/TA (vessel wall area/total area) and PAMT (the thickness of medial smooth cell layer) were significantly higher in B group than those of A and C group. (3) The concentration of TXB2 and 6-keto-PGF1alpha in plasma and lung as well as the ratio of TXB2/6-keto-PGF1alpha were significantly higher in rats of B group than those of A and C group.. Aspirin may inhibit hypoxic hypercapnia pulmonary hypertension and pulmonary vessel remodeling.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Carotid Arteries; Epoprostenol; Hypercapnia; Hypertension, Pulmonary; Hypoxia; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Thromboxane A2

In the perinatal period, glucocorticoids are frequently administered to enhance pulmonary maturity or prevent chronic lung disease of prematurity. Recently, it has been suggested that the perinatal exposure to glucocorticoids can be associated with unfavorable neurologic development. We studied the hypothesis that 24-h pretreatment with glucocorticoid might modify cerebrovascular responses to high and low partial arterial CO(2) tension in newborn animals in vivo. A closed cranial window was implanted over the left parietal cortex of 20 anesthetized ventilated newborn (<3 d old) pigs. The actual experiments were carried out in 15 pigs: eight pretreated with a total dose of 6 mg/kg of dexamethasone and seven controls. Five pigs were used for preliminary experiments as described in the text. Pial arteriolar diameters were measured during 1) baseline conditions (normocapnia), 2) hypercapnia induced by ventilating the animals with a gas mixture containing 10% CO(2), or 3) hyperventilation with resultant hypocapnia. Under these conditions, the concentrations of 6-keto-PGF(1alpha) in the CSF were measured in five experimental animals and six controls. In summary, the dexamethasone pretreatment 1) attenuated the hypercapnia-induced dilator responses of pial arterioles and prevented the hypercapnia-associated fall in mean arterial blood pressure; 2) caused moderate, although not statistically significant, diminution in 6-keto-PGF(1alpha) levels in the CSF during baseline; 3) blocked hypercapnia-induced elevation of 6-keto-PGF(1alpha); and 4) enhanced vasoconstrictive arteriolar responses to hyperventilation. We speculate that in the clinical setting, the dexamethasone effects may compromise the adjustments of global or regional cerebral blood flow to changing physiologic states in neonates.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Arterioles; Blood Pressure; Carbon Dioxide; Cerebral Arteries; Cerebrospinal Fluid; Cerebrovascular Circulation; Dexamethasone; Hydrogen-Ion Concentration; Hypercapnia; Hyperventilation; Swine; Vasoconstriction; Vasodilation

Specific cerebrovascular dilatory responses in newborn piglets are entirely prostanoid dependent, but require both nitric oxide (NO) and prostanoids in juveniles. We examined endothelial dependency and mechanisms of NO- and prostanoid-mediated cerebrovascular responses in anesthetized newborn and juvenile pigs implanted with closed cranial windows. Light/dye endothelial injury inhibited newborn and juvenile hypercapnic and bradykinin (BK) responses and inhibited dilation to acetylcholine in juveniles. Iloprost and NO act permissively in restoring light/dye inhibited newborn and juvenile responses, respectively. Differences in sensitivity to iloprost and sodium nitroprusside were not observed. Juvenile (not newborn) hypercapnic and BK cerebrovascular responses were sensitive to soluble guanylyl cyclase inhibition. Pial arteriolar diameter and cortical production of prostacyclin, cAMP, and cGMP in response to BK were measured under control conditions, after treatment with indomethacin and/or N(omega)-nitro-L-arginine methyl ester (L-NAME). Indomethacin inhibited BK responses in newborns. Juvenile responses were inhibited by L-NAME, and mildly by indomethacin. Cortical 6-keto-PGF(1 alpha), cAMP, and cGMP increased in response to BK in both age groups. Newborn cerebrovascular responses are largely NO independent, but NO becomes more important with maturation.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Age Factors; Animals; Animals, Newborn; Arterioles; Bradykinin; Cardiotonic Agents; Cardiovascular Agents; Cerebrovascular Circulation; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Epoprostenol; Female; Hypercapnia; Iloprost; Indomethacin; Isoproterenol; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroprusside; Pia Mater; Swine; Vasodilation; Vasodilator Agents

To elucidate the differential reactivity of pulmonary microvessels in the acini to hypoxia, excessive CO2, and increased H+, we investigated changes in the diameter of precapillary arterioles, postcapillary venules, and capillaries in isolated rat lungs on exposure to normocapnic hypoxia (2% O2), normoxic hypercapnia (15% CO2), and isocapnic acidosis (0.01 mol/L HCl). Microvascular diameters were precisely examined using a real-time confocal laser scanning luminescence microscope coupled to a high-sensitivity camera with an image intensifier. Measurements were made under conditions with and without indomethacin or N(omega)-nitro-L-arginine methyl ester to assess the importance of vasoactive substances produced by cyclooxygenase (COX) or NO synthase (NOS) as it relates to the reactivity of pulmonary microvessels to physiological stimuli. We found that acute hypoxia contracted precapillary arterioles that had diameters of 20 to 30 microm but did not constrict postcapillary venules of similar size. COX- and NOS-related vasoactive substances did not modulate hypoxia-elicited arteriolar constriction. Hypercapnia induced a distinct venular dilatation closely associated with vasodilators produced by COX but not by NOS. Arterioles were appreciably constricted in isocapnic acidosis when NOS, but not COX, was suppressed, whereas venules showed no constrictive response even when both enzymes were inhibited. Capillaries were neither constricted nor dilated under any experimental conditions. These findings suggest that reactivity to hypoxia, CO2, and H+ is not qualitatively similar among intra-acinar microvessels, in which COX- and NOS-associated vasoactive substances function differently.

Topics: 6-Ketoprostaglandin F1 alpha; Acidosis; Animals; Arterioles; Capillaries; Carbon Dioxide; Epoprostenol; Hemodynamics; Hydrogen-Ion Concentration; Hypercapnia; Hypoxia; In Vitro Techniques; Indomethacin; Male; Microcirculation; Microscopy, Confocal; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Prostaglandin-Endoperoxide Synthases; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Venules

Experiments addressed the hypothesis that dilator prostanoids contribute to maintenance of low cerebral microvascular tone during hypoxia in the newborn. Anesthetized newborn pigs equipped with closed cranial windows were used to measure responses of pial arterioles (approximately 60 microns) to treatments. Hypoxia (Pao2 approximately equal to 25 mmHg) caused dilation of pial arterioles (approximately 50% increase in diameter). Hypoxia (5 min) caused an increase in cortical cerebrospinal fluid 6-ketoprostaglandin F1 alpha concentration from 907 +/- 171 (normoxia) to 1,408 +/- 213 pg/ml (hypoxia). Pretreatment with indomethacin (5 mg/kg) did not affect pial arteriolar dilation to hypoxia. Conversely, indomethacin treatment during hypoxia caused a rapid decrease in arteriolar diameter to nearly the normoxia diameter within 3 min, returning to the original hypoxia diameter by 10 min. Ibuprofen treatment (30 mg/kg) had no effect on pial arteriolar diameter during normoxia or hypoxia, and pretreatment did not alter dilation to hypoxia. However, pretreatment with ibuprofen abolished the constrictor effect of indomethacin given during hypoxia. These data suggest that the primary mechanism by which hypoxia produces cerebral vasodilation does not involve prostanoids, but prostanoids can contribute to cerebral vasodilation in response to hypoxia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Arterioles; Cerebrovascular Circulation; Hypercapnia; Hypoxia; Ibuprofen; Indomethacin; Pia Mater; Prostaglandins; Swine; Vasoconstriction; Vasodilation

Piglet brains generate superoxide during postischemic reperfusion, and topical application of activated oxygen species alters pial arteriolar responses. We investigated effects of pretreatment with scavengers of superoxide and H2O2 on ischemia-induced alterations of pial arteriolar responses in anesthetized newborn pigs. Four groups were studied: 1) time control, 2) untreated ischemia, 3) ischemia pretreated topically and systemically (conjugated to polyethylene glycol) with superoxide dismutase (SOD) and catalase, and 4) ischemia pretreated with Tiron. Pretreatment with SOD conjugated to polyethylene glycol alone during postischemic reperfusion effectively removed superoxide from its site of generation during postischemic reperfusion, but topical SOD was used also an insurance. Piglets were studied before and after 20 min of total cerebral ischemia caused by maintaining intracranial pressure above mean arterial pressure. As reported previously, before ischemia, hypercapnia and isoproterenol dilated pial arteries and arterioles and hypercapnia but not isoproterenol increased cortical periarachnoid cerebrospinal fluid 6-keto-prostaglandin F1 alpha, measured as an index of cerebral cortical prostacyclin synthesis. After cerebral ischemia, pial arterioles did not dilate in response to hypercapnia and 6-keto-prostaglandin F1 alpha did not increase, but dilation to isoproterenol was unchanged. The present study found that treatment with SOD/catalase or Tiron did not prevent loss of vasodilation to hypercapnia or the loss of hypercapnia-induced cerebral 6-keto-prostaglandin F1 alpha synthesis after cerebral ischemia. The postischemic loss of cerebral vasodilation to hypercapnia does not appear to involve superoxide or a subsequent reduced form of oxygen.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Brain Ischemia; Catalase; Cerebrovascular Circulation; Free Radical Scavengers; Hypercapnia; Hypotension; Isoproterenol; Superoxide Dismutase; Superoxides; Swine; Vasodilation

We observed previously that 20 min of global cerebral ischemia followed by 45 min of reperfusion selectively blocked cerebral vasodilation to hypercapnia and hypotension. This study determines the effects of pretreatment with transforming growth factor-beta (TGF-beta) on cerebrovascular responses after cerebral ischemia in piglets equipped with closed cranial windows. Hypercapnia-induced pial arteriolar dilation was blocked after cerebral ischemia (20 +/- 1 vs. 2 +/- 1% dilation before and after ischemia, respectively). Similarly, the increases in periarachnoid cortical cerebrospinal fluid 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2) concentration in response to hypercapnia were blocked (2.5 +/- 0.2- vs. 0.2 +/- 0.4-fold and 2.1 +/- 0.1- vs. 0.3 +/- 0.4-fold increase in 6-keto-PGF1 alpha and PGE2, respectively). Treatment with topical TGF-beta (400 ng/ml) before and during ischemia-reperfusion attenuated the loss of hypercapnia-induced cerebrovascular dilation (20 +/- 1 vs. 14 +/- 1% dilation before and after ischemia, respectively) and the loss of associated changes in cerebrospinal fluid prostanoids (2.0 +/- 0.2- vs. 1.7 +/- 0.2-fold and 2.3 +/- 0.2- vs. 2.2 +/- 0.3-fold increase in 6-keto-PGF1 alpha and PGE2 before and after ischemia, respectively). The loss of cerebrovascular dilation in response to hemorrhagic hypotension after ischemia was similarly prevented by TGF-beta. Cerebrovascular dilation to topical isoproterenol was unchanged after ischemia. TGF-beta may preserve endothelial cell function. We conclude that topical TGF-beta can attenuate cerebromicrovascular compromise caused by ischemia-reperfusion in newborn pigs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Arterioles; Brain Ischemia; Cerebral Cortex; Cerebrovascular Circulation; Dinoprostone; Female; Hypercapnia; Hypotension; Isoproterenol; Male; Swine; Transforming Growth Factor beta; Vasodilation

To evaluate the role of certain plasma biosubstances on the development of pulmonary hypertension and shock during severe hypoxia, hypercapnia and acidosis, plasma renin activity (PRA), angiotensin II (ATII), angiotensin converting enzyme (ACE), TXB2 and 6-Keto-PGF1 alpha (the stable metabolites of TXA2 and PGI2) were assayed in blood from pulmonary artery and aorta in seven pigs. Pulmonary arterial pressure (PAP) was monitored via Swan-Ganz catheter. During hypoxic and hypercapnic ventilation, PaO2 dropped to 4.7 kPa, PaCO2 rose to 21.1 kPa, pH dropped to 6.82, PAP increased from 2.43 +/- 0.06 to 4.46 +/- 0.45 kPa when acidotic shock developed (all P less than 0.05). Meanwhile ATII levels rose (all P less than 0.05). PRA significantly increased during acidotic shock as compared with normal ventilation (P less than 0.02). ACE dropped significantly (P less than 0.05), TXB2 and 6-keto-PGF1 alpha showed no significant change before and after hypoxic and hypercapnic ventilation.

Topics: 6-Ketoprostaglandin F1 alpha; Acidosis; Animals; Hypercapnia; Hypoxia; Male; Peptidyl-Dipeptidase A; Renin; Shock; Swine; Thromboxane B2

Using awake, chronically catheterized newborn pigs, we measured cerebral blood flow (CBF), net cerebral vascular 6-keto-prostaglandin F1 alpha production, and cerebral metabolic rate of oxygen (CMRO2) during hypercapnia and during hypercapnia at increased mean airway pressure (Paw), both before and after treatment with indomethacin. CBF nearly doubled during hypercapnia. The hypercapnia-induced cerebral hyperemia was maintained when Paw was increased from 3 +/- 2 to 16 +/- 4 cm H2O during hypercapnia. Sagittal sinus pressure increased in proportion to the increase in Paw, and cardiac output was unchanged. Net cerebral production of 6-keto-prostaglandin F1 alpha increased from 9 +/- 1 to 15 +/- 1 ng/min/100 g tissue during hypercapnia and increased dramatically to 57 +/- 1 ng/min/100 g when hypercapnia was coupled with an increase in Paw. CMRO2 was not changed by either hypercapnia or increased Paw. After indomethacin, CBF decreased and cerebral vasodilation to hypercapnia did not occur. After indomethacin, adding increased Paw during hypercapnia dropped CBF below baseline, adversely affecting CMRO2. These results suggest that cerebral hypercapnia hyperemia requires brain prostanoid production and that when Paw is increased during hypercapnia, the contribution of prostanoids to maintaining CBF is increased. Increasing ventilation pressure during hypercapnia in piglets pretreated with indomethacin compromises CBF sufficiently to reduce CMRO2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Brain; Cerebrovascular Circulation; Epoprostenol; Hypercapnia; Indomethacin; Oxygen Consumption; Positive-Pressure Respiration; Swine

Effects of ischemia (20 min) on cerebral cortical prostanoid synthesis and microvascular responses to hypercapnia and topical acetylcholine were examined in anesthetized newborn pigs. Pial arteriolar dilation in response to hypercapnia (10% CO2 ventilation, 10 min) was absent 2 h after ischemia and reversed toward constriction by 24 h postischemia. In sham control piglets, hypercapnia increased cortical periarachnoid fluid prostanoid concentrations. After ischemia, hypercapnia did not affect prostanoid concentrations on the brain surface. Acetylcholine (10(-3) M)-induced pial arteriolar constriction was reversed toward dilation 24 h after cerebral ischemia. Further, acetylcholine-induced prostanoid synthesis was markedly attenuated after ischemia. We conclude that cerebral ischemia-reperfusion alters cerebral prostanoid synthesis and microvascular control in newborn pigs. These abnormalities persist for at least 24 h.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Animals; Animals, Newborn; Brain; Brain Ischemia; Cerebrovascular Circulation; Dinoprost; Dinoprostone; Hypercapnia; Prostaglandins; Swine; Thromboxane B2

In order to investigate the possibility that high-frequency oscillatory ventilation (HFO) might preferentially stimulate intrapulmonary prostacyclin (PGI2) synthesis thereby decreasing pulmonary vascular smooth muscle tone, we determined pulmonary prostacyclin and thromboxane production in neonatal piglets ventilated by conventional means and by HFO (8 Hz). There was no detectable release of prostacyclin or thromboxane into blood passing through the lungs (i.e., pulmonary arterial concentrations were greater than aortic concentrations) during ventilation by conventional means or during HFO. Furthermore, there were no differences between the two modes of ventilation in cardiac output, systemic or pulmonary vascular resistance, or pulmonary vascular response to hypoxia/hypercapnia. We conclude that HFO does not stimulate pulmonary prostacyclin production and does not affect pulmonary vascular resistance or the pulmonary vasoconstriction associated with alveolar hypoxia/hypercapnia when compared to conventional ventilation in anesthetized newborn piglets.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Epoprostenol; Hypercapnia; Hypoxia; Lung; Pulmonary Ventilation; Respiration; Respiration, Artificial; Swine; Thromboxane A2; Thromboxane B2; Thromboxanes

The cerebral blood flow (CBF H/A) and the production of a stable prostacyclin metabolite, 6-Keto PGF 1 alpha ( 6KPGF ) was studied in 5 baboons in control, hypercapnic and hypoxic conditions. In steady-state conditions CBF H/A was measured by the clearance of an intra-arterial bolus injection of 133xenon and arterial and cerebral venous blood was sampled for assay of 6KPGF by radioimmunoassay. Both hypercapnia and hypoxia significantly increased CBF H/A and both increments were abolished by indomethacin. However, only hypoxia showed an increased 6KPGF production. Thus, hypoxia, but not hypercapnia, appears to produce cerebral vasodilation by increasing prostacyclin production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Gas Analysis; Cerebrovascular Circulation; Epoprostenol; Hypercapnia; Hypoxia; Papio; Regional Blood Flow; Vasodilation