Characterisation of the epithermal neutron irradiation facility at the Portuguese research reactor using MCNP.

The radiation field at the epithermal beamline and irradiation chamber installed at the Portuguese Research Reactor (RPI) at the Campus Tecnológico e Nuclear of Instituto Superior Técnico was characterised in the context of Prompt Gamma Neutron Activation Analysis (PGNAA) applications. Radiographic films, activation foils and thermoluminescence dosimeters were used to measure the neutron fluence and photon dose rates in the irradiation chamber. A fixed-source MCNPX model of the beamline and chamber was developed and compared to measurements in the first step towards planning a new irradiation chamber. The high photon background from the reactor results in the saturation of the detector and the current facility configuration yields an intrinsic insensitivity to various elements of interest for PGNAA. These will be addressed in future developments.

Commercial sunscreen lotions prevent ultraviolet radiation-induced depletion of epidermal Langerhans cells in Skh-1 and C3H mice.

There is much controversy regarding the ability of sunscreens to prevent ultraviolet (UV)-induced immune suppression. Epidermal Langerhans cells (LC) play a key antigen-presenting role in the afferent limb of the immune system's response to antigens introduced through the skin. It has been suggested that depletion of LC in UV-exposed skin is a critical step toward the induction of immunosuppression by UV radiation. There are a number of disparate reports with inconsistent results concerning the ability of sunscreens to prevent UV-induced depletion of LC. The purpose of this study was to systematically evaluate the ability of sunscreens to prevent UV-induced LC depletion in mice. Epidermal sheets obtained from skin biopsies taken from mice exposed to UV radiation from Kodacel-filtered FS20 sunlamps, which do not emit UV power at wavelengths < 290 nm, were immunoperoxidase stained for LC using a rat monoclonal antibody against mouse Ia (major histocompatibility complex class II antigen). Time course and dose-response curves for LC depletion were generated for Skh-1 and C3H mice. Dose-response curves for acute UV exposure induced depletion of LC in Skh-1 and C3H mice were similar, but not identical. LC density in the skin of Skh-1 mice that received chronic UV exposure (3 days/week for 8 weeks) was reduced by 62% after 2 weeks of exposure, but returned to normal levels by 6 weeks. Five commercial sunscreen lotions with labeled sun protection factors (SPF) of 4, 8, 15, 30 and 45 were tested for their capacity to block UV-induced depletion of LC. LC were depleted approximately 75% in the skin of unprotected or placebo lotion treated Skh-1 mice exposed to UV given on two consecutive days. Conversely, LC depletion was prevented in similarly UV exposed Skh-1 mice protected with a SPF 30 sunscreen. In C3H mice the levels of protection against LC depletion provided by the five sunscreens were proportional to the level of protection predicted by their labeled SPF. Comparisons of dose-response curves showed that significantly higher doses of UV were required for LC depletion and induction of skin edema than for the induction of local suppression of contact hypersensitivity. Thus, at UV doses where sunscreens provide complete protection against immunosuppression of contact hypersensitivity, prevention of LC depletion and skin edema would be expected.

Sunscreens prevent local and systemic immunosuppression of contact hypersensitivity in mice exposed to solar-simulated ultraviolet radiation.

Ultraviolet (UV) irradiation causes the immunosuppression of contact hypersensitivity (CH) responses in animals and humans. There are conflicting reports regarding the effectiveness of sunscreens in preventing UV-induced suppression of both local-type CH (induced by the application of the contact sensitizer directly to UV-exposed skin) and systemic-type CH (induced by the application of the contact sensitizer to an unirradiated skin site 3 days after UV exposure). The purposes of this study were as follows: 1. to derive solar simulator UV dose-response curves for the induction of local and systemic CH suppression in C3H mice; 2. to establish minimum immune suppression doses (MISDs) for local and systemic CH; 3. to determine the local and systemic immune protection capacity of two commercial sunscreen lotions with labeled sun protection factors (SPFs) of 4 and 8. Dose-response curves for the induction of local and systemic CH suppression were derived by exposing groups of mice to a range of full-spectrum UV doses (0.37-21.4 kJ m-2) on two consecutive days delivered from a filtered 1000 W xenon arc lamp solar simulator. The MISDs, defined as the lowest dose tested to cause approximately 50% suppression of the normal CH response, were obtained from the dose-response curves. Although the local and systemic immunosuppression dose-response curves were not statistically different, the MISD for local suppression of CH (1.35 kJ m-2) was about fivefold lower than that for systemic CH suppression (6.76 kJ m-2). The MISD was used as the endpoint to determine sunscreen immune protection levels. Both sunscreens, applied at 2 mg cm-2, provided immune protection against the induction of local and systemic CH suppression in mice exposed to an effective UV dose of 1 MISD given through the sunscreen, i.e. 4 MISD to SPF 4 sunscreen-protected mice and 8 MISD to SPF 8 sunscreen-protected mice mounted CH responses that were significantly greater than those elicited in unprotected mice exposed to 1 MISD of solar-simulated UV radiation. The calculated immune protection factors for these sunscreens exceeded the level of protection predicted by their labeled SPFs, i.e. the local immune protection factor of both sunscreens was 15 and the systemic immune protection factors were 8 for the SPF 4 sunscreen and 15 for the SPF 8 sunscreen. Our data show that these two sunscreens provide levels of immune protection which exceed the levels predicted by their labeled SPFs in immunoprotection tests conducted in mice exposed to a relevant MISD of UV radiation from a source emitting a UV power spectrum similar to that of sunlight.

Sunscreen lotions prevent ultraviolet radiation-induced suppression of antitumor immune responses.

Exposure to subcarcinogenic doses of ultraviolet (UV) radiation suppresses tumor immunity, thus permitting the emergence and growth of highly immunogenic skin cancers in mice. Sunscreens prevent UV carcinogenesis; however, there are conflicting reports regarding their ability to block UV-induced tumor immune suppression. In this study we critically evaluated the effects of UV spectrum and dose on the tumor immune protective capacity of 4 marketed sunscreen lotions with labeled sun protection factors (SPF) 8-45. Effective tumor immune suppression doses (TISD), i.e., the lowest dose tested to induce outgrowth of transplanted nonmelanoma skin tumors in 100% of UV-exposed C3H mice, were established for 3 different UV sources. TISD were significantly lower for unfiltered (FS) and Kodacel-filtered (KFS) UVB-type FS20 sunlamps compared with a filtered xenon arc lamp solar simulator. Sunscreen tumor immune protection levels matched those predicted by their labeled SPF when sunscreen-protected mice were exposed to a fixed TISD of solar simulator UV radiation. SPF 30 and 45 sunscreens also blocked activation of tumor antigen-specific suppressor T-lymphocytes in mice exposed to solar simulator UV radiation. In comparison, sunscreens with SPF > or = 15 provided partial to complete protection, as measured by tumor incidence, for mice exposed to UV radiation from KFS. All sunscreens tested reduced tumor growth rates in KFS UV-exposed mice. None of the sunscreens tested provided measurable tumor immune protection for mice exposed to FS UV radiation. Thus, sunscreen lotions provide an extent of tumor immune protection consistent with their labeled SPF when appropriate testing conditions are employed.

Evaluation of an economical sunlamp that emits a near solar UV power spectrum for conducting photoimmunological and sunscreen immune protection studies.

Expense and inconvenience have restricted the use of the filtered xenon are lamp (solar simulator) as a UV source for conducting large-scale animal studies. Because sunscreen immunoprotective levels are significantly affected by the UV power spectrum of the source it is imperative that a solar simulating source be used for accurate measurements of sunscreen protection levels that are relevant to human LV exposures from sunlight. However, relatively inexpensive sunlamps, e.g. the UVA-340, that emit a UV power spectrum similar to that of a solar simulator are available. Unlike FS-type UVB sunlamps, which have a significant amount of effective immunosuppressive non-solar UV energy at wavelengths below 295 nm, the immunosuppression effectiveness spectrum of UVA-340 sunlamps was nearly identical to that of a solar simulator. The purpose of this study was to evaluate this sunlamp for conducting photoimmunological and sunscreen immune protection studies. Groups of C3H mice were exposed to a range of UVA-340 sunlamp doses (0.25 kJ/m2 to 20.0 kJ/m2) to establish a dose-response curve and determine the minimum immune suppression dose (MISD) for iduction of local-type suppression of contact hypersensitivity (CH). The MISD, defined as the lowest UV dose given to produce approximately 50% suppression of the CH response in mice, was determined to be 1.0 kJ/m2 for UVA-340 sunlamps. Immune protection tests on four marketed sunscreen lotions (sun protection factors [SPF] 4, 8, 15 and 30) were then conducted with UVA-340 sunlamps using MISD as the endpoint. The immune protection factors for these sunscreens were equivalent to the level of protection predicted by their labeled SPF. These results are similar to those we have previously obtained using a solar simulator. We conclude from these data that the immunosuppressive effects of UVA-340 sunlamps are similar to those of a solar simulator; however, further studies are needed to determine if UVA-340, or similar, sunlamps are a viable alternative to the solar simulator for conducting large-scale animal experiments that require a relevant UV solar spectrum.

Ultraviolet spectral energy differences affect the ability of sunscreen lotions to prevent ultraviolet-radiation-induced immunosuppression.

Acute exposure to UV radiation causes immunosuppression of contact hypersensitivity (CH) responses. Past studies conducted with unfiltered sunlamps emitting nonsolar spectrum UV power (wavelengths below 295 nm) or using excessive UV doses have suggested sunscreens may not prevent UV-induced immunosuppression in mice. This study was thus designed to evaluate critically the effects of different UV energy spectra on the immune protection capacity of sunscreen lotions. Minimum immune suppression doses (MISD), i.e. the lowest UV dose to cause approximately 50% suppression of the CH response to dinitrofluorobenzene in C3H mice, were established for three artificial UV sources. The MISD for each UV source was 0.25 kJ/m2 for unfiltered FS20 sunlamps (FS), 0.90 kJ/m2 for Kodacel-filtered FS20 sunlamps (KFS), which do not emit UV power at wavelengths < 290 nm, and 1.35 kJ/m2 for a 1000 W filtered xenon arc lamp solar simulator. Using MISD as baseline, sunscreens with labeled sun protection factors (SPF) of 4, 8, 15 and 30 were tested with each UV source to establish their relative immune protection factors. The immune protection factor of each sunscreen exceeded its labeled SPF in tests conducted with the solar simulator, which has a UV power spectrum (295-400 nm) similar to that of sunlight. Conversely, sunscreen immune protection factors were significantly less than the labeled SPF in tests conducted with FS and KFS. Comparison of the immunosuppression effectiveness spectra showed that relatively small amounts of nonsolar spectrum UV energy, i.e. UVC (200-290 nm) and/or shorter wavelength UVB (between 290 and 295 nm), produced by FS and KFS contributes significantly to the induction of immunosuppression. For example, 36.3% and 3.5% of the total immunosuppressive UV energy from FS and KFS, respectively, lies below 295 nm. Sunscreen absorption spectra showed that transmission of immunosuppressive UV energy below 295 nm for FS was at least eight-fold higher than that for KFS. Compared to the solar simulator UV spectrum the transmission of nonsolar immunosuppressive UV energy through sunscreens was > 15-fold higher for FS and > or = 1.5-fold higher for KFS. These data demonstrate that relevant evaluations of sunscreen immune protection can only be obtained when tests are conducted with UV sources that produce UV power spectra similar to that of sunlight and UV doses are employed that are based on established MISD.

Minimum doses of ultraviolet radiation required to induce murine skin edema and immunosuppression are different and depend on the ultraviolet emission spectrum of the source.

Many photo immunological studies have used UV radiation sources that emit nonsolar UV spectral energy and UV doses based on nonimmunological endpoints, e.g. erythema and skin edema. Interpretation of these data has led to misunderstanding when extrapolated to hypothetical effects in humans exposed to solar UV. The purpose of this study was to: (1) establish UV dose response relationships for murine skin edema and immunosuppression, and (2) determine how different UV spectra affect these relationships. Back skin and ear minimum edema doses (MEdD) for Kodacel-filtered FS20 sunlamp UV (290-400 nm) were greater than two-fold higher than those for unfiltered FS20 sunlamp UV (250-400 nm). Xenon are solar simulator UV (295-400 nm) MEdD were > 10-fold higher than those for unfiltered sunlamp UV. Back skin and ear MEdD differed two- to five-fold between C3H/HeN, SWR/J and HRA/Skh-1 mice. The minimum immunosuppression doses (MISD) in C3H mice showed similar UV source spectrum dependence. The solar simulator UV MISD was 5.4- and 1.5-fold higher than for unfiltered and Kodacel-filtered sunlamp UV MISD, respectively. Furthermore, MISD were from 3- to 50-fold higher than the MEdD for the three UV sources. The UV bioeffectiveness spectra indicated that UVC energy (250-290 nm) contributed 12% and 18%, respectively, of the total skin edema and immunosuppression UV energy. These data demonstrate the variability in UV sensitivity among mouse strains, the significant differences between murine MEdD and MISD and how these differences are influenced by nonsolar regions (below 295 nm) of the UV spectrum.

Commercial sunscreen lotions prevent ultraviolet-radiation-induced immune suppression of contact hypersensitivity.

Ultraviolet (UV) radiation suppresses certain immunologic responses, such as contact hypersensitivity (CH). Some previous studies, using sunlamps emitting nonsolar-spectrum UV or excessive UV doses, have questioned the ability of sunscreens to prevent UV-induced immune suppression. Our study evaluated the immune protection capacities of commercial sunscreen lotions in relation to the effects of UV spectrum and dose. C3H mice were exposed to a fixed UV dose from Kodacel-filtered FS sunlamps that caused maximum Langerhans cell depletion and suppression of CH. Kodacel film blocks UV energy below 290 nm, thus eliminating immune-suppressive effects of UVC (200-290 nm) not present in sunlight. CH was equally suppressed in unprotected and placebo-lotion-treated, UV-exposed mice. Mice protected with sun protection factor (SPF)-15 and SPF-30 sunscreens mounted normal CH responses. SPF-4 and SPF-8 sunscreen-protected mice had CH responses significantly greater than those of unprotected mice. Direct effects of UV spectral differences on the immune protection value of an SPF-15 sunscreen were determined by exposing mice to UV radiation from unfiltered and Kodacel-filtered sunlamps and a 1000-W xenon lamp solar simulator (UV spectrum nearly equivalent to sunlight). The sunscreen immune protection value was 30 times the minimum immune suppression dose for the solar simulator, while being 7.5 times this dose for Kodacel-filtered and 2 times the dose for unfiltered sunlamps. These results demonstrate that commercial sunscreen lotions prevent UV-induced immune suppression at a level exceeding the labeled SPF when tested with an environmentally relevant UV source.

Effects of ischemia on brain blood flow and oxygen consumption of newborn pigs.

Brain circulation after 20 min of total brain ischemia was examined in unanesthetized newborn pigs. Except in the cerebrum, reactive hyperemia was observed throughout the brain, peaking by 5 min and subsiding by 20 min of reperfusion. Brain blood flow after 15 min of reperfusion matched the control. Blood flow to the cerebrum then decreased at 40 and 90 min reperfusion, while the rest of the brain was unaffected. Blood flow to the cerebrum returned to control by 24 h. Cerebral vascular resistance doubled by 15 min reperfusion, remained elevated at 90 min reperfusion, but returned to control by 24 h. Cerebral oxygen consumption followed a pattern similar to blood flow. Ninety minutes postischemia, hypercapnia-induced hyperemia was greatly attenuated in the cerebrum, reduced modestly in the diencephalon-mesencephalon, but unaffected in the rest of the brain. Thus 20 min of global brain ischemia in piglets does not produce reactive hyperemia in the cerebrum that is detectable at 5 min reperfusion but does in the remainder of the brain. Subsequent hemodynamic abnormalities apparently are confined to the cerebrum. Blood flow throughout the brain returns to normal by 24 h. Thus cerebral hemodynamic effects of total global ischemia are regionally dependent.

Cerebral ischemia alters cerebral microvascular reactivity in newborn pigs.

The effects of cerebral ischemia on cerebral microvascular reactivity and prostanoid synthesis were examined in chloralose-anesthetized newborn pigs. Microvascular responses and periarachnoid cerebrospinal fluid (CSF) prostanoid concentrations were determined between 10 and 140 min after a 20-min period of total cerebral ischemia, as well as in sham-control piglets without cerebral ischemia. After cerebral ischemia, the decrease in pial arteriolar diameter in response to topical norepinephrine (10(-4) M) was similar in sham (-27 +/- 6%) and postischemic (-25 +/- 5%) piglets. However, the increase in pial arteriolar diameter in response to hypercapnia (10% CO2 ventilation) that was observed in sham piglets (+21 +/- 5%) was absent after ischemia (-2 +/- 3%). In contrast, dilations of pial arterioles in response to topical prostaglandin (PG)E2 (at 100 ng PGE2/ml: sham, +13 +/- 3%; postischemia, +21 +/- 4%) and topical isoproterenol (10(-6) M) (sham, +29 +/- 4%; postischemia, +23 +/- 3%) were not decreased by prior cerebral ischemia. In sham piglets, norepinephrine and hypercapnia produced increases in cortical periarachnoid prostanoid concentrations, whereas after cerebral ischemia, neither stimulus increased cortical periarachnoid prostanoid concentrations. The results are consistent with the hypothesis that failure of hypercapnia to dilate pial arterioles after cerebral ischemia results from the inability of this stimulus to increase cerebral vasodilator prostanoid synthesis.

Lumbar CSF eicosanoids in neonates.

Lumbar CSF eicosanoids were measured in 11 neonates with perinatal asphyxia and 12 neonates with suspected sepsis. In the asphyxia group low levels of thromboxane B2 and prostaglandin F2a were detected in five neonates, all of which had had a lumbar puncture prior to 4 hours of age. In the group with suspected sepsis two infants had positive blood cultures and one had strep meningitis. CSF eicosanoids were nondetectable in all patients in this second group with the exception of the infant with meningitis. With meningitis CSF eicosanoids were markedly elevated. These findings suggest that lumbar CSF eicosanoids do not appear to be a clinically useful tool. The data further suggest that eicosanoids are involved in the inflammatory response to meningitis.

Postischemic cerebral microvascular responses to norepinephrine and hypotension in newborn pigs.

We examined the effects of 20 minutes' cerebral ischemia on cerebral microcirculatory responses to topical norepinephrine and systemic hypotension in three groups (sham-operated control, 2-3 hours postischemia, and 24 hours postischemia) of anesthetized newborn pigs equipped with closed cranial windows. Cerebral ischemia may eliminate the prostanoid vasodilator system from the cerebral circulation. Norepinephrine (10(-4) M) decreased pial arteriolar diameters similarly in all three groups (27%, 28%, and 21%, respectively), but only the sham-operated group exhibited pial arteriolar dilation in response to hypotension (28% at 33 mm Hg). Two-three and 24 hours after cerebral ischemia, hypotension decreased pial arteriolar diameters (21% and 17%, respectively). In sham-operated piglets, norepinephrine and hypotension increased cortical periarachnoid cerebrospinal fluid prostanoid concentrations. However, neither norepinephrine nor hypotension altered cerebral prostanoid production 2-3 or 24 hours after cerebral ischemia. Therefore, we conclude that after cerebral ischemia, autoregulatory pial arteriolar dilation in response to hypotension is absent, while vasoconstriction in response to norepinephrine is intact.

Ischemia alters cerebral vascular responses to hypercapnia and acetylcholine in piglets.

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.

Indomethacin restricts cerebral blood flow during pressure ventilation of newborn pigs.

Unanesthetized newborn pigs were studied to evaluate the immediate (10 min) and delayed (45 min) effects of increased ventilation pressure coupled with cyclooxygenase inhibition. Cardiac output and cerebral blood flow were measured at a low (5 cm H2O) and high (30 cm H2O) mean airway pressure (Paw) before and 45 min after 5 mg/kg of indomethacin. In a second group, these parameters were also measured 10 min after indomethacin was given during ventilation at a Paw of 30 cm H2O. Before treatment with indomethacin, increasing Paw decreased cardiac output without affecting cerebral blood flow. Baseline (Paw = 5 cm H2O) cerebral blood flow decreased 40% 45 min after indomethacin treatment. Adding the stress of a ventilation-induced drop in cardiac output did not further depress cerebral blood flow. When indomethacin was administered during high Paw, cerebral blood flow decreased markedly within 10 min. Cerebral oxygen consumption was maintained by increasing oxygen extraction. Therefore, indomethacin decreases cerebral blood flow at a high Paw. The fall in cerebral blood flow decreases brain oxygen delivery. However, cerebral oxygen consumption is maintained by an increase in oxygen extraction.

Adrenergic and prostanoid mechanisms in control of cerebral blood flow in hypotensive newborn pigs.

The interaction between adrenergic and prostanoid mechanisms in the control of cerebral hemodynamics in the conscious, hypotensive newborn pig was investigated. Pretreatment with the selective alpha 1- and alpha 2-adrenoceptor antagonists prazosin and yohimbine, respectively, had no effect on cerebral blood flow, calculated cerebral vascular resistance, or cerebral metabolic rate either before or after hemorrhagic hypotension. Indomethacin treatment (5 mg/kg ia) of piglets following hemorrhage caused a significant decrease in blood flow to all brain regions within 20 min. This decrease in cerebral blood flow resulted from increased cerebral vascular resistances of 54 and 177%, 20 and 40 min after treatment, respectively. Cerebral oxygen consumption was reduced from 2.42 +/- 0.28 to 1.45 +/- 0.28 ml.100 g-1.min-1 and to 1.0 +/- 0.28 ml.100 g-1.min-1 20 and 40 min after indomethacin, respectively, in hemorrhaged piglets. Decreases in cerebral blood flow and metabolic rate and increases in vascular resistance on treatment with indomethacin were the same as in animals pretreated with vehicle, prazosin, or yohimbine. These data are consistent with the hypothesis that the prostanoid system contributes to the maintenance of cerebral blood flow and cerebral metabolic rate during hypotension in the newborn, as reported previously. These data do not implicate removal of sympathetic modulation by prostanoids as a mechanism for indomethacin-induced cerebral vasoconstriction in hypotensive newborn piglets.

Adrenergic mediation of vasopressin secretion in newborn pigs.

Effects of inhibition of alpha 1-(prazosin) and alpha 2-(yohimbine) adrenoreceptors on plasma lysine vasopressin concentration during normotension and hemorrhagic hypotension were studied in unanesthetized newborn pigs. During the normotensive period, treatment with prazosin and yohimbine both increased plasma lysine vasopressin concentration (vehicle = 3.4 +/- 1.21 microU/ml; prazosin = 35.8 +/- 10.8 microU/ml; and yohimbine = 20.1 +/- 9.5 microU/ml). Prazosin caused a decline in arterial pressure (vehicle = 60 +/- 6 mmHg; prazosin = 49 +/- 5 mmHg), which may account for the increase in plasma lysine vasopressin concentration, whereas yohimbine increased arterial pressure (73 +/- 3 mmHg). On hemorrhage to equivalent arterial pressure, plasma lysine vasopressin concentration increased to similar levels in vehicle- (110.3 +/- 28.7 microU/ml) and prazosin-treated (92.6 +/- 14.2 microU/ml) piglets. In contrast, on hemorrhage of yohimbine-treated piglets, the increase in plasma lysine vasopressin concentration was augmented remarkably (527.0 +/- 103.2 microU/ml) in comparison to the other groups. We conclude that, in unanesthetized newborn pigs, treatment with the alpha 2-adrenoreceptor antagonist yohimbine increased plasma lysine vasopressin concentration and markedly accentuated the vasopressin response to hemorrhage. An alpha 2-adrenergic receptor-mediated mechanism appears to be an important inhibitory component in the vasopressin secretory system of the newborn pig.

Indomethacin does not alter the circulating catecholamine response to asphyxia in the neonatal piglet.

The response of circulating catecholamines to asphyxia in unanesthetized, spontaneously breathing neonatal piglets was measured before and after treatment with indomethacin. Prior to treatment with indomethacin, baseline levels [geometric mean, pg/ml (95% confidence limits)] of D, E, and N were 162 (99-266), 174 (52-579), and 380 (286-506), respectively. Inhalation of 10% O2/9% CO2 for 20 min caused significant increases in arterial levels of all three catecholamines to 389 (230-659, 1514 (993-2306), and 3802 (2731-5293), respectively. Treatment with indomethacin (5 mg/kg, intravenous) did not significantly alter either baseline levels of the catecholamines or the levels after 20 min of the asphyxiating gas. In time control piglets, baseline levels and the response to asphyxia were similar before and after placebo. These results suggest that the circulating catecholamine response to asphyxia of the neonatal piglet is independent of the prostaglandin system.

Effect of therapeutic dose of indomethacin on the cerebral circulation of newborn pigs.

The effects of treatment with 0.2 mg/kg of indomethacin on the cerebral blood flow and cerebral oxygen consumption of hypotensive, unanesthetized, newborn pigs were investigated. Hypotension was induced by hemorrhage (30 ml/kg) which reduced mean arterial pressure from 60 to 34 mm Hg. The decline in cerebral vascular resistance that occurred with hemorrhage allowed blood flow to all brain regions and cerebral oxygen consumption to continue unchanged. Treatment with 0.2 mg of indomethacin decreased plasma 6-keto-prostaglandin F1 alpha markedly and caused a modest increase in cerebral vascular resistance from 0.75 +/- 0.07 to 0.85 +/- 0.02 mm Hg X 100 g X min/ml at 40 min posttreatment. As a result, blood flow throughout the brain fell about 20%. Similarly, cerebral oxygen consumption declined from 2.88 +/- 0.13 to 2.03 +/- 0.21 ml O2/100 g X min following treatment of hypotensive piglets with 0.2 mg/kg of indomethacin. However, all piglets were conscious 40 min after treatment. We conclude that, although 0.2 mg/kg of indomethacin affects cerebral hemodynamics of hypotensive piglets, the effects are very modest in comparison to large increases in cerebral vascular resistance, decreases in cerebral blood flow and oxygen consumption, and coma that follow treatment of hypotensive piglets with 5 mg/kg of indomethacin.

Vasopressin responses to asphyxia and hemorrhage in newborn pigs.

Vasopressin may be important in maintenance of arterial pressure and redistribution of cardiac output in hypotensive and asphyxiated newborns. We used chronically instrumented, unanesthetized, 4-day-old pigs to investigate the effects of hypotensive hemorrhage and asphyxia on plasma vasopressin concentration and to determine the effects of cyclooxygenase inhibition on these responses. Asphyxia [arterial O2 partial pressure (PaO2) = 40-50 Torr, arterial CO2 partial pressure (PaCO2) = 60-80 Torr) increases plasma lysine vasopressin (LVP) from 2.2 +/- 0.8 to 52.4 +/- 15.0 microU/ml. Neither the baseline nor stimulated plasma LVP was affected by indomethacin (5 mg/kg) or meclofenamate (5 mg/kg). Hemorrhage (30 ml/kg) increased plasma LVP from 2.8 +/- 0.8 to 163.4 +/- 28.1 (20 min) and 135.1 +/- 18.5 microU/ml (60 min). The effects of vehicle and indomethacin (5 mg/kg) 20 min after hemorrhage on plasma LVP 60 min after hemorrhage were not different. Changes in plasma vasopressin caused by asphyxia and hemorrhage in the unanesthetized newborn pig are similar to the responses observed in adults of other species. This study does not suggest that prostanoids are involved in these responses in newborn pigs.

Maintenance of cerebral circulation during hemorrhagic hypotension in newborn pigs: role of prostanoids.

The possibility that the prostanoid system contributes to the capability of the newborn piglet to maintain cerebral blood flow and cerebral metabolic rate during hypotension was investigated. The effect of hemorrhage on net (arterial-to-venous) cerebral prostacyclin production and the effects of indomethacin on cerebral hemodynamic response to hemorrhage and on the cerebral oxygen utilization following hemorrhage were determined in chronically instrumented, unanesthetized newborn pigs. Hemorrhage decreased arterial pressure about 35% but did not affect cerebral blood flow or cerebral O2 consumption. Hemorrhage was accompanied by an increase in net cerebral 6-keto-PGF1 alpha production from 4.0 +/- 1.1 to 15.3 +/- 4.9 ng/100g X min (mean +/- SEM). Indomethacin treatment of piglets following hemorrhage inhibited the net cerebral production of 6-keto-PGF1 alpha and caused a decrease in blood flow (approximately equal to 40%) to all brain regions within 20 minutes. The decrease in cerebral blood flow was the result of an increase in cerebral vascular resistance of 57 and 180%, 20 and 40 minutes post treatment, respectively. Cerebral O2 consumption was reduced from 2.5 +/- 0.3 ml/100 g X min to 1.5 +/- 0.3 ml/100 g X min 20 minutes following treatment of hemorrhaged piglets with indomethacin and to 1.1 +/- 0.3 ml/100 g X min 40 minutes after treatment. Six of 8 piglets for whom the data were recorded that were administered indomethacin following hemorrhage became comatose with cerebral O2 consumption of 0.4 +/- 0.1 ml O2/100 g X min by 40 minutes after treatment. These data are consistent with the hypothesis that the prostanoid system contributes to the maintenance of cerebral blood flow and cerebral metabolic rate during hypotension in the newborn.