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In newborn infants, permanent closure of a major blood vessel connecting the main pulmonary artery to the aorta is essential to allow adequate circulation of blood to major organs. Platelet aggregation now emerges as a crucial step in this process in newborn mice and, possibly, in preterm infants (pages 75–82).

1. The hypothesis that the relative vasoconstrictor ineffectiveness of prostaglandin E2 (PGE2) and PGF2 alpha on cerebral vessels of newborn pigs might be due to fewer receptors for these prostanoids was tested by comparing receptors for PGE2 (EP) and PGF2 alpha (FP) in cerebral microvessels from newborn and adult pigs. 2. Specific binding of [3H]-PGE2 and [3H]-PGF2 alpha to membranes prepared from brain microvessels showed that EP and FP receptor density (Bmax) in tissues from newborn animals was less than 50% of that determined in tissues from adults. By contrast, estimates of affinity (KD) were unchanged. 3. Specifically bound [3H]-PGE2 to brain microvessels from both the newborn and adult was displaced by AH 6809 (EP1-selective antagonist) by 80-90%, and only by approximately 30-35% by both 11-deoxy PGE1 (EP2/EP3 agonist) and MB 28,767 (EP3 agonist); butaprost (EP2 agonist) was completely ineffective. 4. PGE2, 17-phenyl trinor PGE2 (EP1 agonist), PGF2 alpha and fenprostalene (PGF2 alpha analogue) caused significantly less increase in inositol 1,4,5-triphosphate (IP3) in brain microvessels from the newborn than in those from adult pigs. The stimulation of IP3 by PGE2 and 17-phenyl trinor PGE2 was almost completely inhibited by the EP1 antagonist, AH 6809. 5. PGE2, 11-deoxy PGE1 and MB 28,767 produced small reduction of adenosine 3':5'-cyclic monophosphate (cyclic AMP) production in adult vessels but no effect in newborn tissues. 6. The lower density of EP and FP receptors in microvessels of newborn pigs compared to adults may explain the reduced ability of PGE2 and PGF2 alpha to stimulate production of IP3 in tissues from newborn animals. This in turn, may provide an explanation for previous observations demonstrating that these prostanoids elicit contraction of adult cerebral microvessels, but exert minimal effects on these vessels in newborn animals.

Retinopathy of prematurity (ROP) is a major cause of visual impairment in premature infants. It is characterized by an arrest in normal retinal vascular development associated with microvascular degeneration, followed by an abnormal hypoxiainduced neovascularization. Recent studies point out that ROP is a multifactorial disease, implicating both oxygen-dependent and oxygen-independent mechanisms. Oxygen-dependent factors leading to microvascular degeneration include generation of reactive oxygen species and suppression of specific oxygen-regulated vascular survival factors, such as vascular endothelial growth factor (VEGF) and erythropoietin. The other major mechanism for the initial capillary loss is oxygen-independent and implicates a deficit in growth factor IGF-1/IGFBP3. The proliferative, second phase of ROP is triggered by increases in vascular growth factors concentrations, in an attempt to compensate for the hypoxic retina. Novel signaling pathways for vascular repair, implicating both metabolite signaling and inflammatory lipids signaling, represent new therapeutic avenues for ROP.

To assess whether prostanoids have a role in setting the blood pressure limits of cerebral blood flow autoregulation in newborn animals, we measured cerebral blood flow and prostanoid concentrations in blood from the sagittal sinus over a wide range of mean systemic blood pressures (17-117 mm Hg) in eight newborn piglets treated with 30 mg/kg i.v. ibuprofen and in eight vehicle-treated piglets. Blood pressure was adjusted by inflating balloon-tipped catheters placed at the aortic isthmus and root to induce hypertension and hypotension, respectively, 80 minutes apart in each piglet. Cerebral blood flow and concentrations of prostaglandins E and F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2 in blood from the sagittal sinus and left subclavian artery were measured 20 minutes before (baseline) and during each blood pressure adjustment. In vehicle-treated piglets, cerebral blood flow was constant at blood pressures between 50 and 90 mm Hg (r = 0.06, p = 0.85). When blood pressure was reduced to less than 50 mm Hg, thromboxane B2 concentration in the sagittal sinus increased by 597 +/- 42% and concentrations of the prostaglandins increased by an average of 308 +/- 45% (p less than 0.05). When blood pressure was raised to greater than 90 mm Hg, concentrations of the prostaglandins increased by an average of 46 +/- 11%, with no change in the concentration of thromboxane B2. Treatment with ibuprofen reduced the baseline concentrations of all prostanoids and prevented their changing during hypotension and hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Fetuses with pulmonary stenosis and constriction of the ductus arteriosus or the recipient twin in the context of a twin-to-twin transfusion syndrome may present with severe right ventricular myocardial dysfunction. Free O2 radicals are known to be increased in hypertrophied adult myocardium secondary to an increase in endocavitary pressure. This study investigates whether products of reactive O2 species generation are abnormally elevated in the myocardium of fetuses with increased right ventricular pressure. Banding of the main pulmonary artery was performed in five fetal lambs at 90 to 100 days of gestation. Three other animals had a sham intervention and were used as controls. Postoperative observation lasted on average 42 days (range 33-49 days). The levels of hydroperoxides were found to be significantly higher in the right ventricle of the stenosed lambs (6.6 +/- 3.5 nmol/mg protein) compared to the left ventricle of the same lambs (0.7 +/- 0.7 nmol/mg protein), and compared to the right (0.12 +/- 0.1 nmol/mg protein) and the left (0.5 +/- 0.8 nmol/mg protein) ventricles of the controls. It is concluded that during fetal life, an increase in right ventricular pressure is associated with a marked accumulation of products of reactive O2 species generation in the right ventricular myocardium.

Distribution of alpha(1)-adrenoceptor (alpha(1)AR) subtype (alpha(1A), alpha(1B), alpha(1D)) proteins in brain, heart, kidney, and liver of 1-week-old rats and in brain, heart, aorta, kidney, liver, vas deferens, prostate, and adrenal glands of adult rats was investigated by Western analysis, using receptor subtype specific polyclonal antibodies. High levels of immunoreactive alpha(1A)AR and alpha(1D)AR in brain and heart and of alpha(1B)AR in liver and heart of neonatal rats were detected. In adult rat tissues, the abundance of alpha(1A)AR protein was most marked in the brain, intermediate in heart, aorta, liver, vas deferens, and adrenals, and minimal in the kidney and prostate; relative to other tissues, the expression of alpha(1B)AR was higher in brain and heart and that of alpha(1D)AR in brain. All the three receptor subtypes increased with age in the brain cortex, whereas the abundance of alpha(1B)AR increased in the heart but decreased in the liver; alpha(1A)AR and alpha(1D)AR in liver, kidney, and heart were not affected by age. It is concluded that alpha(1)AR subtypes are widely expressed in different neonatal and adult rat tissues.

We investigated whether prostaglandins regulate endothelial nitric oxide synthase (eNOS) in the pig cerebral vasculature during the neonatal period. Prostaglandins, eNOS mRNA, eNOS protein, and NO production were higher in cerebral microvessels of newborn (1 day old) than in those of adult (6- to 8-month-old) pigs. The treatment of isolated cerebral microvessels of newborn animals with ibuprofen for 24 h reduced eNOS mRNA and nitrite production to levels in the adult; this effect of ibuprofen was prevented by concurrent treatment with prostaglandin (PG)E(2) analog 16,16-dimethyl-PGE(2), nonselective PGE(2) receptor analog 11-deoxy PGE(1), and prostaglandin EP(3) receptor agonists sulprostone and MB 28,767 but was not modified by PGI(2) analog carbaprostacyclin, PGD(2), and EP(1) receptor agonist 17-phenyl trinor PGE(2). Correspondingly, 16, 16-dimethyl-PGE(2) and MB 28,767 increased eNOS mRNA expression of adult microvessels to values in the newborn. Data similar to those with isolated cerebral vessels were obtained through histochemical analysis (NADPH-diaphorase positivity) of brain from newborn animals treated in vivo with ibuprofen in combination or not with sulprostone. Furthermore, substance P-induced NO-mediated cerebral vasorelaxation was decreased to adult values through the treatment of newborn pigs with ibuprofen; this effect was prevented by concomitant treatment with sulprostone. It is concluded that PGE(2) regulates eNOS in newborn pig cerebral microvessels via EP(3) receptors; this may be physiologically required during normal neurovascular development.

1. Negative inotropic effects of several beta-adrenoceptor (betaAR) antagonists on electrically-stimulated right atria, left atria, right ventricles and left ventricular papillary muscles from reserpine-treated rats were used as a measure of their inverse agonist activities. 2. Beta1AR antagonists acebutolol, atenolol and metoprolol, beta2AR antagonist ICI-181,551 and nonselective betaAR antagonists alprenolol, nadolol, propranolol and timolol produced negative inotropic effects, which were most marked on the right atria. 3. The nonselective betaAR antagonist pindolol did not exhibit inverse agonist activity but inhibited the negative inotropic activities of ICI-118,551, atenolol and propranolol. 4. The negative inotropic effects of lidocaine, nifedipine and pentobarbitone were similar on all the four myocardial preparations. 5. The positive inotropic efficacy of salbutamol on right and left atria but not on right ventricles and papillary muscles was comparable to that of isoprenaline. The antagonist activity of ICI-118,551 against isoprenaline was greater on right atria than on other cardiac regions. 6. Beta1AR proteins were expressed in all regions of the heart but of beta2AR were primarily localized in the right atrium. 7. It is concluded that beta2AR play a greater role in right atria than in other cardiac regions and almost all betaAR antagonists behave as inverse agonists.

To determine the relative contribution of cyclooxygenase (COX)-1 and COX-2 in regulating prostaglandin (PG) E2 and PGF2alpha receptors (EP and FP, respectively) densities and their functions in retinal vasculature of neonatal pigs.Newborn pigs were treated intravenously every 8 hours for 48 hours with saline, 40 mg/kg nonselective COX inhibitor ibuprofen, 80 mg/kg COX-1 inhibitor valeryl salicylate, or 5 mg/kg DuP697 and 5 mg/kg NS398, COX-2 inhibitors. Retinal microvessel EP and FP receptor densities were measured by radioligand binding and receptor-coupled effects by determining second-messenger inositol 1,4,5-trisphosphate (IP3) and vasomotor responses. Retinal blood flow (RBF) response to incremental increases in blood pressure (BP) was measured by a microsphere technique.Valeryl salicylate, DuP697, and NS398 reduced retinal PGE2 and PGF2alpha concentrations in the newborn by approximately half, whereas ibuprofen caused further reduction to levels observed in adults. Retinal vessel EP1, EP3, and FP receptor densities increased approximately threefold after treatments with COX-1 or COX-2 inhibitors, and five- to sixfold after ibuprofen treatment. EP and FP receptor upregulation was associated with corresponding increases in IP3 production and retinal vasoconstriction in response to PGF2alpha, fenprostalene (an FP agonist), PGE2, 17-phenyl trinor PGE2 (an EP1 agonist), and MB28,767 (an EP3 agonist) and with enhanced RBF autoregulation of high BP (or =125 mm Hg). Conversely, EP2 receptor density and coupled functions were minimally affected by COX inhibition.Data suggest that increased COX-1- and COX-2-catalyzed prostaglandin synthesis contribute equivalently to the downregulation of retinovascular EP1, EP3, and FP receptors and their vasoconstrictor functions in newborn pigs; the EP2 receptor was not significantly influenced by ontogenic alterations in prostaglandin levels.

The myocardial effect of alpha-1A adrenoceptor (alpha-1 AR) agonists in neonatal rats are mediated by alpha-1A AR and not by alpha-1B AR, although both receptor subtypes are equally expressed; the functions of alpha-1B AR are not known. Here, we report that alpha-1 B ARs inhibit the activities of alpha-1A ARs in neonatal rat myocardium so that the inactivation of alpha-1 B ARs by chloroethylclonidine (CEC) potentiated the effects of nonselective alpha-1 AR agonist phenylephrine (PE) on myocardial protein synthesis and early gene (c-fos and c-jun) expression. CEC did not modify the hypertrophic effect of angiotensin II. The potentiation of the effects of PE by CEC was associated with a translocation of Ca(++)-dependent protein kinase C (PKC)alpha, which did not occur in the absence of CEC. Alpha-1A AR-selective agonist A61603 was approximately 1000-fold more potent than PE as a positive inotropic agent; it caused the translocation of PKC alpha, which was not affected by CEC. 5-Methylurapidil antagonized the effects of PE and A61603, suggesting that these were mediated via alpha-1A ARs. Alpha-1D AR antagonist BMY 7378 did not modify PE-induced translocation of PKC. CEC potentiated the effects of PE on Ca++ transients in Fura 2-AM-loaded dispersed cardiomyocytes, and this potentiation was prevented by nifedipine. In whole-cell patch-clamp recordings of cultured cardiomyocytes, CEC potentiated the effect of norepinephrine on Ca++ channel currents, which was blocked by 5-methylurapidil. We conclude that alpha-1A ARs are positively and alpha-1B ARs are negatively coupled to nifedipine-sensitive Ca++ channels, possibly via Gi protein, and this antagonistic relationship between alpha-A AR and alpha-1B AR in the neonatal heart might be required physiologically for normal alpha-1 AR-mediated responses and myocardial development.

Noticeable progress has been achieved in the determination of dynamic topochromatic variables for the structural representation of compounds and their situation in a given population. These independent structural variables can be further combined into more complex variables. Their contributions to the evolution of an associated property can therefore be evaluated with certainty. The risk of having correlated variables is avoided while the structural description remains exhaustive. In order to enhance the interpretative ability of the QSAR model, one or several physicochemical properties can be taken with these structural parameters as explanatory variables. Typically, partition coefficients, 3-D and quantum mechanical data are used for this purpose. The structural aspects not taken into account by the physicochemical parameters are reflected in the remaining topochromatic variables. The use of these new concepts is presented in a study of carbazole mutagenicity. The model explains 99% of the total variance with one external property and four additional topochromatic variables. The modulation of the heat of formation of an intermediate by two topochromatic variables suggests a much more precise interpretation than a simple combination of the usual external variables.

This study investigated the mechanism of the positive inotropic effects of class 1 antiarrhythmic agents using electrically stimulated right atria (sinoatrial node excised), left atria and right ventricles of rats. Quinidine, disopyramide and procainamide produced concentration-dependent positive inotropic effects on right and left atria; effects on the right atria were greater than on left atria. At concentration producing positive inotropic effects on atria, the contractions of right ventricles were slightly increased by quinidine, unaffected by disopyramide and decreased by procainamide. The positive inotropic effects of quinidine were inhibited by propranolol, reserpine and mecamylamine but not by cocaine, hexamethonium and d-tubocurarine; propranolol also antagonized the positive inotropic effects of disopyramide and procainamide. Bupivacaine, which like quinidine blocks transient outward potassium current, slightly increased the contractions of right atria but not of left atria and ventricles. The atrium-specific positive inotropic effects of quinidine were mimicked by atropine, pirenzepine and dimethylphenylpiperazinium but not by nicotine, cytisine and butyrylcholine; the effects of atropine, dimethylphenylpiperazinium and pirenzepine were also blocked by propranolol. Quinidine increased the release of norepinephrine from atria but not from the ventricles; this release was greater from the right than from the left atria. It is concluded that quinidine- and atropine-like agents exert atrium-specific positive inotropic effects by blocking muscarinic receptors and permitting a dominance of acetylcholine effects via a release of norepinephrine from sympathetic nerve terminals.

The elimination, disposition and protein binding of ibuprofen (IBU) in premature infants were studied for use in the prevention of intraventricular hemorrhage and closure of patent ductus arteriosus. The kinetic profile of i.v. IBU lysine (10 mg/kg bolus) given within the first 3 h after birth was studied in 21 premature neonates (mean birthweight = 944.7 g, range: 575-1450 g; gestational age: 26.8 weeks, range: 22-31 weeks). Blood samples (0.3 ml/sample) were obtained at time 0 and at 1, 3, 6, 12, 24, 48, and 72 h post-dose for IBU by high-performance liquid chromatography (HPLC). Kinetic analyses assumed applicability of one open-compartment model and calculations from the model-independent areas under the time concentration curve (AUC). Data (mean +/- SEM) show that apparent volume of distribution (AVd) was 62.1 +/- 3.9 ml/kg, plasma t1/2 beta was 30.5 +/- 4.2 h, elimination rate constant (Kel) was 0.032 +/- 0.004 h-1, plasma clearance was 2.06 +/- 0.33 ml/kg/h and plasma concentration (Cp) at 1 h was 180.6 +/- 11.1 mg/l. Gestational age and birthweight were not related to drug elimination. In 10 neonates, IBU maintenance dose of 5 mg/kg once daily on days 2 and 3 generated mean Cp of 116.6 +/- 54.5 mg/l and 113.6 +/- 58.2 mg/l, respectively. Protein binding by ultrafiltration and capillary electrophoresis showed that the percentage bound IBU was significantly lower in full term cord plasma (94.98 +/- 0.39%, n = 26) compared to adult plasma protein (mean +/- SE = 98.73 +/- 0.31%, n = 8, p0.0001). Compared to data from adults and older children, IBU elimination is markedly prolonged in neonates and protein binding is slightly lower. Thus, investigational and clinical therapeutic regimens should be adjusted to account for decreased drug disposition to ensure safe and effective therapy.

The present study was done to determine possible ontogenic differences in the functions of rat myocardial alpha1, adrenoceptor (alpha1 AR) subtypes in view of reported greater inotropic responses of myocardium of neonatal than of adult rats to alpha1, AR agonists. Methoxamine, phenylephrine and norepinephrine were used as alpha1 AR agonists. Phenylephrine and norepinephrine were used in the presence of 3 microM propranolol. It was found that the ratios of chloroethylclonidine (CEC)-insensitive alpha1 AR subtype (alpha1A AR) to CES-sensitive alpha, AR subtype (alpha1B AR) were approximately 50:50 in neonatal (1 week old) and 20:80 in adult rat ventricles. alpha1A AR selective antagonists WB 4101 and 5-methylurapidil+ (5-MU) inhibited the inotropic effects of alpha1, AR agonists both on neonatal and on adult rat ventricles; in contrast, selective inactivation of alpha1B AR by CEC inhibited the inotropic effects of alpha1 AR agonists only on ventricles from adult but not from neonatal animals. WB 4101 inhibited methoxamine-induced increases in inositol phosphates by ventricular slices from both adult and neonatal rats; in contrast, CEC inhibited these effects of methoxamine only in tissues from adult but not in tissues from neonatal animals. In conclusion, this study, to our knowledge, demonstrates for the first time that the effects of alpha AR agonists on right ventricular contractions and phosphoinositol turnover are mediated primarily by alpha 1A AR subtype in the neonatal and by both alpha1A AR and alpha1B AR subtypes in the adult rat.

To test whether early postnatal (0 to 3 hours) intravenous administration of ibuprofen will prevent patent ductus arteriosus (PDA) in preterm neonates.Prospective sequential controlled trial with three treatment arms.Level 3 perinatal-neonatal intensive care nursery.Thirty-four premature newborn infants born from February to August 1993 with a mean birth weight of 913 g (range, 565 to 1460 g) and gestational age of 26.9 weeks (range, 22.4 to 31.0).Infants were consecutively assigned within 3 hours of age to treatment with either one dose of ibuprofen lysine (10 mg/kg intravenously) followed by 5 mg/kg per dose intravenously at 24 and 48 hours of age (n = 12), one dose of ibuprofen lysine (10 mg/kg intravenously; n = 11), or saline (n = 11).Primary outcome variable was the presence of ductus arteriosus by echocardiography and clinical assessments at 3, 7, and 21 days of life. Secondary outcome variables included presence of intraventricular hemorrhage, renal function, ventilatory and oxygen needs, hematologic changes, gastrointestinal function, time to full enteral feeding, duration of hospitalization, and age at discharge.The three groups of patients were comparable in birth weight, gestational age, antenatal administration of betamethasone, and other perinatal characteristics. Ibuprofen treatment significantly reduced plasma levels of prostaglandins, and the levels remained low for 72 hours in newborns who received three doses of the drug. The incidence of PDA and other variables did not differ between patients who received a single dose of ibuprofen and those given saline. However, compared with the saline-treated newborns, babies who received three doses of ibuprofen had no PDA (0/12 vs 7/11 for saline; P.02), had lower daily mean airway pressures (mean +/- SD, 5.2 +/- 1.1 cm H2O vs 8.3 +/- 2.8 cm H2O for saline; P.02) and better oxygenation index (2.6 +/- 0.6 vs 4.7 +/- 1.8 for saline; P.02) at the end of the first week of life, and required fewer days of ventilation (25 +/- 14 days vs 44 +/- 26 days for saline; P.03). Babies given three doses of ibuprofen tended to tolerate full oral feedings earlier (35 +/- 19 days vs 56 +/- 34 days for saline; P = .09), had shorter duration of hospitalization (71.2 +/- 22.6 days vs 127.3 +/- 74.7 days for saline; P.05), and were discharged to home at an earlier postconceptional age (37.8 +/- 2.0 weeks vs 44.8 +/- 9.8 weeks for saline; P.05). ibuprofen treatment in this phase I trial was not associated with any apparent early neurological, intestinal, renal, hepatic, or hematologic complications.Administration of three doses of ibuprofen within 3 hours after birth in preterm neonates reduced the incidence of PDA without causing notable early adverse drug reactions in this phase I trial. Early closure of the ductus arteriosus was also associated with better respiratory outcome and earlier discharge from the hospital.

We recently reported that brain synaptosomes of newborn pigs contained fewer PGE2 (EP) and PGF2 alpha (FP) receptors than adult tissues. In the present study we investigated whether this was the result of down-regulation of these receptors by high levels of PGE2 and PGF2 alpha in the brain of newborn animals. Newborn pigs (1-3 days old) were treated with ibuprofen (40 mg/kg) or indomethacin (5 mg/kg) i.v. every 4 hr for 24 hr to reduce prostaglandins to adult levels. At the end of the treatment, EP and FP receptor density and receptor-linked second messenger formation in brain synaptosomes were measured. It was found that ibuprofen and indomethacin treatment increased EP and FP receptor densities in brain synaptosomes of newborn animals to levels found in the adult; this up-regulation of EP receptors was prevented by EP receptor agonist, 16,16-dimethyl-PGE2, and the up-regulation of FP receptors was prevented by the FP agonist, fenprostalene. PGE2, butaprost (an agonist for EP2 receptor subtype mediating cAMP stimulation) and 11-deoxy-PGE1 (an agonist for EP2 and EP3 receptors) caused a comparable increase of cAMP in brain synaptosomes of ibuprofen-treated and adult animals, which was significantly greater than in those of vehicle-treated animals. Also, PGF2 alpha and its analog, fenprostalene, caused a much greater increase in IP3 production in brain synaptosomes of ibuprofen-treated than in vehicle-treated pigs. These findings suggest that the relatively low EP and FP receptor densities in newborn pigs are caused by the high levels of prostaglandins and that these receptors can be up-regulated by inhibiting prostaglandin synthesis.

To study the role of free radicals in autoregulation of retinal blood flow (RBF) and choroidal blood flow (ChBF) and the contribution of the cyclooxygenase pathway in free radical formation during blood pressure changes in 1- to 3-day-old pigs.Blood pressure was adjusted by inflating balloon-tipped catheters placed at the aortic isthmus and the aortic root to induce hypertension and hypotension, respectively. Blood flow was measured using the microsphere technique. Also, the effects of peroxides on retinal artery diameter were studied on eyecup preparations using time-frame photography processed by digital imaging.Blood gases and intraocular pressure (13 +/- 1 mm Hg) remained stable throughout the experiments. In control animals, RBF was constant only between 30 and 75 mm Hg of ocular perfusion pressure and ChBF increased as a function of ocular perfusion pressure (tau = 0.58, P0.01). Inhibition of peroxidation with the free radical scavenger 21-aminosteroid U74389F (2.5 mg/kg) widened the range of RBF and ChBF autoregulation (ocular perfusion pressure from 30 to 131 mm Hg). Hypertension caused an increase in the products of peroxidation, malondialdehyde, and hydroperoxides, as well as in prostaglandin E2, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha in the retina and choroid of control animals; these changes were inhibited by the free radical scavengers U74389F (2.5 mg/kg) and high-dose allopurinol (140 mg/kg) as well as by the cyclooxygenase inhibitors ibuprofen (40 mg/kg) and indomethacin (5 mg/kg). In isolated eyecup preparations, H2O2 and cumene hydroperoxide dilated retinal vessels, and this effect was completely blocked by indomethacin.These findings indicate that free radicals play a major role in setting the upper limit of RBF and ChBF autoregulation of the newborn animal. In addition, there exists a positive feedback interaction between free radicals and cyclooxygenase activity in ocular tissues, such that during hypertension the cyclooxygenase pathway is an important producer of free radicals and in turn is also activated by them.

PGE2 and PGF2 alpha decrease cerebral metabolism in the adult but increase it in the newborn. The present study was done using synaptosomes from newborn and adult pigs to find out whether these diverse cerebral effects of prostanoids are a consequence of newborn synaptosomes containing fewer or no EP2 receptors for PGE2 (mediating cAMP increase and in turn cerebral metabolism decrease) and PGF2 alpha receptors [mediating IP3 (inositol 1,4,5-triphosphate) increase and in turn cerebral metabolism decrease]. It was found that maximum binding values (fmol/mg protein) of [3H]PGE2 and [3H]PGF2 alpha were, respectively, only 11.6 +/- 0.8 and 8.6 +/- 1.4 on newborn synaptosomes compared with 41.8 +/- 1.8 and 31.2 +/- 4.8 on adult tissues. EP1 receptors were virtually absent in newborn and adult preparations. Practically all the PGE2 receptors on newborn synaptosomes were EP3 subtype, whereas adult brain synaptosomes contained both EP2 and EP3 subtypes; this was indicated by the ability of MB 28,767, a specific EP3 receptor agonist, to cause 100% displacement of [3H]PGE2 binding to synaptosomes of the newborn but only 51% in the case of the adult. Also, PGE2, 11-deoxy PGE1 (a nonselective EP2 and EP3 agonist) and MB 28,767 (an EP3 agonist) caused comparable decreases in cAMP formation in synaptosomes from the newborn, whereas in those from the adult, PGE2 and 11-deoxy PGE1 increased and MB 28,767 decreased cAMP production. PGF2 alpha markedly increased IP3 synthesis in synaptosomes of the adult but not of the newborn.(ABSTRACT TRUNCATED AT 250 WORDS)

At concentrations higher than that required to produce maximal vasoconstriction, tyramine caused concentration-dependent relaxation of rat aortic strips contracted maximally by tyramine, norepinephrine, phenylephrine, 5-hydroxytryptamine, prostaglandin F2 alpha, endothelin, angiotensin II and potassium; isoproterenol did not relax potassium-contracted strips. The vasorelaxant effect of tyramine was not antagonized by propranolol, pindolol or nadolol, all of which markedly antagonized the effects of isoproterenol. The vasorelaxant activity of tyramine was endothelium-independent and not inhibited by hemoglobin, methylene blue or L-NG-nitro arginine; it did not exhibit tachyphylaxis and was neither inhibited by cocaine, guanethidine, reserpine and chemical sympathectomy nor by alpha adrenoceptor, dopamine receptor, 5-hydroxytryptamine receptor, histamine receptor and adenosine receptor antagonists. Inhibition of cyclooxygenase, lipoxygenase and monamine oxidase activities did not decrease the vasorelaxant activity of tyramine. The vasorelaxant effect of tyramine was not decreased by altering external calcium from 0.25 to 4 mM nor was it potentiated by nifedipine. Phenylethylamine was the minimum structural requirement for this propranolol-resistant vasorelaxant activity; beta-carbon and 3-ring hydroxylation abolished this activity, but N-methylation partly overcame the effect of beta-hydroxylation. The vasopressor effect of tyramine in anesthetized rat was reversed to vasodepressor effect by phenoxybenzamine plus propranolol. The propranolol-resistant vasorelaxant effect of tyramine was also confirmed on isolated human placenta arteries. At vasorelaxant concentrations, tyramine did not increase cyclic GMP and cyclic AMP but inhibited inositol-1,4,5-triphosphate. It is suggested that at high concentrations tyramine and related phenylethylamines cause endothelium- and beta-2 adrenoceptor independent vasorelaxation either via specific tyramine receptors or nonselectively.

To assess whether prostaglandins contribute to the control of basal retinal and choroidal hemodynamics, retinal (RBF) and choroidal blood flow (ChBF) were measured by a microsphere technique in 1- to 4-day-old pigs before and after (at 20 and 60 min) administration of indomethacin (0.3 mg/kg, n = 6 or 10 mg/kg, n = 5), ibuprofen (40 mg/kg, n = 7), naproxen (20 mg/kg, n = 5) or vehicle (n = 8). In 40 other animals, PGF2 alpha, PGE2, and 6-keto-PGF1 alpha were measured in the retina and choroid at times corresponding to blood flow measurements. Mean arterial blood pressure and blood gases and pH were not altered by any of the agents. Except for the lower dose of indomethacin (0.3 mg/kg), which did not change retinal and choroidal prostaglandin concentrations, the prostaglandin levels were decreased similarly (P0.01) by the three drugs. However, RBF and ChBF were not changed by ibuprofen and naproxen, but decreased to the same extent after low and high doses of indomethacin. The data suggest that the effects of indomethacin on RBF and ChBF cannot be simply attributed to prostaglandin synthesis inhibition, and that prostaglandins may not play a significant role in controlling basal blood flow to the retina and choroid.

The role of prostanoids in setting the range of autoregulation of retinal blood flow (RBF) and choroidal blood flow (ChBF) in the newborn was assessed. The RBF, ChBF, and arterial and cerebral sinus concentrations of PGE, PGF2 alpha, 6-keto-PGF1 alpha and TXB2 were measured over a wide range of mean systemic blood pressure (blood pressure (BP): 17-117 mm Hg) in newborn piglets treated with ibuprofen (30 mg/kg iv) or its vehicle (n = 8, in each group). Hypertension and hypotension were induced 80 min apart on each animal, by inflating balloon-tipped catheters placed at the aortic isthmus and root, respectively. Blood flow and prostanoid concentrations were measured 20 min before (basal) and during the induced changes in BP. In vehicle-treated piglets, RBF did not change with BP between 50 and 90 mm Hg (r = 0.33, P = 0.27), but changed as a function of BP beyond this range (tau = 0.52, P less than 0.01); ChBF increased with BP throughout the range studied (17-117 mm Hg; tau = 0.89, P less than 0.001). The relationship between O2 delivery to the retina and choroid and BP (tau greater than 0.43, P less than 0.01) was similar to that seen between RBF and ChBF with BP. The concentration of all prostanoids increased when BP was reduced to less than 50 mm Hg. When BP was raised to more than 90 mm Hg, prostaglandin concentrations increased, and those of TXB2 did not change. Ibuprofen treatment reduced the basal concentrations of all prostanoids to nearly undetectable levels and prevented their changes during hypotension and hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrovascular concentrations of prostaglandin E (PGE), prostaglandin F2 alpha (PGF2 alpha), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) were determined over a blood pressure range of 17-117 mm Hg (induced by inflation of balloon-tipped catheters placed in the thoracic descending aorta and at the aortic root) in eight newborn piglets to access the role of prostanoids in cerebral blood flow (CBF; measured using radioactive microspheres) autoregulation. Basal systemic blood pressure, heart rate, blood gases, total CBF, and prostanoid concentrations were stable. CBF was constant between 50 and 90 mm Hg, but beyond this range CBF varied directly with blood pressure (tau = 0.48; p less than 0.05). Sagittal sinus concentrations of PGE, PGF2 alpha, and 6-keto-PGF1 alpha varied with blood pressure according to a quadratic function (R2 = 0.92 to 0.96; p less than 0.0001), exhibiting lowest values between mean blood pressures of 60 and 90 mm Hg. During hypotension (17-49 mm Hg), there was a greater relative increase in sagittal sinus concentrations of TXB2 than of PGE, PGF2 alpha, and 6-keto-PGF1 alpha; at the lowest blood pressures, TXB2 increased by 658 +/- 44%, and prostaglandins increased on the average by 331 +/- 49% (p less than 0.01) from their values during normotension (50-90 mm Hg). During hypertension (91-117 mm Hg), cerebrovascular production and concentrations of prostaglandins increased by 142 +/- 31% and 45 +/- 10%, respectively, but did not change for TXB2.(ABSTRACT TRUNCATED AT 250 WORDS)

Isoprostanes Induce Retinal Vasoobliteration, a Key Feature of Retinopathy of Prematurity (ROP)

This article focuses on some of the problems encountered with two of the drugs currently given to newborns.

• In nine of 102 children admitted to the Montreal Children's Hospital with a diagnosis of aseptic meningitis, the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) developed. Patients with and without SIADH were similar with respect to clinical symptoms, duration of illness, and CSF inflammatory response. The SIADH group differed in that the largest age group was 1 to 5 years. ( AJDC 1985;139:292-294)

Antenatal B has been shown to decrease the incidence and severity of RDS. Among low birth weight infants RLF remains the most common serious complication after intraventricular hemorrhage. Steroids have been used postnatally in an attempt to treat RLF, without success. However, the possible protective role of steroids has not been evaluated. In view of the extensive use of B in our center, we have assessed by multivariant analysis its effect on RLF. Among 204 infants in the 1000-1500gms category, no statistically significant difference was found between those who received B and those who did not. However, among the 51 infants weighing