Prolonged hypercapnia-evoked cerebral hyperemia via K(+) channel- and prostaglandin E(2)-dependent endothelial nitric oxide synthase induction.

Mechanisms for secondary sustained increase in cerebral blood flow (CBF) during prolonged hypercapnia are unknown. We show that induction of endothelial NO synthase (eNOS) by an increase in prostaglandins (PGs) contributes to the secondary CBF increase during hypercapnic acidosis. Ventilation of pigs with 6% CO(2) (PaCO(2 approximately)65 mm Hg; pH approximately 7.2) caused a approximately 2.5-fold increase in CBF at 30 minutes, which declined to basal values at 3 hours and gradually rose again at 6 and 8 hours; the latter increase was associated with PG elevation, nitrite formation, eNOS mRNA expression, and in situ NO synthase (NOS) reactivity (NADPH-diaphorase staining). Subjecting free-floating brain sections to acidotic conditions increased eNOS expression, the time course of which was similar to that of CBF increase. Treatment of pigs with the cyclooxygenase inhibitor diclofenac or the NOS inhibitor Nomega-nitro-L-arginine blunted the initial rise and prevented the secondary CBF increase during hypercapnic acidosis; neuronal NOS blockers 1-(2-trifluoromethylphenyl) imidazole and 3-bromo-7-nitroindazole were ineffective. Diclofenac abolished the hypercapnia-induced rise in cerebrovascular nitrite production, eNOS mRNA expression, and NADPH-diaphorase reactivity. Acidosis (pH approximately 7.15, PCO(2 approximately )40 mm Hg; 6 hours) produced similar increases in prostaglandin E(2) (PGE(2)) and eNOS mRNA levels in isolated brain microvessels and in NADPH-diaphorase reactivity of brain microvasculature; these changes were prevented by diclofenac, by the receptor-operated Ca(2+) channel blocker SK&F96365, and by the K(ATP) channel blocker glybenclamide. Acidosis increased Ca(2+) transients in brain endothelial cells, which were blocked by glybenclamide and SK&F96365 but not by diclofenac. Increased PG-related eNOS mRNA and NO-dependent vasorelaxation to substance P was detected as well in rat brain exposed to 6 hours of hypercapnia. PGE(2) was the only major prostanoid that modulated brain eNOS expression during acidosis. Thus, in prolonged hypercapnic acidosis, the secondary CBF rise is closely associated with induction of eNOS expression; this seems to be mediated by PGE(2) generated by a K(ATP) and Ca(2+) channel-dependent process.

Preservation of neural function in the perinate by high PGE(2) levels acting via EP(2) receptors.

Despite increasingly frequent and longer lasting hypoxic episodes during progressive labor, the neonate is alert and vigorous at birth. We investigated whether high levels of PGs during the perinatal period assist in preserving neural function after such "stressful" hypoxic events. Visual evoked potentials (VEPs) and electroretinograms (ERGs) were recorded before and 45 min after mild moderate asphyxic hypoxia (two 4-min asphyxic-hypoxic periods induced by interrupting ventilation at 8-min intervals) in newborn piglets <12 h old treated or not treated with inhibitors of PG synthase (ibuprofen or diclofenac) with or without PG analogs. At 45 min after the hypoxic episode, P2 and b-wave amplitudes were slightly decreased and latencies were delayed. These changes in the VEP and ERG returned to near normal by 120 min. Ibuprofen and diclofenac decreased brain and retinal PG levels and markedly intensified 45 min after hypoxia-induced changes in VEP and ERG, but cerebral and retinal blood flows improved. Combined treatment with PG synthase inhibitor in combination with 16,16-dimethyl-PGE(2) (a PGE(2) analog), but not with PGI(2) and PGF(2alpha) analogs, and in combination with the EP(2) receptor agonist butaprost (but not EP(1) or EP(3) agonists), prevented ibuprofen- and diclofenac-aggravated postasphyxia electrophysiological changes. In conclusion, high levels of PGE(2) in nervous tissue, via actions on EP(2) receptors, seem to contribute to preservation of neural function in the perinate subjected to frequent hypoxic events.

Nifedipine and nimodipine competitively inhibit uridine kinase and orotidine-phosphate decarboxylase: theoretical relevance to poor outcome in stroke.

Nifedipine and nimodipine, dihydropyridine calcium channel blockers, are commonly used as antihypertensive and antianginal agents in patients at risk for stroke. At least one stroke trial suggests that patients receiving calcium channel blockers at the time of an acute stroke have worse outcomes than those receiving other or no antihypertensive medications. We hypothesize that the poor outcome may not be related to blood pressure changes but instead may be mediated by competitive inhibition of important enzymes of pyrimidine synthesis whose products are needed to repair nerve cell membranes after an acute stroke. Both drugs acted as competitive inhibitors of the only enzymes that are known to synthesize the nucleotide uridine-5'-phosphate: uridine kinase and orotidine-5'-phosphate decarboxylase. Nifedipine produced Ki values of 28 microM for uridine kinase and 105 microM for orotidine-5'-phosphate decarboxylase. Nimodipine produced Ki values of 20 microM for uridine kinase and 18 microM for orotidine-5'-phosphate decarboxylase. For uridine kinase, these inhibitors bound more tightly than the physiologic substrates uridine or cytidine. For the decarboxylase, the inhibitors bound less tightly than the normal physiologic substrate orotidine-5'-phosphate. Additional experiments are needed to determine whether the concentrations of nifedipine or nimodipine, and of cytidine, uridine, and orotidine-5'-phosphate in human brain, are such that this inhibition would affect stroke outcome.

Prevalence and determinants of valvulopathy in patients treated with dexfenfluramine.

BACKGROUND: Valve regurgitation has been associated with dexfenfluramine, but its prevalence and severity are uncertain. Additional factors that may contribute to valve regurgitation in patients exposed to this drug are poorly understood. METHODS AND RESULTS: Echocardiography was performed on subjects recruited from 26 prescribing sites in 15 states. The total sample of 412 subjects included 172 dexfenfluramine patients and 172 unexposed controls matched for age, sex, and body mass index and 68 unmatched subjects meeting the same entry criteria (51 dexfenfluramine patients and 17 controls). Mean treatment duration was 6.9 months; mean interval from treatment discontinuation to echocardiogram was 8.5 months. Each echocardiogram was interpreted independently by 3 echocardiographers. FDA-grade regurgitation (at least mild aortic regurgitation or at least moderate mitral regurgitation) was significantly more frequent in dexfenfluramine patients (7.6% versus 2.1% for controls; P=0.01; odds ratio, 3.82). This difference was primarily due to more frequent mild aortic regurgitation in dexfenfluramine patients (6.3% versus 1.6% in controls; P<0.02; odds ratio, 4.15). No differences were found in sclerosis or mobility for either the aortic or mitral valve. Factors independently related to FDA-grade regurgitation or any grade of aortic regurgitation were older age, higher diastolic blood pressure at the time of echocardiography, and shorter time from drug discontinuation to echocardiogram. CONCLUSIONS: Dexfenfluramine use is associated with an increase in the prevalence of abnormal valve regurgitation. Age and blood pressure may also affect the prevalence of regurgitation. Dexfenfluramine-related valve regurgitation may regress after drug discontinuation.

Developmental regulation of endothelial nitric oxide synthase in cerebral vessels of newborn pig by prostaglandin E(2).

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 M&B 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 M&B 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.

Hematologic effects of cis-platinum-bleomycin therapy.

A prospective study of the hematologic findings in 19 patients receiving cis-platinum (C-P) bleomycin (B) for squamous cell carcinoma of the head and neck was performed. CP 3 mg/kg was given on day 1, B 15 mg/m2 on day 3 and then by continuous infusison from day 3 to 10. Hematocrits declined in all patients from a mean of 41.6 +/- 3.9 to 36.6 +/- 4.9 (p less than 0.001) with the nadir seen by 10 days, reticulocyte count was unchanged. In 1 patient marked hemolysis occurred over 10-day period associated with the appearance of irregular spherocytes on smear, a situation similar to the index case which initiated this study. 5 other patients had spherocytes. A significant lymphopenia in the absence of neutropenia and thrombocytopenia was also observed.

Mortality from leukaemia and cancer in shipyard nuclear workers.

A review of death certificates in New Hampshire, Maine, and Massachusetts for 1959-77 yielded a total of 1722 deaths among former workers at the Portsmouth Naval Shipyard where nuclear submarines are repaired and refuelled. Next of kin were contacted for 592. All deaths under age 80 were classified as being in former nuclear or non-nuclear workers depending on information supplied by next of kin. With U.S. age-specific proportional cancer mortality for White males as a standard, the observed/expected ratio of leukaemia deaths was 5.62 (6 observed, 1.1 expected) among the 146 former nuclear workers. For all cancer deaths, this ratio was 1.78. Among non-nuclear workers there was no statistically significant increase in proportional mortality from either leukaemia or from all cancers. The excess proportional leukaemia and cancer mortality among nuclear workers exceeds predictions based on previous data of radiation effects in man.