nitroarginine and Hyperoxia

Endothelins (ET) have opposite vascular effects mediated through different receptors: ET(A) receptors mediating vasoconstriction and ET(B) receptors mediating vasoconstriction as well as vasodilation. The role of ET in acute hypoxic pulmonary vasoconstriction (HPV) was studied after dual ET receptor blockade with bosentan and nitric oxide (NO) synthase inhibition with nitro-L-arginine (L-NA). We started from the hypothesis that ET antagonism may inhibit HPV but, if not, would do so after NO synthase inhibition. HPV was evaluated in anesthetized lambs, with an intact pulmonary circulation, by the increase in the mean pulmonary artery pressure (Ppa) minus occluded Ppa (Ppao) gradient in response to hypoxia (inspiratory oxygen fraction of 0.1) at different levels of pulmonary flow (multipoint pressure/flow relationships). ET receptor antagonism decreased pulmonary and systemic vascular tone both in hyperoxia and hypoxia. ET antagonism had no effect on HPV. NO synthase inhibition increased pulmonary vascular tone more in hypoxia than in hyperoxia so that HPV was enhanced. After L-NA, bosentan still decreased pulmonary vascular tone in hypoxia but did not affect the magnitude of HPV. The present results suggest that ET and NO are involved in the regulation of basal pulmonary vascular tone. Furthermore, the vasodilator effect of bosentan persisted in the presence of NO synthase inhibition, suggesting a non NO-dependent vasodilator mechanism. The results from these experiments are in agreement with the idea that ET do not play a major role in HPV in the perinatal lamb, even when it is enhanced by NO synthase inhibition.

Topics: Animals; Animals, Newborn; Blood Pressure; Bosentan; Constriction, Pathologic; Dilatation, Pathologic; Endothelin Receptor Antagonists; Endothelins; Hyperoxia; Hypoxia; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Pulmonary Artery; Pulmonary Circulation; Sheep, Domestic; Sulfonamides; Vascular Resistance

Recent studies suggest that a bronchial-derived relaxing factor (BrDRF) decreases the contractility of newborn, but not fetal, rat pulmonary arteries (PAs) by a nitric oxide (NO)-mediated mechanism. We studied the effect of an adjacent bronchus on PA contractility to norepinephrine (NE) in late-gestation fetal (n = 7), neonatal (1 day old, n = 9), ventilated neonatal (24-h ventilation from birth with 100% oxygen, n = 9), and adult sheep (n = 6) in the presence and absence of the NO synthase inhibitor N(omega)-nitro-l-arginine (l-NNA). The sheep were anesthetized and killed, and fifth-generation PA rings with and without an attached adjacent bronchus (PA+Br) were contracted in standard tissue baths with NE (10(-8)-10(-6) M). NE contractions were expressed as fraction of KCl (118 mM) contraction and as grams of contraction force. NE contractions were significantly diminished by the presence of an attached bronchus in the neonatal and ventilated neonatal and adult, but not fetal, lambs. Hyperoxic ventilation markedly increased NE contractions in PA and PA+Br. l-NNA significantly enhanced NE contractions in PA+Br in postnatal but not in fetal lambs. Pretreatment with l-NNA abolished the difference between NE contractions in PA and PA+Br in neonatal but not in hyperoxic ventilated neonatal lambs. We conclude that there is a BrDRF that is developmentally regulated and has vascular activity postnatally but not during fetal life. The effect of BrDRF is predominantly mediated by NO in air-breathing neonatal lambs but may involve a second non-NO mediator following hyperoxic ventilation. We speculate that BrDRF may have an important role in postnatal changes in pulmonary arterial reactivity.

Topics: Aging; Animals; Animals, Newborn; Bronchi; Endothelium-Dependent Relaxing Factors; Endothelium, Vascular; Enzyme Inhibitors; Female; Hyperoxia; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Norepinephrine; Pulmonary Artery; Pulmonary Circulation; Pulmonary Ventilation; Vascular Resistance; Vasoconstriction

Hyperoxia reduces the hemodynamic latency and enhances the response magnitude of the evoked local cerebral blood flow (LCBF). The objective of this study was to test the hypothesis that a change in the production of nitric oxide (NO) is involved in a unique change in evoked LCBF during hyperoxia. We measured LCBF in alpha-chloralose-anesthetized rats by laser-Doppler flowmetry. Systemic administration of the NO synthase inhibitor N(omega)-nitro-L-arginine (LNA) caused a decline in the baseline level of LCBF (P<0.01). The LNA intravenous injection during hyperoxia (hyperoxia with LNA) reduced the normalized evoked LCBF (normalization with respect to the baseline level of LCBF) in response to somatosensory stimulation by approximately 37% when compared under normal conditions (normoxia without LNA) (P<0.01), although that during normoxia (normoxia with LNA) did not cause a significant difference in the normalized evoked LCBF. The integrated neuronal activity under hyperoxia with LNA was approximately 11% lower than that under normoxia without LNA (P<0.05), although there was no significant difference in integrated neuronal activity between normoxia with LNA and normoxia without LNA. These results do not support our hypothesis and suggest the existence of another interaction mechanism involving oxygen for the enhancement of evoked LCBF under hyperoxia.

Topics: Animals; Cerebrovascular Circulation; Electrophysiology; Evoked Potentials, Somatosensory; Heart Rate; Hyperoxia; Laser-Doppler Flowmetry; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley; Somatosensory Cortex

Exposure of premature human infants to hyperoxia results in the obliteration of developing retina capillaries, leading to a vision-threatening retinopathy termed retinopathy of prematurity (ROP). The authors hypothesized that this process may be mediated in part by endothelial nitric oxide (NO)-derived oxidants such as peroxynitrite and tested this hypothesis in a mouse model of ROP.. Normal mice, mice treated with the nitric oxide synthase (NOS) inhibitor N:(G)-nitro-L-arginine (L-NNA), and knockout mice carrying a homozygous targeted disruption of the gene for endothelial NOS (eNOS) were studied in an experimental model of ROP. Retinas were compared for extent of capillary obliteration in hyperoxia, vascular endothelial growth factor (VEGF) expression, nitrotyrosine formation, and vitreous neovascularization.. Oxygen-induced retinal vaso-obliteration was significantly reduced by L-NNA treatment (43% decrease from controls). The eNOS-deficient mice showed a similar reduction in vaso-obliteration (46% decrease from controls), and vitreous neovascularization was also substantially reduced (threefold decrease). Retinal nitrotyrosine formation, a measure of in situ peroxynitrite modification of proteins, was significantly elevated in normal mice during hyperoxia, in a spatial and temporal pattern consistent with a role in oxygen-induced vaso-obliteration. This was not seen in eNOS-deficient mice. VEGF expression was similar in both groups of mice, although suppression in hyperoxia was slightly blunted in eNOS-deficient mice.. These data suggest a role for NO and peroxynitrite in the pathogenesis of ROP. Therapies aimed at modulation of eNOS activity may have therapeutic potential for preventing ROP.

Topics: Animals; Endothelial Growth Factors; Enzyme Inhibitors; Humans; Hyperoxia; Infant, Newborn; Lymphokines; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroarginine; Retinal Neovascularization; Retinal Vessels; Retinopathy of Prematurity; Tyrosine; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

We investigated the distribution and regulation of the optic nerve head (ONH) tissue partial pressure of oxygen (PO2) under various stimuli and the role of the nitric oxide in the ONH circulation. Tissue PO2 was measured using double-barreled recess microelectrodes in the intact eyes of miniature pigs during normoxia, hyperoxia, hypoxia, variations of systemic blood pressure, and after inhibition of the endothelial nitric oxide synthesis by the administration of nitro-L-arginine. Measurements were performed in front of the ONH at intervascular and juxta-arteriolar areas and at a depth of 50 and 200 microm within the ONH at the center and the rim. During normoxia, PO2 was heterogeneously distributed in the ONH, higher close to the arterioles than in intervascular areas. Hyperoxia induced a significant increase of juxta-arteriolar tissue PO2, while in intervascular areas no change was noticed. Hypoxia did not modify intervascular tissue PO2 at 200 microm depth within the ONH. Variations of the systemic blood pressure did not induce any significant change in ONH tissue PO2. Similarly, no modification was noticed after the administration of nitro-L-arginine. There is a remarkable autoregulatory capacity of the ONH circulation that may compensate for parameters such as hyperoxia, hypoxia, and variations of the systemic blood pressure. Endothelially derived nitric oxide inhibition does not modify the ONH tissue PO2, probably because the tissue PO2 is stabilized by compensatory regulation.

Topics: Animals; Blood Pressure; Endothelium, Vascular; Homeostasis; Hyperoxia; Hypoxia; Microelectrodes; Muscle, Smooth, Vascular; Nitric Oxide; Nitroarginine; Optic Disk; Oxygen; Oxygen Consumption; Perfusion; Regional Blood Flow; Swine; Swine, Miniature