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The goal of this study was to investigate the effects of nitric oxide (NO)- mediated vasodilation in preventing medullary hypoxia, as well as the likely pathways by which superoxide (O2-) conversely enhances medullary hypoxia. To do so, we expanded a previously developed mathematical model of solute transport in the renal medulla that accounts for the reciprocal interactions among oxygen (O2), NO, and O2- to include the vasoactive effects of NO on medullary descending vasa recta. The model represents the radial organization of the vessels and tubules, centered around vascular bundles in the outer medulla and collecting ducts in the inner medulla. Model simulations suggest that NO helps to prevent medullary hypoxia both by inducing vasodilation of the descending vasa recta (thus increasing O2 supply) and by reducing the active sodium transport rate (thus reducing O2 consumption). That is, the vasodilative properties of NO significantly contribute to maintaining sufficient medullary oxygenation. The model further predicts that a reduction in tubular transport efficiency (i.e., the ratio of active sodium transport per O2 consumption) is the main factor by which increased O2- levels lead to hypoxia, whereas hyperfiltration is not a likely pathway to medullary hypoxia due to oxidative stress. Finally, our results suggest that further increasing the radial separation between vessels and tubules would reduce the diffusion of NO towards descending vasa recta in the inner medulla, thereby diminishing its vasoactive effects therein and reducing O2 delivery to the papillary tip. [ABSTRACT FROM AUTHOR]

Antiangiogenesis, targeting vascular endothelial growth factor (VEGF), has become a well-established treatment for patients with cancer. This treatment is associated with nitric oxide (NO) suppression and a dose-dependent activation of the endothelin system, resulting in preeclampsia-like features, particularly hypertension and renal injury. Studies in endothelium NO synthase (eNOS)-deficient mice and pharmacological treatment with endothelin receptor blockers and sildenafil indicate that an activated endothelin system, rather than NO suppression, mediates the side effects of angiogenesis inhibitors. Activation of the endothelin system is also observed in preeclamptic women, where it is related to the increased placental production of sFlt-1, the soluble form of the VEGF receptor-1. This receptor binds VEGF, thereby having the same consequences as antiangiogenic treatment with VEGF inhibitors. The side effects of antiangiogenic treatment in patients with cancer may be dose limiting, thereby impairing its therapeutic potential. In addition, because endothelin exerts proangiogenic effects, investigation of the effects of endothelin receptor blockade in patients with cancer treated with angiogenesis inhibitors is warranted. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a chronic disease characterized by a progressive increase in vasomotor tone, narrowing of the vasculature with structural remodeling, and increase in pulmonary vascular resistance. Current treatment strategies include nitric oxide therapy and methods to increase cGMP-mediated vasodilatation. cGMP-dependent protein kinases (PKG) are known mediators of nitric oxide- and cGMP-induced vasodilatation. Deletion of PKG-1 in mice has been shown to induce PH, however, the exact mechanisms by which loss of PKG-1 function leads to PH is not known. In a mouse model with a selective mutation in the NH2-terminus leucine zipper protein interaction domain of PKG-1α [leucine zipper mutant (LZM)], we found a progressive increase in right ventricular systolic pressure and right heart hypertrophy compared with wild-type (WT) mice and increased RhoA-GTPase activity in the lungs. When exposed to chronic hypoxia, LZM mice developed modestly enhanced right ventricular remodeling compared with WT mice. Tadalafil, a phosphodiesterase-5 inhibitor that increases cGMP levels, significantly attenuated hypoxiainduced cardiopulmonary remodeling in WT mice but had no effect in LZM mice. We conclude that a functional leucine zipper domain in PKG-1α is essential for maintenance of a low pulmonary vascular tone in normoxia and for cGMP-mediated beneficial effects of phosphodiesterase- 5 inhibition in hypoxic cardiopulmonary remodeling. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)-β plays a central role in vascular homeostasis and in the pathology of vascular disease. There is a growing appreciation for the role of nitric oxide (NO) and carbon monoxide (CO) as highly diffusible, bioactive signaling molecules in the vasculature. We hypothesized that both NO and CO increase endocytosis of TGF-β receptor type 1 (TβR1) in vascular smooth muscle cells (VSMCs) through activation of dynamin-2, shielding cells from the effects of circulating TGF-β. In this study, primary cultures of VSMCs from Sprague-Dawley rats were treated with NO-releasing molecule 3 (a NO chemical donor), CO-releasing molecule 2 (a CO chemical donor), or control. NO and CO stimulated dynamin-2 activation in VSMCs. NO and CO promoted time- and dose-dependent endocytosis of TβR1. By decreasing TβR1 surface expression through this dynamin- 2-dependent process, NO and CO diminished the effects of TGF-β on VSMCs. These findings help explain an important mechanism by which NO and CO signal in the vasculature by decreasing surface expression of TβR1 and the cellular response to TGF-β. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) regulates renal function. Luminal flow stimulates NO production in the thick ascending limb (TAL). Transient receptor potential vanilloid 4 (TRPV4) is a mechano-sensitive channel activated by luminal flow in different types of cells. We hypothesized that TRPV4 mediates flow-induced NO production in the rat TAL. We measured NO production in isolated, perfused rat TALs using the fluorescent dye DAF FM. Increasing luminal flow from 0 to 20 nl/min stimulated NO from 8 3 to 45 ± 12 arbitrary units (AU)/min (n = 5; P < 0.05). The TRPV4 antagonists, ruthenium red (15 μmol/l) and RN 1734 (10 μmol/l), blocked flow-induced NO production. Also, luminal flow did not increase NO production in the absence of extracellular calcium. We also studied the effect of luminal flow on NO production in TALs transduced with a TRPV4shRNA. In nontransduced TALs luminal flow increased NO production by 47 ± 17 AU/min (P < 0.05; n = 5). Similar to nontransduced TALs, luminal flow increased NO production by 39 ± 11 AU/min (P < 0.03; n = 5) in TALs transduced with a control negative sequence-shRNA while in TRPV4shRNA-transduced TALs, luminal flow did not increase NO production (∆10 ± 15 AU/min;n = 5). We then tested the effect of two different TRPV4 agonists on NO production in the absence of luminal flow. 4α-Phorbol 12,13-didecanoate (1 μmol/l) enhanced NO production by 60 ± 11 AU/min (P < 0.002; n = 7) and GSK1016790A (10 mol/l) increased NO production by 52 ± 15 AU/min (P < 0.03; n = 5). GSK1016790A (10 ηmol/l) did not stimulate NO production in TRPV4shRNA-transduced TALs. We conclude that activation of TRPV4 channels mediates flow-induced NO production in the rat TAL. [ABSTRACT FROM AUTHOR]

Treatment of aortic smooth muscle cells with PDGF induces the upregulation of protein tyrosine phosphatase 1B (PTP1B). PTP1B, in turn, decreases the function of several growth factor receptors, thus completing a negative feedback loop. Studies have reported that PDGF induces the downregulation of PKG as part of a repertoire of dedifferentiation of vascular smooth muscle cells. Other studies have reported that chronic nitric oxide (NO) treatment also induces the downregulation of PKG. In the present study, we tested the hypothesis that the downregulation of PKG by PDGF or NO in differentiated rat aortic smooth muscle cells can be attributed to the upregulation of PTP1B. We found that treatment with PDGF or NO induced an upregulation of PTP1B levels. Overexpression of PTP1B induced a marked downregulation of PKG mRNA and protein levels, whereas the expression of dominant negative PTP1B or short interfering RNA directed against PTP1B blocked the capacity of PDGF or NO to decrease PKG levels. We conclude that the upregulation of PTP1B by PDGF or NO is both necessary and sufficient to induce the downregulation of PKG via an effect on PKG mRNA levels. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether pretreatment with single low loading dose of Tongxinluo (TXL), a traditional Chinese medicine, 1 hour before myocardial ischemia can attenuate the no-reflow and ischemia-reperfusion injury by regulating endothelial nitric oxide synthase (eNOS) via the protein kinase A (PKA) pathway. Methods and Results: In a 90-minute ischemia and 3-hour reperfusion model, Minipigs were randomly assigned to sham, control, TXL (0.05g/kg, gavaged 1 hour prior to ischemia), TXL+H-89 (a PKA inhibitor, intravenously infused at a dose of 1.0 μg·kg-1·min-1 per minute 30 minutes before ischemia), and TXL+Nω-nitro-L-arginine (L-NNA, an eNOS inhibitor, intravenously administered at a dose of 10 mg/kg 30 minutes prior to ischemia) groups. TXL decreased creatine kinase (CK) activity (P<0.05), reduced the no-reflow area from 48.6% to 9.5% and infarct size from 78.5% to 59.2% (P<0.05), whereas these effects of TXL were partially abolished by H-89 and completely reversed by L-NNA. TXL elevated the PKA activity and the expression of PKA, Thr 198 phosphorated-PKA, Ser 1179 phosphorated-eNOS (p-eNOS), and Ser 635 p-eNOS in the ischemic myocardium. H-89 repressed the TXL-induced enhancement of PKA activity and the phosphorylation of Ser 635 p-eNOS, and L-NNA counteracted the phosphorylation of eNOS at Ser 1179 and Ser 635 without apparent influence on the PKA activity. Conclusion: Pretreatment with single low loading dose of TXL 1 hour before ischemia reduces the myocardial no-reflow and ischemia-reperfusion injury by up-regulating the phosphorylation of eNOS at Ser 1179 and Ser 635, and this effect is partially mediated by the PKA pathway. [ABSTRACT FROM AUTHOR]

Bay 41-8543 is a nitric oxide (NO)-independent stimulator of soluble guanylyl cyclase (sGC). Responses to iv injections of BAY 41-8543 were investigated under baseline and elevated tone conditions, and when NO synthase (NOS) was inhibited with Nω-nitro-L-arginine methyl ester (L-NAME). Under baseline conditions, iv injections of BAY 41-8543 caused small decreases in pulmonary arterial pressure, larger decreases in systemic arterial pressure, and increases in cardiac output. When pulmonary arterial pressure was increased to approximately ~30 mm Hg with an iv infusion of U46619, iv injections of BAY 41-8543 produced larger dose-dependent decreases in pulmonary arterial pressure, and the relative decreases in pulmonary and systemic arterial pressure in response to the sGC stimulator were similar. Treatment with L-NAME markedly decreased responses to BAY 41-8543 when pulmonary arterial pressure was increased to similar values (~30 mm Hg) in U46619-infused and in U46619-infused plus L-NAME treated animals. The iv injection of a small dose of sodium nitroprusside (SNP) when combined with BAY 41-8543 enhanced pulmonary and systemic vasodilator responses to the sGC stimulator in L-NAME treated animals. The present results indicate that BAY 41-8543 has similar vasodilator activity in the systemic and pulmonary vascular beds when pulmonary vasoconstrictor tone is increased with U46619. These results demonstrate that pulmonary and systemic vasodilator responses to BAY 41-8543 are significantly attenuated when NOS is inhibited by L-NAME and show that vasodilator responses to BAY 41-8543 are enhanced when combined with a small dose of SNP in L-NAME treated animals. The present results are consistent with the concept that pulmonary and systemic vasodilator responses to the sGC stimulator are NO-independent, however, the vasodilator activity of the compound is greatly diminished when endogenous NO production is inhibited with L-NAME. These data show that BAY 41-8543 has similar vasodilator activity in the pulmonary and systemic vascular beds in the rat. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GC) remain the first choice of treatment in asthma, but GC therapy is not always effective and is associated with side effects. In a porcine study in our laboratory, simultaneous administration of GC and nitric oxide (NO) attenuated the endotoxin-induced inflammatory response and made GC treatment more effective than inhaled NO or steroids alone. In the present study, we aimed to further investigate the interactions between NO and GC treatment in two murine models of asthma. Inflammation was induced by endotoxin, ovalbumin, or a combination of both. With an animal ventilator and a forced oscillation method (FlexiVent), lung mechanics and airway reactivity to methacholine in response to various treatments were assessed. We also describe histology and glucocorticoid receptor (GR) protein expression in response to inhaled NO treatment [40 ppm NO gas or NO donors sodium nitroprusside (SNP) or diethylamine NONOate (DEA/NO)]. SNP and GC provided protection against bronchoconstriction to a similar degree in the model of severe asthma. When GC-treated mice were given SNP, maximum airway reactivity was further reduced. Similar effects were seen after DEA/NO delivery to GC-treated animals. Using 1-H-[1,2,41-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), a soluble guanylate cyclase inhibitor, we found this effect of NO donors to be mediated through a cGMP-independent mechanism. In the severe model, prolonged NO treatment restored or even increased the nuclear levels of GR. In conclusion, in our murine model of severe asthma GC treatment provided protection to only a limited degree against bronchoconstriction, while concomitant treatment with a NO donor was markedly more potent than the use of either NO or GC alone. [ABSTRACT FROM AUTHOR]

L-Serine administration reduces mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats rendered hypertensive by chronic oral treatment with the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). To determine if the fall in MAP was due to decreases in vascular resistance or cardiac output (CO), and to record regional hemodynamic effects, we measured the distribution of fluorescent microspheres to single bolus intravenous injections of L-serine (1 mmol/kg) in 14-wk-old male WKY, SHR, and L-NAME-treated WKY rats. MAP and total peripheral resistance (TPR) were significantly higher (P < 0.01), whereas CO was lower in L-NAME-treated WKY (P < 0.01) and SHR (P < 0.05). L-Serine administration led to a rapid fall in MAP (WKY 22%, L-NAME-WKY 46%, SHR 34%,) and TPR (WKY 24%, L-NAME-WKY 68%, SHR 53%), whereas CO was elevated. In WKY rats, L-serine induced an increase in blood flow only in the small intestine (53%) while it was more profound in several vascular beds of hypertensive rats [L-NAME-WKY: small intestine (238%), spleen (184%), diaphragm (85%), and liver (65%); SHR: small intestine (2 17%), spleen (202%), diaphragm (116%), large intestine (105%), pancreas (96%), and liver (93%)I. Pretreatment with a combination of apamin (a small calcium-activated potassium channel inhibitor) and charybdotoxin (an intermediate calciumactivated potassium channel inhibitor) abolished the L-serine-induced changes in blood flow and TPR. L-Serine acts predominantly on apaminand charybdotoxin-sensitive potassium channels in the splanchnic circulation to increase blood flow, thereby contributing to the fall in TPR and the pronounced blood pressure-lowering effect of L-serine in hypertensive rats. [ABSTRACT FROM AUTHOR]

Extracellular fluid volume is highly regulated, at least in part, by peripheral resistance and renal function. Nitric oxide (NO) produced by NO synthase type 3 (NOS 3) in the nonrenal vasculature may promote fluid retention by reducing systemic vascular resistance and arterial pressure. In contrast, NO produced by renal NOS 3 promotes water excretion by reducing renal vascular resistance, increasing glomerular filtration, and inhibiting reabsorption along the nephron. Thus, the net effect of NO from NOS 3 on urinary volume (UV) is unclear. We hypothesized that NO produced by NOS 3 promotes water excretion primarily due to renal tubular effects. We gave conscious wild-type and NOS 3 -/- mice an acute volume load and measured UV, blood pressure, plasma renin concentration (PRC), Na+, vasopressin, and urinary Na+ and creatinine concentrations. To give the acute volume load, we trained mice to drink a large volume of water while in metabolic cages. On the day of the experiment, water was replaced with 1% sucrose, and mice had access to it for 1 h. Volume intake was similar in both groups. Over 3 h, wild-type mice excreted 62 ± 10% of the volume load, but NOS 3 -/- excreted only 42 ± 5% (P < 0.05). Blood pressure in NOS 3 -/- was 118 ± 3 compared with 110 ± 2 mmHg in wild-type mice (P < 0.05), but it did not change following volume load in either strain. PRC, vasopressin, and glomerular filtration rate were similar between groups. Urinary Na+ excretion was 49.3 ± 7.0 in wild-type vs. 37.8 ± 6.4 μmol/3 h in NOS 3 -/- mice (P < 0.05). Bumetanide administration eliminated the difference in volume excretion between wild-type and NOS 3 -/- mice. We conclude that 1) NO produced by NOS 3 promotes water and Na+ excretion and 2) the renal epithelial actions of NO produced by NOS 3 supersede the systemic and renal vascular actions. [ABSTRACT FROM AUTHOR]

The ATP-sensitive potassium (KATP) channel couples intracellular metabolic state to membrane excitability. Recently, we demonstrated that neuronal KATP channels are functionally enhanced by activation of a nitric oxide (NO)/cGMP/ cGMP-dependent protein kinase (PKG) signaling cascade. In this study, we further investigated the intracellular mechanism underlying PKG stimulation of neuronal KKATP channels. By performing singlechannel recordings in transfected HEK293 and neuroblastoma SHSY5Y cells, we found that the increase of Kir6.2/SURI (i.e., the neuronal-type KATP) channel currents by PKG activation in cellattached patches was diminished by 5-hydroxydecanoate (5-HD), an inhibitor of the putative mitochondrial KATP channel; N-(2-mercaptopropionyl)glycine, a reactive oxygen species (ROS) scavenger, and catalase, a hydrogen peroxide (H2O2)-decomposing enzyme. These reagents also ablated NO-induced KATP channel stimulation and prevented the shifts in the single-channel open and closed-time distributions resulting from PKG activation and NO induction. Bath application of H2O2 reproduced PKG stimulation of Kir6.2/SUR1 but did not activate tetrameric Kir6.2LRKR368/369/370/37 I AAAA channels. Moreover, neither the PKG activator nor exogenous H2O2 was able to enhance the function of KATP channels in the presence of Ca2+ chelators and calmodulin antagonists, whereas the stimulatory effect of H2O2 was unaffected by 5-RD. Altogether, in this report we provide novel evidence that activation of PKG stimulates neuronal KATP channels by modulating intrinsic channel gating via a 5-HDsensitive factor(s)IROS/Ca2+/calmodulin signaling pathway that requires the presence of the SURI subunit. This signaling pathway may contribute to neuroprotection against ischemic injury and regulation of neuronal excitability and neurotransmitter release by modulating the function of neuronal KATP channels. [ABSTRACT FROM AUTHOR]

This study determined the role of nitric oxide (NO) in neurogenic vasodilation in mesenteric resistance arteries of the toad Bufo marinus. NO synthase (NOS) was anatomically demonstrated in perivascular nerves, but not in the endothelium. ACh and nicotine caused TTX-sensitive neurogenic vasodilation of mesenteric arteries. The ACh-induced vasodilation was endothelium-independent and was mediated by the NO! soluble guanylyl cyclase signaling pathway, inasmuch as the vasodilation was blocked by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and the NOS inhibitors Nω-nitro-L-arginine methyl ester and N°'-nitro-L-arginine. Furthermore, the ACh-induced vasodilation was significantly decreased by the more selective neural NOS inhibitor N5-(1-imino-3-butenyl)-L-ornithine. The nicotine-induced vasodilation was endothelium-independent and mediated by NO and calcitonin gene-related peptide (CGRP), inasmuch as pretreatment of mesenteric arteries with a combination of Nω-nitro-L-arginine and the CGRP receptor antagonist CGRP-(8-37) blocked the vasodilation. Clotrimazole significantly decreased the ACh-induced response, providing evidence that a component of the NO vasodilation involved Ca2+-activated K+ or voltage-gated K+ channels. These data show that NO control of mesenteric resistance arteries of toad is provided by nitrergic nerves, rather than the endothelium, and implicate NO as a potentially important regulator of gut blood flow and peripheral blood pressure. [ABSTRACT FROM AUTHOR]

Systemic intermedin (IMD) 1-47 administration has been reported to result in vasodilation and marked hypotension through calcitoninrelated receptor complexes. However, its effects on the coronary circulation and the heart have not been examined in vivo. The present study was therefore planned to determine the primary in vivo effect of IMD1-47 on coronary blood flow and cardiac function and the involvement of the autonomic nervous system and nitric oxide (NO). In 35 anesthetized pigs, IMD1-47, infused into the left anterior descending coronary artery at doses of 87.2 pmol/min, at constant heart rate and arterial blood pressure, augmented coronary blood flow and cardiac function. These responses were graded in a further five pigs by increasing the infused dose of IMDI-47 between 0.81 and 204.1 pmol/min. In the 35 pigs, the blockade of cholinergic receptors (intravenous atropine, 5 pigs), α-adrenoceptors (intravenous phentolamine, 5 pigs), and βi-adrenoceptors (intravenous atenolol, 5 pigs) did not abolish the cardiac response to IMD1-47, the effects of which were prevented by blockade of 32-adrenoceptors (intravenous butoxamine, 5 pigs), NO synthase (intracoronary Nω-nitro-L-arginine methyl ester, 5 pigs), and calcitonin-related receptors (intracoronary CGRP8-37/AM22-52, 10 pigs). In porcine coronary endothelial cells, IMD1-47 induced the phosphorylation of endothelial NO synthase and NO production through cAMP signaling leading to ERK, Akt, and p38 activation, which was prevented by the inhibition of β2-adrenoceptors, calcitonin-related receptor complexes, and K+ channels. In conclusion, IMD1-47 primarily augmented coronary blood flow and cardiac function through the involvement of calcitonm-related receptor complexes and β2-adrenoreceptor-mediated NO release. The intracellular signaling involved cAMP-dependent activation of kinases and the opening of K+ channels. [ABSTRACT FROM AUTHOR]

Sonic hedgehog (SHH) plays an important role in postnatal tissue repair. The present study tested the hypothesis that impaired SHH pathway results in delayed wound healing by suppressing cutaneous nitric oxide (NO) function in type 1 diabetes. Adult male C57/B6 mice and streptozotocin (STZ)-induced type 1 diabetic mice were used. Although cutaneous SHH and Patched-i (Ptc-1 encoded by PTCH, PTCH 1) proteins were increased significantly on day 4 after wounding compared with day 0 in normal mice, both were decreased significantly in STZ-induced diabetic mice. Topical application of SHH restored wound healing delay in STZ-induced diabetic mice, with a concomitant augmentation of both cutaneous constitutive nitric oxide synthase (NOS) activity and nitrite level. The effects of SHH on wound healing and cutaneous NO function were markedly inhibited by SHH receptor inhibitor cyclopamine. After 24-h treatment in vitro, SHH (5-20 μg/ml) significantly increased cutaneous endothelial NOS protein expression, NOS activity and NO level in normal mice and STZ-induced diabetic mice in a concentration-dependent manner, an effect that was blunted by cyclopamine and NOS inhibitor Nω-nitro-L-arginine methyl ester. The phosphatidylinositol 3-kinase inhibitor LY-294002 significantly blunted the increase of NOS activity and NO level induced by SHH treatment in human umbilican vein endothelial cells. These results demonstrate that the SHH pathway is activated in a normal wound, and its reduction results in impaired NO function and wound healing in diabetes. Strategies aimed at augmenting the endogenous SHH pathway may provide an effective means in ameliorating delayed diabetic wound healing. [ABSTRACT FROM AUTHOR]

In advanced cirrhosis, decreased lung transfer for carbon monoxide (TLCO) and increased alveolar-arterial oxygen tension difference (PA-aO2 ⩾15 mmHg while breathing ambient air) are frequently detected. Pulmonary membrane diffusion capacity for CO (DmCO) and pulmonary capillary blood volume (Vcap) can be derived from the simultaneous measurement of TLCO and lung transfer for nitric oxide (TLNO). Measurements of single-breath TLNO and TLCO were performed in 49 cirrhotic patients with advanced liver cirrhosis and in 35 healthy controls to derive Vcap, DmCO, and TLNO:TLCO ratio. Twenty-five patients had increased PA-aO2, of whom 11 had hepatopulmonary syndrome (HPS). Compared with controls, non-HPS patients with normal PA-aO2 had a significant ∼10% decrease in TLCO, DmCO, and Vcap but similar TLNO:TLCO ratios. Compared with non-HPS patients with normal PA-aO2, non-HPS patients with increased PA-aO2 had lower Vcap and higher TLNO:TLCO ratio but similar DmCO. HPS patients had lower Vcap and higher TLNO:TLCO ratios than both subgroups of non-HPS patients. In cirrhotic patients, TLNO: TLCO ratios correlated positively, and TLCO (percentage of the predicted value) and Vcap (percentage of the predicted value) correlated negatively with PA-aO2 (r² = 0.25, P = 0.0003, r² = 0.48, P < 0.0001 and r² = 0.57, P < 0.0001, respectively). We concluded that, in cirrhotic patients, lower TLCO and increased PA-aO2 are associated with lower Vcap. In addition, high TLNO:TLCO ratios in patients with increased PA-aO2 suggest a decreased thickness of the capillary blood layer in these patients. [ABSTRACT FROM AUTHOR]

de Waard MC, van der Velden J, Boontje NM, Dekkers DH, van Haperen R, Kuster DW, Lamers JM, de Crbm R, Duncker Di. Detrimental effect of combined exercise training and eNOS overexpression on cardiac function after myocardial infarction. Am J Physiol Heart Circ Physiol 296: H 1513--HI 523, 2009; doi: 10.1152/ajpheart.00485.2008.-It has been reported that exercise after myocardial infarction (Ml) attenuates left ventriFular (LV) pump dysfunction by normalization of myofilament function. This benefit could be due to an exercise-induced upregulation of endothelial nitric oxide synthase (eNOS) expression and activity. Consequently, we first tested the hypothesis that the effects of exercise after MI can be mimicked by elevated eNOS expression using transgenic mice with overexpression of human eNOS (eNOSTg). Bosh exercise and eNOSTg attenuated LV remodeling and dysfunction after MI in mice and improved cardiomyocyte maximal force development F[submax]. However, only exercise training restored myofilament Ca[sup2+]-sensitivity and sarco(endo)plasmic reticulum Ca[sup2+]-ATPase (SERCA)2a protein levels and improved the first derivative of LV pressure at 30 mmHg. Conversely, only eNOSTg improved survival. In view of these partly complementary actions, we subsequently tested the hypothesis that combining exercise and eNOSTg would provide additional protection against LV remodeling and dysfunction after MI. Unexpectedly, the combination of exercise and eNOSTg abolished the beneficial effects on LV remodeling and dysfunction of either treatment alone. The latter was likely due to perturbations in Ca[sup2+] homeostasis, as myofilament F[submax] actually increased despite marked reductions in the phosphorylation status of several myofilament proteins, whereas the exercise-induced increases in SERCA2a protein levels were lost in eNOSTg mice. Antioxidant treatment with N-acetylcysteine or supplementation of tetrahydrobiopterin and L-arginine presented these detrimental effects on LV function while partly restoring the phosphorylation status of myofilament proteins and further enhancing myofilament F[submax] .In conclusion, the combination of exercise and elevated eNOS expression abolished the cardioprotective effects of either treatment alone after Ml, which appeared to be, at least in part, the result of increased oxidative stress secondary to eNOS "uncoupling." [ABSTRACT FROM AUTHOR]

Reactive species of oxygen and nitrogen have been collectively implicated in pulmonary oxygen toxicity, but the contributions of specific molecules are unknown. Therefore, we assessed the roles of several reactive species, particularly nitric oxide, in pulmonary injury by exposing wild-type mice and seven groups of genetically altered mice to >98% 02 at 1, 3, or 4 atmospheres absolute. Genetically altered animals included knockouts lacking either neuronal nitric oxide synthase (nN0S1), endothelial nitric oxide synthase (eN0S1), inducible nitric oxide synthase (iNOS1), extracellular superoxide dismutase (SOD31), or glutathione peroxidase 1 (GPx11 as well as two transgenic variants (S1179A and S1179D) having altered eNOS activities. We confirmed our earlier finding that normobaric hyperoxia (NBO2) and hyperbaric hyperoxia (HBO2) result in at least two distinct but overlapping patterns of pulmonary injury. Our new findings are that the role of nitric oxide in the pulmonary pathophysiology of hyperoxia depends both on the specific NOS isozyme that is its source and on the level of hyperoxia. Thus, iNOS predominates in the etiology of lung injury in NBO2, and SOD3 provides an important defense. But in HBO2, nNOS is a major contributor to pulmonary injury, whereas eNOS is protective. In addition, we demonstrated that nitric oxide derived from nNOS is involved in a neurogenic mechanism of HBO2-induced lung injury that is linked to central nervous system oxygen toxicity through adrenergic/cholinergic pathways. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PHT) in neonates is often refractory to the current best therapy, inhaled nitric oxide (NO). The utility of a new class of pulmonary vasodilators, Rho-kinase (ROCK) inhibitors, has not been examined in neonatal animals. Our objective was to examine the activity and expression of RhoA/ROCK in normal and injured pulmonary arteries and to determine the short-term pulmonary hemodynamic (assessed by pulse wave Doppler) effects of ROCK inhibitors (15 mg·kg-1 ip Y-27632 or 30 mg/kg ip fasudil) in two neonatal rat models of chronic PHT with pulmonary vascular remodeling (chronic hypoxia, 0.13 FIO2, or 1 mg·kg-1·day-1 ip chronic bleomycin for 14 days from birth). Activity of the RhoA/ROCK pathway and ROCK expression were increased in hypoxia- and bleomycin-induced PHT. In both models, severe PHT [characterized by raised pulmonary vascular resistance (PVR) and impaired right ventricular (RV) performance] did not respond acutely to inhaled NO (20 ppm for 15 mm) or to a single bolus of a NO donor, 3-morpholinosydnonimine hydrochloride (SIN-I; 2 µg/kg ip). In contrast, a single intraperitoneal bolus of either ROCK inhibitor (Y-27632 or fasudil) completely normalized PVR but had no acute effect on RV performance. ROCK-mediated vasoconstriction appears to play a key role in chronic PHT in our two neonatal rat models. Inhibitors of ROCK have potential as a testable therapy in neonates with PHT that is refractory to NO. [ABSTRACT FROM AUTHOR]

Examines the effect of nitric oxide (NO) on gastric wound healing. Analysis of cell migration, proliferation and apoptosis speed on the cell culture; Evaluation of the NO dual regulatory function during apoptosis; Inhibition of cell migration using NO.

Examines the reduction of hepatocellular injury by the scavenging nitric oxide (NO) after endotoxin challenge. Upregulation of NO in the liver; Assessment of injury with biochemical assays, light and transmission electron microscopy; Reduction of hepatocellular injury by the scavenging NO.

Investigates the enhancement of nitric oxide (NO)-mediated protection against vascular leakage by zaprinast, a phosphodiesterase inhibitor in reperfused lungs of the rabbit. Coadministration of nitric oxide and zaprinast; Elevation of pulmonary arterial pressure; Amplification of the beneficial effect of the NO-cyclic guanylic acid axis.

Determines the protective roles of nitric oxide (NO) and testosterone in endotoxemia. Physiological effects of NO; Responses of NO to inflammatory mediators; Inhibition of NO production.

Focuses on the role of nitric oxide (NO) in the inflammatory process. Detrimental effects of NO; Mechanism of enhancement of neutrophil migration; Regulation of adhesion molecule gene expression.

Determines whether vasodilator doses of inhaled nitric oxide (NO) prevented the progression of pulmonary hypertension (PH) and vascular changes in monocrotaline-induced PH. Reduction in mean arterial pressure with short-term NO inhalation in rats three weeks after monocrotaline administration; Comparison of rats exposed to air and rats exposed to NO.

The article examines caveolin-1 (cav-1) as a critical regulator of pulmonary vascular architecture and the bioavailability of nitric oxide in pulmonary hypertension. Mice are used as the laboratory animal. The growth of pulmonary hypertension in cav-1 animals happened despite the increased vascular NO production. It concludes that the increased NO production in cav-1 mice can provide a counter-regulatory mechanism and that the caveolin-1 plays an antihypertensive and homeostatic function.

The author discusses a report published within the issue on nitric oxide (NO) therapy for glaucoma by J. Y. Chang. Topics discussed include physiological role of NO and its pathophysiological loss in disease models, role of nitric oxide in murine conventional outflow physiology, and potential translational aspect of NO therapy.