nitroarginine and Pulmonary-Edema

Nitric oxide (NO) regulation of endothelial function is involved in the development of acute lung injury. The role of NO in contrast media-induced increases in pulmonary vascular permeability was investigated in a rat model.. Nonionic (iohexol) and ionic (ioxaglate) contrast media were intravenously injected at 1.5 mL/min in rats. Pulmonary vascular permeability was evaluated by measuring the amount of Evans blue dye uptake as a quantitative marker of albumin extravasation in lung tissue.. Intravenous injections of contrast media at doses of 4 and 6 g I/kg induced a dose-dependent increase in pulmonary vascular permeability. L-Arginine (an NO synthase substrate) and N(G)-nitro-L-arginine (L-NNA) (an NO synthase inhibitor) prevented and aggravated, respectively, the increase in pulmonary vascular permeability induced by the contrast medium. An aggravating action of L-NNA was confirmed by morphological and histological observations, this action being blocked by L-arginine (300 mg/kg) but not by D-arginine. Isosorbide dinitrate (1-20 mg/kg), an NO donor, had a dose-dependent protective effect on ioxaglate-increased vascular permeability.. Our experimental findings suggest that contrast media at high doses produce pulmonary edema by inhibiting endothelial NO production, and nitrovasodilators protect against this adverse effect in rats.

Topics: Animals; Arginine; Capillary Permeability; Contrast Media; Enzyme Inhibitors; Injections, Intravenous; Iohexol; Ioxaglic Acid; Isosorbide Dinitrate; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Vasodilator Agents

Nitric Oxide's (NO) function in vasomotor control, inflammation, and signal transduction makes it an attractive potential mediator of the capillary leak seen in acute lung injury. Despite extensive study, the role of NO in intestinal ischemia/reperfusion-induced capillary leak remains controversial. Rats were treated with vehicle, norepinephrine, or L-NNA (nitric oxide synthase inhibitor) and then underwent sham laparotomy or 30 min SMA occlusion followed by 1 to 12 h of reperfusion. Evan's Blue dye was administered 1 h before animals were euthanized. Ratios of bronchoalveolar lavage or small-intestine lavage to serum dye concentrations were calculated as measures of capillary leak. Circulating neutrophil activation was measured with a nitroblue tetrazolium reduction assay. In vehicle-treated animals, both capillary leakage and PMN activation peaked at 4 h of reperfusion. These parameters returned to baseline by 12 h. Treatment with L-NNA accelerated ischemia/reperfusion-induced PMN activation as well as accelerated capillary leak from 4 to 1 h. Treatment with norepinephrine (hypertensive control) increased the magnitude of lung capillary leak but had no effect on the timing of ischemia/reperfusion-induced PMN activation or ischemia/reperfusion-induced capillary leak. These data show that intestinal ischemia/reperfusion-induced systemic capillary leak is associated with systemic neutrophil activation. Nitric oxide synthase inhibition accelerates ischemia/reperfusion-induced capillary leak and mediates the capillary leak seen in acute lung injury by modulating neutrophil activation.

Topics: Acute Disease; Animals; Bronchoalveolar Lavage Fluid; Capillaries; Enzyme Inhibitors; Male; Neutrophil Activation; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Norepinephrine; Pulmonary Circulation; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Respiratory Distress Syndrome; Vasoconstrictor Agents

Excitatory amino acid toxicity, resulting from overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors, is a major mechanism of neuronal cell death in acute and chronic neurological diseases. We have investigated whether excitotoxicity may occur in peripheral organs, causing tissue injury, and report that NMDA receptor activation in perfused, ventilated rat lungs triggered acute injury, marked by increased pressures needed to ventilate and perfuse the lung, and by high-permeability edema. The injury was prevented by competitive NMDA receptor antagonists or by channel-blocker MK-801, and was reduced in the presence of Mg2+. As with NMDA toxicity to central neurons, the lung injury was nitric oxide (NO) dependent: it required L-arginine, was associated with increased production of NO, and was attenuated by either of two NO synthase inhibitors. The neuropeptide vasoactive intestinal peptide and inhibitors of poly(ADP-ribose) polymerase also prevented this injury, but without inhibiting NO synthesis, both acting by inhibiting a toxic action of NO that is critical to tissue injury. The findings indicate that: (i) NMDA receptors exist in the lung (and probably elsewhere outside the central nervous system), (ii) excessive activation of these receptors may provoke acute edematous lung injury as seen in the "adult respiratory distress syndrome," and (iii) this injury can be modulated by blockade of one of three critical steps: NMDA receptor binding, inhibition of NO synthesis, or activation of poly(ADP-ribose) polymerase.

Topics: Animals; Arginine; Benzamides; Cyclic GMP; Enzyme Inhibitors; In Vitro Techniques; Lung; Lung Injury; Magnesium; Male; Models, Biological; N-Methylaspartate; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Perfusion; Poly(ADP-ribose) Polymerase Inhibitors; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Vasoactive Intestinal Peptide

The modulatory role of endogenous nitric oxide (NO) on pulmonary edema induced by acetylcholine (ACh), capsaicin, substance P (SP) and 5-hydroxytryptamine (5-HT) was investigated by using an inhibitor of NO synthase, N-omega-nitro-L-arginine (L-NNA). The effects of endogenous NO on the hemodynamic response to ACh, 5-HT and SP were also investigated. The capillary filtration coefficient (Kf,c), the total pressure gradient (delta Pt) and its four components [arterial (delta Pa), pre- (delta Pa') and post-capillary (delta Pv'), and venous gradient (delta Pv)] were evaluated on isolated, ventilated, perfused rabbit lungs. ACh (10(-8) to 10(-4) M) and SP (10(-10) to 10(-6) M) induced a concentration-dependent increase in the Kf,c. Capsaicin (10(-4) M) and 5-HT (10(-4) M) also increased this parameter. L-NNA (10(-4) M) completely inhibited the effects of ACh and capsaicin on the Kf,c, without preventing the effects of SP and 5-HT. ACh induced a concentration-dependent vasoconstriction in the precapillary segment. Pretreatment with L-NNA enhanced this increase in delta Pa' but also increased delta Pv' and delta Pv. 5-HT increased delta Pt and delta Pa proportionally to the concentration. This effect was enhanced by L-NNA, which also increased delta Pa'. SP had no significant hemodynamic effect. Pretreatment with L-NNA did not modify the response to SP. Sodium nitroprusside (10(-5) M) induced a left shift of the concentration-response curve to ACh on the Kf,c, although it did not change the response to SP. Sodium nitroprusside also inhibited the hemodynamic effect of ACh. It was concluded that endogenous NO is involved in ACh-and capsaicin-induced edema via a prejunctional stimulatory effect on the C-fibers. Endogenous NO can also modulate ACh- and 5-HT-induced vasoconstriction by exerting a vasodilator action on the whole pulmonary vascular bed.

Topics: Acetylcholine; Animals; Arginine; Dose-Response Relationship, Drug; Female; Male; Nitric Oxide; Nitroarginine; Nitroprusside; Perfusion; Pulmonary Circulation; Pulmonary Edema; Rabbits; Substance P; Vasoconstriction

This study was undertaken to determine whether endothelium-derived relaxing factor (EDRF) modulates the pulmonary and systemic hemodynamic responses to massive sympathetic nervous system (SNS) activation and, in so doing, also modulates the degree of SNS-induced left ventricular (LV) dysfunction and the likelihood for pulmonary edema formation. The SNS of 13 anesthetized untreated rabbits and 14 anesthetized rabbits pretreated with the EDRF inhibitor, N omega-nitro-L-arginine (L-NNA, 20 mg/kg), was massively activated with an intracisternal injection of veratrine. Pulmonary and systemic arterial pressures increased to the same extent in both groups, but LV end-diastolic pressure was significantly lower in untreated rabbits. During this time, cardiac output decreased by 37% in L-NNA pretreated rabbits compared with 8% in untreated animals. Peak systemic and pulmonary vascular resistances increased significantly in L-NNA rabbits, whereas only systemic vascular resistance increased significantly in untreated rabbits. However, this increase in systemic vascular resistance was threefold less than that observed for L-NNA-treated animals. Although the degree of LV dysfunction was greater in the L-NNA rabbits, pulmonary edema developed less frequently in this group. We suggest that when EDRF release is inhibited during massive SNS activity, pulmonary vascular resistance increases markedly, which causes the right ventricle to fail. We further suggest that the reduced right ventricular output maintains pulmonary microvascular pressure below levels required for edema development.

Topics: Animals; Arginine; Epinephrine; Extravascular Lung Water; Hemodynamics; In Vitro Techniques; Nitric Oxide; Nitroarginine; Norepinephrine; Pulmonary Circulation; Pulmonary Edema; Rabbits; Sympathetic Nervous System; Ventricular Dysfunction, Left; Ventricular Function, Right; Veratrine