Involvement of nitric oxide pathways in neurogenic pulmonary edema induced by vagotomy

Abstract

OBJECTIVE: The objective of this study was to evaluate the involvement of peripheral nitric oxide (NO) in vagotomy-induced pulmonary edema by verifying whether the nitric oxide synthases (NOS), constitutive (cNOS) and inducible (iNOS), participate in this mechanism. INTRODUCTION: It has been proposed that vagotomy induces neurogenic pulmonary edema or intensifies the edema of other etiologies. METHODS: Control and vagotomized rats were pretreated with 0.3 mg/kg, 3.0 mg/kg or 39.0 mg/kg of L-NAME, or with 5.0 mg/kg, 10.0 mg/kg or 20.0 mg/kg of aminoguanidine. All animals were observed for 120 minutes. After the animals' death, the trachea was catheterized in order to observe tracheal fluid and to classify the severity of pulmonary edema. The lungs were removed and weighed to evaluate pulmonary weight gain and edema index. RESULTS: Vagotomy promoted pulmonary edema as edema was significantly higher than in the control. This effect was modified by treatment with L-NAME. The highest dose, 39.0 mg/kg, reduced the edema and prolonged the survival of the animals, while at the lowest dose, 0.3 mg/kg, the edema and reduced survival rates were maintained. Aminoguanidine, regardless of the dose inhibited the development of the edema. Its effect was similar to that observed when the highest dose of L-NAME was administered. It may be that the non-selective blockade of cNOS by the highest dose of L-NAME also inhibited the iNOS pathway. CONCLUSION: Our data suggest that iNOS could be directly involved in pulmonary edema induced by vagotomy and cNOS appears to participate as a protector mechanism.

Pulmonary Weight; Nitric oxide synthase; L-NAME; Aminoguanidine; Edema Index


BASIC RESEARCH

IPhysiological Sciences, Universidade Estadual de Londrina, Campus Universitário Londrina, Londrina, Paraná, Brazil

IIFederal University of São Paulo (UNIFESP), São Paulo/SP, Brazil

IIIUniversity of São Paulo (USP), Ribeirão Preto/SP, Brazil

ABSTRACT

OBJECTIVE: The objective of this study was to evaluate the involvement of peripheral nitric oxide (NO) in vagotomy-induced pulmonary edema by verifying whether the nitric oxide synthases (NOS), constitutive (cNOS) and inducible (iNOS), participate in this mechanism.

INTRODUCTION: It has been proposed that vagotomy induces neurogenic pulmonary edema or intensifies the edema of other etiologies.

METHODS: Control and vagotomized rats were pretreated with 0.3 mg/kg, 3.0 mg/kg or 39.0 mg/kg of L-NAME, or with 5.0 mg/kg, 10.0 mg/kg or 20.0 mg/kg of aminoguanidine. All animals were observed for 120 minutes. After the animals' death, the trachea was catheterized in order to observe tracheal fluid and to classify the severity of pulmonary edema. The lungs were removed and weighed to evaluate pulmonary weight gain and edema index.

RESULTS: Vagotomy promoted pulmonary edema as edema was significantly higher than in the control. This effect was modified by treatment with L-NAME. The highest dose, 39.0 mg/kg, reduced the edema and prolonged the survival of the animals, while at the lowest dose, 0.3 mg/kg, the edema and reduced survival rates were maintained. Aminoguanidine, regardless of the dose inhibited the development of the edema. Its effect was similar to that observed when the highest dose of L-NAME was administered. It may be that the non-selective blockade of cNOS by the highest dose of L-NAME also inhibited the iNOS pathway.

CONCLUSION: Our data suggest that iNOS could be directly involved in pulmonary edema induced by vagotomy and cNOS appears to participate as a protector mechanism.

Keywords: Pulmonary Weight; Nitric oxide synthase; L-NAME; Aminoguanidine; Edema Index.

INTRODUCTION

Neurogenic pulmonary edema (NPE) is a fatal complication of severe insults to the central nervous system.1, It is proposed that neurogenic pulmonary edema is a functional disturbance provoked by adverse stimuli from outside the lungs and that in the rat, the pulmonary afferent fiber is essential to the production of this edema.3 Autonomic nervous dysfunction, possibly sympathetic nerve over-excitation or vagus nerve dysfunction by vagotomy or by lesion of vagal nuclei in the medulla, has been show to induce NPE.2 Studies involving NPE by intracisternal injection of fibrinogen and thrombin have indicated that bilateral vagotomy or the treatment with atropine increased the severity of the edema.4 Vagotomy increases the amount of edema for a given degree of pulmonary hypertension.5 Vagotomy-induced pulmonary edema has been discussed as neurogenic pulmonary edema. The lungs of vagotomized rats showed alveolar edema.6 Blood volume and hematocrit reading became considerably reduced during the development of acute pulmonary edema caused by bilateral cervical vagotomy, depending on whether pulmonary hemorrhage occurs as a complication of the edema and congestion.7

Since 1966, it has been proposed that bilateral interruption of afferent impulses of the tenth cranial nerve is the factor that initiates vagotomy-induced lung edema.8 A subsequent observation concluded that vagal capsaicin-sensitive nerves wielded an inhibitory effect on the development of fibrin injection into the cisterna magna-induced pulmonary edema.9 It was proposed that an unknown neurotransmitter released from capsaicin-sensitive nerves may participate in increasing the lung vascular permeability caused by sympathetic nerve stimulation and that norepinephrine may also play a role in the regulation of permeability through alpha- and beta-adrenoceptors.10

It has been recognized that the main site of nitric oxide (NO) production in the circulatory system is in the lungs.11 NO is produced by a group of enzymes known as nitric oxide synthases (NOS). These enzymes convert L-arginine into NO and L-citruline. Three isoforms of NOS have been identified, including two constitutive forms: neuronal (nNOS) and endothelial (eNOS), and an inducible form (iNOS). NO is a potent vasodilator in bronchial circulation and may play an important role in regulating airway blood flow. It also modulates vascular tone through its vasodilatory properties. Excess amounts of NO may cause hypotension associated with sepsis, and decreased NO levels within the lungs may contribute to the pathologic states associated with pulmonary hypertension. NO may also play a critical role in ventilation-perfusion coupling in the lung. This theory is supported by the fact that endogenous NO levels in the lung change rapidly in direct proportion to inspired oxygen.12

NO has been related to pulmonary edema of various etiologies. Pulmonary exhaled NO was lower in mountaineers prone to high-altitude pulmonary edema than in those resistant to this condition.13,14 Reduced exhaled NO may be as a result of altered pulmonary NO synthesis and/or transport and clearance, in line with the hypothesis that, in these subjects,