Papel do óxido nítrico na regulação da circulação pulmonar: implicações fisiológicas, fisiopatológicas e terapêuticas

Abstract

Nitric oxide (NO) is an endogenous vasoactive compound that contributes to pulmonary vascular homeostasis and is produced by three nitric oxide synthase (NOS) isoforms-neuronal NOS (nNOS); inducible NOS (iNOS); and endothelial NOS (eNOS)-all three of which are present in the lung. Studies using pharmacological inhibitors or knockout mice have shown that eNOS-derived NO plays an important role in modulating pulmonary vascular tone and attenuating pulmonary hypertension. However, studies focusing on the role of iNOS have shown that this isoform contributes to the pathophysiology of acute lung injury and acute respiratory distress syndrome. This review aimed at outlining the role played by NO in the control of the pulmonary circulation, both under physiological and pathophysiological conditions. In addition, we review the evidence that the L-arginine-NO-cyclic guanosine monophosphate pathway is a major pharmacological target in the treatment of pulmonary vascular diseases.Keywords: Nitric oxide; Arginine; Nitric oxide synthase; Cyclic GMP; Pulmonary circulation. ResumoO nitric oxide (NO, óxido nítrico) é um mediador endógeno vasoativo que contribui para a homeostase vascular pulmonar. O NO é produzido por três isoformas das nitric oxide synthases (NOS, óxido nítrico sintases)-NOS neuronial (nNOS); NOS induzida (iNOS); e NOS endotelial (eNOS)-estando as três presentes no pulmão. Estudos que utilizaram inibidores farmacológicos ou camundongos knockout têm demonstrado que o NO derivado da eNOS desempenha importantes papéis ao modular o tônus vascular pulmonar e atenuar a hipertensão pulmonar. Por outro lado, estudos focados no papel da iNOS têm mostrado que essa isoforma contribui para a fisiopatologia da lesão pulmonar aguda e da síndrome do desconforto respiratório agudo. Esta revisão objetivou delinear o papel desempenhado pelo NO no controle da circulação pulmonar, tanto em condições fisiológicas como fisiopatológicas. Além disso, revisamos as evidências de que a via L-arginina-NO-guanosina monofosfato cíclico seja um importante alvo farmacológico para a terapia de doenças vasculares pulmonares.Descritores: Óxido nítrico; Arginina; Óxido nítrico sintase; GMP cíclico; Circulação pulmonar. Discovery of NO and its synthesis in the lungsIn the late 1980s, Furchgott and Zawadzki proposed that the vascular smooth muscle relaxation in rabbit aorta was secondary to the release of a vasodilating substance by the endothelium. (6) Subsequently, they discovered that this vasodilating substance was NO. (7) Endogenous NO is formed from the amino acid L-arginine through a catalyzed reaction by the NOS family of enzymes, which convert L-arginine into NO and L-citrulline, requiring two cosubstrates: oxygen and reduced nicotinamide adenine dinucleotide.(1)The three known isoforms of NOS were identified in the lung, two of them being more intensely and constitutively expressed in neuron bodies (nNOS) or in the endothelial cells of pulmonary vessels (eNOS). An inducible isoform (iNOS) is found in alveolar macrophages, and it...

Change in Oxidative Stress Biomarkers During 30 Days in Saturation Dive: A Pilot Study

“…As widely reported, modifications in PO 2 (hyperoxia/hypoxia) can increase ROS accumulation in the whole body [ 7 , 13 , 14 , 34 , 35 , 36 ]. Additionally, NO has fundamental roles, especially in regulating peripheral [ 37 ] and pulmonary vascular tone [ 38 ]. However, NO can react with ROS to generate peroxynitrite (ONOO), adding another source of damage to cells [ 39 ].…”

Omentin protects against LPS-induced ARDS through suppressing pulmonary inflammation and promoting endothelial barrier via an Akt/eNOS-dependent mechanism

“…eNOS, which is downstream of Akt, acts as a crucial regulator of vascular growth and EC function. 46 , 47 Omentin has been reported to promote endothelium-dependent vasodilation in aorta isolated from rat and to reduce cytokine-induced inflammatory responses in cultured ECs; these effects were prevented by a NOS inhibitor. 29 , 31 Moreover, omentin promotes EC differentiation and survival by activating Akt/eNOS signaling in both ischemic muscles and cultured ECs.…”

Functional Changes in Pulmonary Arterial Endothelial Cells Associated with BMPR2 Mutations

“…NO, the primary pulmonary vasodilator, is both produced and released by the endothelium. The primary functions of NO are the regulation of vascular tone, inhibition of VSM cell proliferation, and platelet aggregation [40]. The imbalance between vasodilators and vasoconstrictors in the pulmonary circulation contributes to the narrowing of the pulmonary artery [39].…”