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...

Plasma nitric oxide in dogs with pulmonary hypertension secondary or not to left-sided heart disease

“…That is, left cardiac remodeling and PH should be present in these dogs. Maybe, to MMVD, initially there may be endothelial dysfunction with a reduction in NO by eNOS (Le Corvoisier et al, 2000;Dias-Junior et al, 2008) and subsequently, by the activation of inflammatory factors and iNOS activity, NO increases (Belder et al, 1993). This could explain why our results presented higher nitrite and nitrate values in dogs with PH secondary to MMVD and lower in dogs with PH not secondary to MMVD, since in this last group the left cardiac remodeling was not present.…”

“…We did not measure NOS, but due to the known inflammatory character of the underlying diseases, both MMVD and respiratory diseases could have a potential to induce iNOS activity (Belder et al, 1993). It has already been demonstrated in chronic CHF in humans that there is a negative regulation of eNOS, which decreases the bioavailability of NO and justifies changes in the endothelium, since eNOS is mainly expressed in the blood vessels endothelial cells (Le Corvoisier et al, 2000;Dias-Junior et al, 2008). Furthermore, cytokines stimulate iNOS, an enzyme that is also found in alveolar macrophages and has expression regulated by inflammatory mediators, that is, it is proinflammatory (Belder et al, 1993;Macdonald et al, 1996).…”

Plasma nitric oxide in dogs with pulmonary hypertension secondary or not to left-sided heart disease

“…That is, left cardiac remodeling and PH should be present in these dogs. Maybe, to MMVD, initially there may be endothelial dysfunction with a reduction in NO by eNOS (Le Corvoisier et al, 2000;Dias-Junior et al, 2008) and subsequently, by the activation of inflammatory factors and iNOS activity, NO increases (Belder et al, 1993). This could explain why our results presented higher nitrite and nitrate values in dogs with PH secondary to MMVD and lower in dogs with PH not secondary to MMVD, since in this last group the left cardiac remodeling was not present.…”

“…We did not measure NOS, but due to the known inflammatory character of the underlying diseases, both MMVD and respiratory diseases could have a potential to induce iNOS activity (Belder et al, 1993). It has already been demonstrated in chronic CHF in humans that there is a negative regulation of eNOS, which decreases the bioavailability of NO and justifies changes in the endothelium, since eNOS is mainly expressed in the blood vessels endothelial cells (Le Corvoisier et al, 2000;Dias-Junior et al, 2008). Furthermore, cytokines stimulate iNOS, an enzyme that is also found in alveolar macrophages and has expression regulated by inflammatory mediators, that is, it is proinflammatory (Belder et al, 1993;Macdonald et al, 1996).…”

Pulmonary hypertension associated with cardiopulmonary bypass and cardiac surgery

“…NO is a vasodilator which manages vascular tone, plays a role in platelet aggregation, intracellular killing, and inflammation, and prevents the rapid growth of VSMCs 67,83,84 . The mechanism for which NO promotes vasodilation begins with NO activating sGC which produces intracellular cGMP 83 .…”

RC-3095, a Selective Gastrin-Releasing Peptide Receptor Antagonist, Does Not Protect the Lungs in an Experimental Model of Lung Ischemia-Reperfusion Injury

“…eNOS activity mainly observed in the cytoplasm of the endothelial layer of the lung tissue, with a similar distribution among all groups. This finding therefore demonstrates that this enzyme does not have any function in LIRI [ 26 ].…”

Plasma nitric oxide in dogs with pulmonary hypertension secondary or not to left-sided heart disease

“…That is, left cardiac remodeling and PH should be present in these dogs. Maybe, to MMVD, initially there may be endothelial dysfunction with a reduction in NO by eNOS (Le Corvoisier et al, 2000;Dias-Junior et al, 2008) and subsequently, by the activation of inflammatory factors and iNOS activity, NO increases (Belder et al, 1993). This could explain why our results presented higher nitrite and nitrate values in dogs with PH secondary to MMVD and lower in dogs with PH not secondary to MMVD, since in this last group the left cardiac remodeling was not present.…”

“…We did not measure NOS, but due to the known inflammatory character of the underlying diseases, both MMVD and respiratory diseases could have a potential to induce iNOS activity (Belder et al, 1993). It has already been demonstrated in chronic CHF in humans that there is a negative regulation of eNOS, which decreases the bioavailability of NO and justifies changes in the endothelium, since eNOS is mainly expressed in the blood vessels endothelial cells (Le Corvoisier et al, 2000;Dias-Junior et al, 2008). Furthermore, cytokines stimulate iNOS, an enzyme that is also found in alveolar macrophages and has expression regulated by inflammatory mediators, that is, it is proinflammatory (Belder et al, 1993;Macdonald et al, 1996).…”

Pulmonary hypertension associated with cardiopulmonary bypass and cardiac surgery

“…NO is a vasodilator which manages vascular tone, plays a role in platelet aggregation, intracellular killing, and inflammation, and prevents the rapid growth of VSMCs 67,83,84 . The mechanism for which NO promotes vasodilation begins with NO activating sGC which produces intracellular cGMP 83 .…”

RC-3095, a Selective Gastrin-Releasing Peptide Receptor Antagonist, Does Not Protect the Lungs in an Experimental Model of Lung Ischemia-Reperfusion Injury

“…eNOS activity mainly observed in the cytoplasm of the endothelial layer of the lung tissue, with a similar distribution among all groups. This finding therefore demonstrates that this enzyme does not have any function in LIRI [ 26 ].…”

Plasma nitric oxide in dogs with pulmonary hypertension secondary or not to left-sided heart disease

“…That is, left cardiac remodeling and PH should be present in these dogs. Maybe, to MMVD, initially there may be endothelial dysfunction with a reduction in NO by eNOS (Le Corvoisier et al, 2000;Dias-Junior et al, 2008) and subsequently, by the activation of inflammatory factors and iNOS activity, NO increases (Belder et al, 1993). This could explain why our results presented higher nitrite and nitrate values in dogs with PH secondary to MMVD and lower in dogs with PH not secondary to MMVD, since in this last group the left cardiac remodeling was not present.…”

“…We did not measure NOS, but due to the known inflammatory character of the underlying diseases, both MMVD and respiratory diseases could have a potential to induce iNOS activity (Belder et al, 1993). It has already been demonstrated in chronic CHF in humans that there is a negative regulation of eNOS, which decreases the bioavailability of NO and justifies changes in the endothelium, since eNOS is mainly expressed in the blood vessels endothelial cells (Le Corvoisier et al, 2000;Dias-Junior et al, 2008). Furthermore, cytokines stimulate iNOS, an enzyme that is also found in alveolar macrophages and has expression regulated by inflammatory mediators, that is, it is proinflammatory (Belder et al, 1993;Macdonald et al, 1996).…”

Pulmonary hypertension associated with cardiopulmonary bypass and cardiac surgery

“…NO is a vasodilator which manages vascular tone, plays a role in platelet aggregation, intracellular killing, and inflammation, and prevents the rapid growth of VSMCs 67,83,84 . The mechanism for which NO promotes vasodilation begins with NO activating sGC which produces intracellular cGMP 83 .…”

RC-3095, a Selective Gastrin-Releasing Peptide Receptor Antagonist, Does Not Protect the Lungs in an Experimental Model of Lung Ischemia-Reperfusion Injury

“…eNOS activity mainly observed in the cytoplasm of the endothelial layer of the lung tissue, with a similar distribution among all groups. This finding therefore demonstrates that this enzyme does not have any function in LIRI [ 26 ].…”