Endothelin Mediates Increased Pulmonary Vascular Tone in Patients With Heart Failure

Abstract

Background-In patients with chronic heart failure (HF), the pulmonary circulation is a major source of endothelin-1 (ET), and ET levels correlate with pulmonary vascular resistance (PVR). The role of ET in causing pulmonary vasoconstriction in HF is not known, however, in part because of the confounding effects of ET receptor antagonists on systemic hemodynamics. Methods and Results-To directly test the hypothesis that ET causes pulmonary vasoconstriction in patients with HF, we infused the selective ET A receptor antagonist sitaxsentan at increasing rates (0.3125 to 10 mg/min) into a left lower-lobe segmental pulmonary artery in 8 patients with left ventricular (LV) systolic failure (LV ejection fraction, 24Ϯ4%) and 4 control subjects with normal LV function. Changes in local PVR distal to the infusion site were assessed by measuring the change in pulmonary blood flow velocity with a Doppler-tipped wire and the mean pulmonary artery pressure (MPAP). Total PVR at baseline was elevated in HF patients (177Ϯ23 dyne · s · cm Ϫ5 ) versus controls (89Ϯ21 dyne · s · cm Ϫ5; PϽ0.05). In patients with HF, sitaxsentan caused an infusion rate-dependent decrease in local PVR (PϽ0.05 versus baseline; PϽ0.05 versus controls). In contrast, sitaxsentan infusion had no effect on local PVR in controls. Heart rate, mean arterial pressure, cardiac index, and MPAP were not affected by sitaxsentan in either group. Key Words: endothelin Ⅲ heart failure Ⅲ hypertension, pulmonary S econdary reactive pulmonary hypertension is frequent in patients with left ventricular systolic failure. 1 In such patients, plasma endothelin-1 (ET) is elevated and correlates with survival. 2 The pulmonary circulation is a major source of ET in heart failure (HF), and pulmonary ET spillover correlates strongly with pulmonary vascular resistance (PVR), 3 leading to the suggestion that ET contributes to secondary pulmonary hypertension in patients with chronic HF. 1,4 In vitro, ET is a potent constrictor in pulmonary resistance vessels. Stimulation of ET A receptors uniformly causes constriction, whereas stimulation of ET B receptors may cause either constriction or dilation, the latter reflecting the release of nitric oxide. 5 The contribution of ET to secondary pulmonary hypertension in patients with HF is not known, in part because of the difficulty of assessing pulmonary vascular reactivity in the presence of confounding changes in systemic hemodynamics. Conclusion-SelectiveSitaxsentan is a nonpeptide, high-affinity competitive antagonist that is 6000-fold selective for the human ET A (versus ET B ) receptor. 6 We previously found that short-term systemic administration of sitaxsentan caused a greater decrease in pulmonary versus systemic vascular tone in patients with moderate to severe HF, suggesting that ET plays a role in mediating pulmonary hypertension in such patients. 7 To directly test this hypothesis, sitaxsentan was infused into a segmental pulmonary artery, and the effect on pulmonary arterial tone was assessed by measuring the change in local ...

Endothelial Dysfunction and Lung Capillary Injury in Cardiovascular Diseases

“…In the pulmonary circulation, the endothelium-mediated local control of vasomotility is primarily based on a balanced release of nitric oxide (NO) and ET-1 with the evidence suggesting that raised pulmonary pressure owing to left-sided heart disease is critically sensitive to an imbalance of these two opposing systems 29,30 .…”

Pulmonary hypertension in left heart disease

“…In addition, persistently increased pulmonary venous pressure (and consequent passive increase of Ppa) may lead to pathological changes in the pulmonary veins and arteries, including muscularisation of the arterioles, medial hypertrophy and neointima formation of distal pulmonary arteries [15], leading to the increase of pulmonary vascular resistance (PVR). In addition to structural changes in the pulmonary vessels, endothelial damage may lead to dysfunction and an imbalance in the production of vasoactive mediators such as nitric oxide (NO) and endothelin (ET)-1 resulting in impaired vascular smooth muscle relaxation [16,17]. The importance of NO in pulmonary vascular tone in patients with heart failure has been shown using infusions of NG-mono-methyl-L-arginine, an inhibitor of NO production, which results in a lower degree of dose-dependent vasoconstriction in heart failure patients with elevated PVR index (PVRI) compared with those with normal PVRI or healthy individuals [16].…”

Hepatopulmonary syndrome in pediatric patients (clinical presentation)

“…При портальной ги-пертензии имеет место транслокация грамнегатив-ных бактерий и эндотоксинов, что ведет к активации высвобождения медиаторов воспаления -фактора некроза опухоли и оксида азота, которые проявляют свои вазоактивные свойства [11,12]. Прогрессиро-ванию гепатопульмонального синдрома способству-ет также система эндотелина-1 [13]. Повышенная экспрессия эндотелинового рецептора типа В на по-верхности эндотелиальных клеток ассоциирована с усиленной выработкой оксида азота [11].…”

“…В результате развивается нару-шение оксигенации крови и дыхательная недоста-точность [14,15]. Характерными клиническими симптомами ге-патопульмонального синдрома являются одышка, усиливающаяся в вертикальном положении, и ци-аноз [13,14,16]. Нарастание одышки при переходе из горизонтального положения в вертикальное носит название платипноэ.…”

“…При тяжелом гепатопульмональном синдроме имеют место телеангиэктазии, изменения дистальных фаланг пальцев по типу «барабанных палочек», цианоз губ и ногтевых лож. У некоторых больных могут развиваться такие внелегочные ос-ложнения, как полицитемия и внутричерепные кро-воизлияния [13,16].…”