The active molecular form of plasma adrenomedullin is extracted in the pulmonary circulation in patients with mitral stenosis: possible role of adrenomedullin in pulmonary hypertension

Adrenomedullin (AM), a novel hypotensive peptide, preferentially dilates pulmonary vessels rather than systemic vessels. This suggests the possibility that AM is a circulating hormone which participates in regulation of the pulmonary circulation. A recent study revealed that two molecular forms of AM, i.e. a mature, active form of AM (AM-m) and an intermediate, inactive, glycine-extended form of AM (AM-Gly), circulate in human plasma. In the present study we investigated the production and clearance sites and pathophysiological significance of the two molecular forms of AM in the pulmonary circulation in patients with mitral stenosis. We measured the plasma levels of AM-m and total AM (AM-T; AM-m+AM-Gly) using a recently developed specific immunoradiometric assay, and thus calculated plasma AM-Gly levels, in blood samples obtained from the femoral vein, pulmonary artery, left atrium and aorta of 28 consecutive patients with mitral stenosis (20 females and eight males; age 53±10 years). Patients with mitral stenosis had significantly higher venous concentrations of AM-T, AM-Gly and AM-m than age-matched normal controls (AM-T, 15.9±2.5 and 10.6±2.1 pmol/l respectively; AM-Gly, 14.0±2.1 and 9.8±1.9 pmol/l respectively; AM-m, 1.9±0.6 and 1.1±0.3 pmol/l respectively; each P < 0.001). There was a significant decrease in the concentrations of AM-m and AM-T between the pulmonary artery and the left atrium (AM-T, 16.1±2.7 and 14.0±2.4 pmol/l respectively; AM-m, 2.0±0.6 and 0.7±0.2 pmol/l respectively; each P < 0.001); however, there were no differences in plasma AM-Gly levels between the pulmonary artery and the left atrium (14.1±2.3 and 13.5±2.3 pmol/l respectively). The venous concentrations of AM-m, AM-Gly and AM-T showed similar correlations with mean pulmonary artery pressure (AM-T, r = 0.67; AM-Gly, r = 0.63; AM-m, r = 0.59; each P < 0.001) and total pulmonary vascular resistance (AM-T, r = 0.77; AM-Gly, r = 0.70; AM-m, r = 0.75; each P < 0.001). These results suggest that the plasma concentration of AM-m is increased in parallel with those of AM-Gly and AM-T, and that the main site for clearance of AM-m from the plasma is the lung; the extracted AM-m in the lungs may help to attenuate the increased pulmonary arterial resistance in secondary pulmonary hypertension due to mitral stenosis.

Download Full-text

55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

Journal of Applied Physiology ◽

10.1152/japplphysiol.00843.2012 ◽

2012 ◽

Vol 113 (9) ◽

pp. 1343-1352 ◽

Cited By ~ 17

Author(s):

Larissa A. Shimoda

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Circulation ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Pulmonary Arterial ◽

Expression And Activity

When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension.

Download Full-text

Evaluation of the severity of mitral stenosis in patient with pulmonary hypertension: Role of exercise hemodynamics

Catheterization and Cardiovascular Interventions ◽

10.1002/ccd.28381 ◽

2019 ◽

Vol 94 (2) ◽

pp. 301-307

Author(s):

Morton J. Kern ◽

Min Kim ◽

Jeannie Yu ◽

Arnold H. Seto

Keyword(s):

Pulmonary Hypertension ◽

Mitral Stenosis ◽

Exercise Hemodynamics

Download Full-text

THE ROLE OF LEFT ATRIAL COMPLIANCE IN THE DEVELOPMENT OF PULMONARY HYPERTENSION IN PATIENTS WITH PURE MITRAL STENOSIS AND SINUS RHYTHM

Basrah Journal of Surgery ◽

10.33762/bsurg.2012.54969 ◽

2012 ◽

Vol 18 (1) ◽

pp. 26-32

Author(s):

Mazin Abd Haza ◽

Muhammed Hashim ◽

Tahsin A Al-Kinani

Keyword(s):

Pulmonary Hypertension ◽

Sinus Rhythm ◽

Mitral Stenosis ◽

Left Atrial

Download Full-text

Phenylalanine induces pulmonary hypertension through calcium-sensing receptor activation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00215.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. L1010-L1020

Author(s):

Rubin Tan ◽

Jiansha Li ◽

Fangbo Liu ◽

Pu Liao ◽

Matthieu Ruiz ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Artery ◽

Pulmonary Circulation ◽

Receptor Activation ◽

Mass Spectrometry Analysis ◽

Sprague Dawley ◽

Calcium Sensing Receptor ◽

Calcium Sensing ◽

Pathophysiological Role

Phenylalanine levels are associated with pulmonary hypertension in metabolic profiling clinical studies. However, the pathophysiological role of phenylalanine on pulmonary circulation is still unclear. We experimentally addressed the direct impact of phenylalanine on pulmonary circulation in rats and explored the underlying molecular pathway. Phenylalanine was injected intraperitoneally into Sprague-Dawley rats (400 mg/100 g body wt) as a single dose or daily in a chronic manner for 2, 3, and 4 wk. Chronic injection of phenylalanine induced pulmonary hypertension with time-dependent severity, evidenced by elevated pulmonary artery pressure and pulmonary vascular resistance as well as pulmonary artery and right ventricular hypertrophy. Using tandem mass spectrometry analysis, we found a quick twofold increase in blood level of phenylalanine 2 h following injection. This increase led to a significant accumulation of phenylalanine in lung after 4 h, which remained sustained at up to a threefold increase after 4 wk. In addition, a cellular thermal shift assay with lung tissues from phenylalanine-injected rats revealed the binding of phenylalanine to the calcium-sensing receptor (CaSR). In vitro experiments with cultured pulmonary arterial smooth muscle cells showed that phenylalanine activated CaSR, as indicated by an increase in intracellular calcium content, which was attenuated or diminished by the inhibition or knockdown of CaSR. Finally, the global knockout or lung-specific knockdown of CaSR significantly attenuated phenylalanine-induced pulmonary hypertension. Chronic phenylalanine injection induces pulmonary hypertension through binding to CaSR and its subsequent activation. Here, we demonstrate a pathophysiological role of phenylalanine in pulmonary hypertension through the CaSR. This study provides a novel animal model for pulmonary hypertension and reveals a potentially clinically significant role for this metabolite in human pulmonary hypertension as a marker, a mediator of disease, and a possible therapeutic target.

Download Full-text

Pulmonary Hypertension and Selective Pulmonary Vasodilators in Acute Lung Injury

Anaesthesia and Intensive Care ◽

10.1177/0310057x9802600104 ◽

1998 ◽

Vol 26 (1) ◽

pp. 26-39 ◽

Cited By ~ 2

Author(s):

D. Blythe ◽

P. V. Van Heerden ◽

B. M. Power

Keyword(s):

Pulmonary Hypertension ◽

Acute Lung Injury ◽

Lung Injury ◽

Pulmonary Circulation ◽

Management Options ◽

Injury Management ◽

Pulmonary Vasodilators ◽

The Common

The pulmonary circulation and the mechanisms which generate pulmonary hypertension are reviewed. The role of these mechanisms in the common pulmonary hypertensive states are analysed, particularly those in acute lung injury. Management options are discussed, with particular emphasis on the use of selective pulmonary vasodilators.

Download Full-text

Important role of endothelium-dependent hyperpolarization in the pulmonary microcirculation in male mice: implications for hypoxia-induced pulmonary hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00487.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. H940-H953 ◽

Cited By ~ 5

Author(s):

Shuhei Tanaka ◽

Takashi Shiroto ◽

Shigeo Godo ◽

Hiroki Saito ◽

Yosuke Ikumi ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Pulmonary Circulation ◽

Nitrosative Stress ◽

Chronic Hypoxia ◽

Systemic Circulation ◽

Physiological Conditions ◽

Pulmonary Microcirculation ◽

Endothelium Dependent Relaxation

Endothelium-dependent hyperpolarization (EDH) plays important roles in the systemic circulation, whereas its role in the pulmonary circulation remains largely unknown. Furthermore, the underlying mechanisms of pulmonary hypertension (PH) also remain to be elucidated. We thus aimed to elucidate the role of EDH in pulmonary circulation in general and in PH in particular. In isolated perfused lung and using male wild-type mice, endothelium-dependent relaxation to bradykinin (BK) was significantly reduced in the presence of Nω-nitro-l-arginine by ~50% compared with those in the presence of indomethacin, and the combination of apamin plus charybdotoxin abolished the residual relaxation, showing the comparable contributions of nitric oxide (NO) and EDH in the pulmonary microcirculation under physiological conditions. Catalase markedly inhibited EDH-mediated relaxation, indicating the predominant contribution of endothelium-derived H2O2. BK-mediated relaxation was significantly reduced at day 1 of hypoxia, whereas it thereafter remained unchanged until day 28. EDH-mediated relaxation was diminished at day 2 of hypoxia, indicating a transition from EDH to NO in BK-mediated relaxation before the development of hypoxia-induced PH. Mechanistically, chronic hypoxia enhanced endothelial NO synthase expression and activity associated with downregulation of caveolin-1. Nitrotyrosine levels were significantly higher in vascular smooth muscle of pulmonary microvessels under chronic hypoxia than under normoxia. A similar transition of the mediators in BK-mediated relaxation was also noted in the Sugen hypoxia mouse model. These results indicate that EDH plays important roles in the pulmonary microcirculation in addition to NO under normoxic conditions and that impaired EDH-mediated relaxation and subsequent nitrosative stress may be potential triggers of the onset of PH. NEW & NOTEWORTHY This study provides novel evidence that both endothelium-dependent hyperpolarization and nitric oxide play important roles in endothelium-dependent relaxation in the pulmonary microcirculation under physiological conditions in mice and that hypoxia first impairs endothelium-dependent hyperpolarization-mediated relaxation, with compensatory upregulation of nitric oxide, before the development of hypoxia-induced pulmonary hypertension.

Download Full-text