The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice

2009 ◽  
Vol 297 (4) ◽  
pp. L658-L665 ◽  
Author(s):  
Norbert Weissmann ◽  
Sascha Hackemack ◽  
Bhola Kumar Dahal ◽  
Soni Savai Pullamsetti ◽  
Rajkumar Savai ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Guanylate Cyclase ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Soluble Guanylate Cyclase ◽  
Pressor Response ◽  
Acute Hypoxia ◽  
Heart Hypertrophy ◽  
Right Heart ◽  
Pulmonary Vascular Remodeling

Severe pulmonary hypertension (PH) is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right heart hypertrophy. In mice with PH induced by chronic hypoxia, we examined the acute and chronic effects of the soluble guanylate cyclase (sGC) activator HMR1766 on hemodynamics and pulmonary vascular remodeling. In isolated perfused mouse lungs from control animals, HMR1766 dose-dependently inhibited the pressor response of acute hypoxia. This dose-response curve was shifted leftward when the effects of HMR1766 were investigated in isolated lungs from chronic hypoxic animals for 21 days at 10% oxygen. Mice exposed for 21 or 35 days to chronic hypoxia developed PH, right heart hypertrophy, and pulmonary vascular remodeling. Treatment with HMR1766 (10 mg·kg−1·day−1), after full establishment of PH from day 21 to day 35, significantly reduced PH, as measured continuously by telemetry. In addition, right ventricular (RV) hypertrophy and structural remodeling of the lung vasculature were reduced. Pharmacological activation of oxidized sGC partially reverses hemodynamic and structural changes in chronic hypoxia-induced experimental PH.

Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats

1995 ◽  
Vol 79 (6) ◽  
pp. 2122-2131 ◽  
Author(s):  
S. J. Chen ◽  
Y. F. Chen ◽  
Q. C. Meng ◽  
J. Durand ◽  
V. S. Dicarlo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Acute Hypoxia ◽  
Subsequent Development ◽  
Hypoxic Exposure ◽  
Heart Hypertrophy ◽  
Endothelin Receptor ◽  
Right Heart ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Pulmonary Hypertension

The current study examined the effects of bosentan, an orally active antagonist of endothelin-A and -B receptors, on the development and maintenance of hypoxia (10% O2)-induced pulmonary hypertension and vascular remodeling in the rat. Pretreatment with bosentan (100 mg.kg-1.day-1, 1 gavage/day for 2 days) completely blocked the pulmonary vasoconstrictor response to acute hypoxia. Chronic bosentan treatment (100 mg.kg-1.day-1 po in the food) instituted 48 h before hypoxic exposure prevented the subsequent development of pulmonary hypertension, attenuated the associated right heart hypertrophy, and prevented the remodeling of small (50–100 microns) pulmonary arteries without altering systemic arterial pressure. Institution of bosentan treatment (for 4 wk) after 2 wk of hypoxia produced a significant reversal of established hypoxia-induced pulmonary hypertension (from 36 +/- 1 to 25 +/- 1 mmHg), right heart hypertrophy, and pulmonary vascular remodeling despite continuing hypoxic exposure. These findings support the hypothesis that endogenous endothelin-1 plays a major role in hypoxic pulmonary vasoconstriction and/or hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that endothelin-receptor blockade may be useful in the treatment of hypoxic pulmonary hypertension humans.

PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats

1992 ◽  
Vol 73 (3) ◽  
pp. 1084-1092 ◽  
Author(s):  
S. Ono ◽  
J. Y. Westcott ◽  
N. F. Voelkel
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxic Exposure ◽  
Pulmonary Vascular Remodeling ◽  
Paf Antagonists ◽  
Isolated Lungs

Chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodeling in rats. Because platelet-activating factor (PAF) levels increase in lung lavage fluid and in plasma from chronically hypoxic rats, we examined the effect of two specific, structurally unrelated PAF antagonists, WEB 2170 and BN 50739, on hypoxia-induced pulmonary vascular remodeling. Treatment with either agent reduced hypoxia-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk of hypoxic exposure (simulated altitude 5,100 m) but did not affect cobalt (CoCl2)-induced pulmonary hypertension. The PAF antagonists had no effect on the hematocrit of normoxic or chronically hypoxic rats or CoCl2-treated rats. Hypoxia-induced pulmonary hypertension was associated with an increase in the vessel wall thickness of the muscular arteries and reduction in the number of peripheral arterioles. In WEB 2170-treated rats, these changes were significantly less severe than those observed in untreated chronically hypoxic rats. PAF receptor blockade had no acute hemodynamic effects; i.e., it did not affect pulmonary arterial pressure or cardiac output nor did it affect the magnitude of acute hypoxic pulmonary vasoconstriction in awake normoxic or chronically hypoxic rats. Isolated lungs from chronically hypoxic rats showed a pressor response to the chemotactic tripeptide N-formyl-Met-Leu-Phe (fMLP) and an increase in the number of leukocytes lavaged from the pulmonary circulation. In vivo treatment with WEB 2170 significantly reduced the fMLP-induced pressor response compared with that observed in isolated lungs from untreated chronically hypoxic rats. These results suggest that PAF contributes to the development of chronic pulmonary hypertension induced by chronic hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) induces the vascular and hemodynamic changes of pulmonary hypertension

2009 ◽  
Vol 296 (4) ◽  
pp. L582-L593 ◽  
Author(s):  
Daniel J. Angelini ◽  
Qingning Su ◽  
Kazuyo Yamaji-Kegan ◽  
Chunling Fan ◽  
John T. Skinner ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Pulmonary Vascular Resistance ◽  
Pulmonary Artery Pressure ◽  
Vascular Resistance ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Heart Hypertrophy ◽  
Right Heart ◽  
Artery Pressure

Pulmonary hypertension (PH) is a serious disease of multiple etiologies mediated by hypoxia, immune stimuli, and elevated pulmonary pressure that leads to vascular thickening and eventual right heart failure. In a chronic hypoxia model of PH, we previously reported the induction of a novel pleiotropic cytokine, hypoxia-induced mitogenic factor (HIMF), that exhibits mitogenic, vasculogenic, contractile, and chemokine properties during PH-associated vascular remodeling. To examine the role of HIMF in hypoxia-induced vascular remodeling, we performed in vivo knockdown of HIMF using short hairpin RNA directed at rat HIMF in the chronic hypoxia model of PH. Knockdown of HIMF partially blocked increases in mean pulmonary artery pressure, pulmonary vascular resistance, right heart hypertrophy, and vascular remodeling caused by chronic hypoxia. To demonstrate a direct role for HIMF in the mechanism of PH development, we performed HIMF-gene transfer into the lungs of rats using a HIMF-expressing adeno-associated virus (AAV). AAV-HIMF alone caused development of PH similar to that of chronic hypoxia with increased mean pulmonary artery pressure and pulmonary vascular resistance, right heart hypertrophy, and neomuscularization and thickening of small pulmonary arterioles. The findings suggest that HIMF represents a critical cytokine-like growth factor in the development of PH.

Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats

2003 ◽  
Vol 285 (1) ◽  
pp. L199-L208 ◽  
Author(s):  
Jan Herget ◽  
Jana Novotná ◽  
Jana Bíbová ◽  
Viera Povýšilová ◽  
Marie Vaňková ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Causative Factor ◽  
Systemic Arterial Pressure ◽  
Collagenolytic Activity ◽  
Pulmonary Vascular Remodeling ◽  
Arterial Blood ◽  
Fraction Of Inspired Oxygen ◽  
Lung Vessels

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 ± 3 mmHg in hypoxic controls, 24 ± 1 mmHg in Batimastat-treated hypoxic rats, and 16 ± 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.

Functional and structural changes with hypoxia in pulmonary circulation of spontaneously hypertensive rats

1994 ◽  
Vol 77 (3) ◽  
pp. 1101-1107 ◽  
Author(s):  
S. P. Janssens ◽  
B. T. Thompson ◽  
C. R. Spence ◽  
C. A. Hales
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Vascular Remodeling ◽  
Spontaneously Hypertensive Rats ◽  
Structural Changes ◽  
Chronic Hypoxia ◽  
Acute Hypoxia ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto

Chronic hypoxic pulmonary hypertension involves both vasoconstriction and vascular remodeling. Spontaneously hypertensive rats (SHR) have an increased systemic vascular resistance and a greater responsiveness to constricting stimuli. We hypothesized that, in contrast to age-matched normotensive Wistar-Kyoto rats (WKY), SHR also display spontaneous pulmonary hypertension in normoxia and increased vascular response to acute and chronic hypoxia. Baseline mean pulmonary arterial pressure (PAP) and total pulmonary resistance (TPR) were higher in SHR than in WKY. With acute hypoxia (10% O2 for 15 min), PAP increased to the same extent in SHR and WKY and cardiac output (CO) was unchanged in WKY but increased in SHR. Thus, the rise in PAP in the SHR might be accounted for by the rise in CO, as TPR did not rise, but not that in the WKY, as TPR increased. After 12 days in hypoxia (10% O2), mean arterial pressure was unchanged in WKY but decreased significantly in SHR without a change in CO. PAP increased by 59% in SHR and 54% in WKY when the rats were taken from the hypoxic chamber for 1 h. Acute hypoxic challenge caused a further increase in PAP only in WKY. Medial wall thickness of alveolar duct and terminal bronchial vessels was similar in WKY and SHR after chronic hypoxia. We conclude that SHR exhibit mild baseline pulmonary hypertension in normoxia and that chronic hypoxia does not produce a disproportionate increase in SHR pulmonary vascular remodeling and pulmonary hypertension.

scholarly journals Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension

2014 ◽  
Vol 306 (12) ◽  
pp. L1090-L1103 ◽  
Author(s):  
Kazuyo Yamaji-Kegan ◽  
Eiki Takimoto ◽  
Ailan Zhang ◽  
Noah C. Weiner ◽  
Lucas W. Meuchel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
Vascular Remodeling ◽  
Lung Inflammation ◽  
Critical Role ◽  
Right Heart Failure ◽  
Right Heart ◽  
Pulmonary Vascular Remodeling ◽  
Mitogenic Factor

Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right heart failure and ultimately death. Injury to endothelium and consequent wound repair cascades have been suggested to trigger pulmonary vascular remodeling, such as that observed during PH. The relationship between injury to endothelium and disease pathogenesis in this disorder remains poorly understood. We and others have shown that, in mice, hypoxia-induced mitogenic factor (HIMF, also known as FIZZ1 or RELMα) plays a critical role in the pathogenesis of lung inflammation and the development of PH. In this study, we dissected the mechanism by which HIMF and its human homolog resistin (hRETN) induce pulmonary endothelial cell (EC) apoptosis and subsequent lung inflammation-mediated PH, which exhibits many of the hallmarks of the human disease. Systemic administration of HIMF caused increases in EC apoptosis and interleukin (IL)-4-dependent vascular inflammatory marker expression in mouse lung during the early inflammation phase. In vitro, HIMF, hRETN, and IL-4 activated pulmonary microvascular ECs (PMVECs) by increasing angiopoietin-2 expression and induced PMVEC apoptosis. In addition, the conditioned medium from hRETN-treated ECs had elevated levels of endothelin-1 and caused significant increases in pulmonary vascular smooth muscle cell proliferation. Last, HIMF treatment caused development of PH that was characterized by pulmonary vascular remodeling and right heart failure in wild-type mice but not in IL-4 knockout mice. These data suggest that HIMF contributes to activation of vascular inflammation at least in part by inducing EC apoptosis in the lung. These events lead to subsequent PH.

Sign in / Sign up

Export Citation Format

Share Document