Role of sex hormones in development of chronic mountain sickness in rats

1994 ◽  
Vol 77 (1) ◽  
pp. 427-433 ◽  
Author(s):  
L. C. Ou ◽  
G. L. Sardella ◽  
J. C. Leiter ◽  
T. Brinck-Johnsen ◽  
R. P. Smith
Keyword(s):  
Gender Differences ◽  
Pulmonary Hypertension ◽  
High Altitude ◽  
Sex Hormones ◽  
Systolic Pressure ◽  
Female Rats ◽  
Hypoxic Exposure ◽  
Chronic Mountain Sickness ◽  
Mountain Sickness

After chronic exposure to hypoxia, Hilltop Sprague-Dawley rats developed excessive polycythemia and severe pulmonary hypertension and right ventricular (RV) hypertrophy, signs consistent with human chronic mountain sickness; however, there were gender differences in the magnitude of the polycythemia and susceptibility to the fatal consequence of chronic mountain sickness. Orchiectomy and ovariectomy were performed to evaluate the role of sex hormones in the gender differences in these hypoxic responses. After 40 days of exposure to simulated high altitude (5,500 m; barometric pressure of 370 Torr and inspired Po2 of 73 Torr), both sham-gonadectomized male and female rats developed polycythemia and had increased RV peak systolic pressure and RV hypertrophy. The hematocrit was slightly but significantly higher in males than in females. Orchiectomy did not affect these hypoxic responses, although total ventricular weight was less in the castrated high-altitude rats. At high altitude, the mortality rates were 67% in the sham-operated male rats and 50% in the castrated animals. In contrast, ovariectomy aggravated the high-altitude-associated polycythemia and increased RV peak systolic pressure and RV weight compared with the sham-operated high-altitude female rats. Both sham-operated control and ovariectomized females suffered negligible mortality at high altitude. The present study demonstrated that 1) the male sex hormones play no role in the development of the excessive polycythemia, pulmonary hypertension, and RV hypertrophy during chronic hypoxic exposure or in the associated high mortality and 2) the female sex hormones suppressed both the polycythemic and cardiopulmonary responses in vivo during chronic hypoxic exposure.

scholarly journals High-Altitude Pulmonary Vascular Diseases

2017 ◽  
Vol 15 (3) ◽  
pp. 149-157 ◽  
Author(s):  
Maniraj Neupane ◽  
Erik R. Swenson
Keyword(s):  
Pulmonary Hypertension ◽  
High Altitude ◽  
Vascular Diseases ◽  
Hypoxic Exposure ◽  
Partial Pressure Of Oxygen ◽  
Chronic Mountain Sickness ◽  
Pulmonary Vasoconstriction ◽  
High Altitude Pulmonary Edema ◽  
Mountain Sickness ◽  
Pulmonary Vascular Diseases

More than 140 million people permanently reside in high-altitude regions of Asia, South America, North America, and Africa. Another 40 million people travel to these places annually for occupational and recreational reasons, and are thus exposed to the low ambient partial pressure of oxygen. This review will focus on the pulmonary circulatory responses to acute and chronic high-altitude hypoxia, and the various expressions of maladaptation and disease arising from acute pulmonary vasoconstriction and subsequent remodeling of the vasculature when the hypoxic exposure continues. These unique conditions include high-altitude pulmonary edema, high-altitude pulmonary hypertension, subacute mountain sickness, and chronic mountain sickness.

scholarly journals HIF2α–arginase axis is essential for the development of pulmonary hypertension

2016 ◽  
Vol 113 (31) ◽  
pp. 8801-8806 ◽  
Author(s):  
Andrew S. Cowburn ◽  
Alexi Crosby ◽  
David Macias ◽  
Cristina Branco ◽  
Renato D. D. R. Colaço ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Systolic Pressure ◽  
Hypoxic Exposure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Endothelium ◽  
Arginase 1

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.

Abstract 230: Gender Differences in the Development of Experimental Pulmonary Hypertension and Associated Right Ventricular Remodeling: The Role of Estrogen Rescue

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Soban Umar ◽  
Rangarajan Nadadur ◽  
Mansoureh Eghbali
Keyword(s):  
Gender Differences ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Ventricular Remodeling ◽  
Therapeutic Potential ◽  
Systolic Pressure ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats ◽  
Ovx Rats

17-beta estradiol or Estrogen (E2) pre-treatment has been shown to attenuate the development of pulmonary hypertension (PH). Here, we aim to investigate the gender differences and the effect of ovariectomy on the development of experimental PH and adverse right ventricular (RV) remodeling. We also evaluate the therapeutic potential of E2 in rescuing PH and adverse RV remodelling in male and female rats. Male and female (intact and ovariectomized (OVX)) rats were treated with a single injection of monocrotaline (MCT, 60mg/kg, s.c.) to induce PH. Twenty one days after MCT, rats developed severe PH. At this point, one set of rats from each group was left untreated to develop PH-induced right ventricular failure (RVF), whereas the other set received E2 (42.5 ug/kg/day, 10-day slow release s.c. pellets). E2-treated rats were observed for an additional 12 days after cessation of therapy to check whether the effects of therapy were long-lived. Saline treated rats served as control (CTRL). Serial echocardiography was performed to monitor cardiopulmonary hemodynamics. Direct RV catheterization was terminally performed to record RV peak systolic pressure (RVPSP). The expression of novel extracellular matrix (ECM) enzymes A Disintegrin And Metalloproteinase (ADAM15 and 17) and Osteopontin (OPN) were assessed by RT-PCR. Intact females developed less severe PH than males and OVX females at day 30 (RVPSP: Females=62±3, Males=74±3, OVX=77±3 mm Hg, p<0.05 vs. respective CTRL). E2 therapy resulted in rescue of PH in all groups (RVPSP: Females=36±4, Males=38±2, OVX=44±2 mm Hg, p<0.05 vs. respective PH-RVF). Intact females also developed less severe RV remodeling compared to males and OVX females. Expression of OPN increased ∼7-9-fold in PH-RVF males and OVX but only ∼2-fold in intact females, (p<0.05 vs. CTRL for all). E2 reversed OPN upregulation in all groups (p<0.05 vs. PH-RVF). Novel ECM-degrading Disintegrin-Metalloproteinases ADAM15 and ADAM17 transcripts were also elevated ∼2-fold in all PH-RVF animals (p<0.05 vs. CTRL). E2-therapy reversed RV remodeling in all groups (p<0.05 vs. PH-RVF). In conclusion, intact females are more protected against the development of PH compared to males and OVX females. E2 rescues PH and adverse RV remodeling in all groups.

scholarly journals Optimal hemoglobin concentration and high altitude: a theoretical approach for Andean men at rest

2004 ◽  
Vol 96 (5) ◽  
pp. 1581-1588 ◽  
Author(s):  
Francisco C. Villafuerte ◽  
Rosa Cárdenas ◽  
Carlos Monge-C
Keyword(s):  
Cardiac Output ◽  
Theoretical Analysis ◽  
High Altitude ◽  
Hemoglobin Concentration ◽  
Mathematical Approach ◽  
Chronic Mountain Sickness ◽  
Physiological Variables ◽  
Mixed Mean ◽  
Mountain Sickness

The beneficial role of erythrocytosis for O2 transport has been questioned by evidence from bloodletting and hemodilution research as well as by studies suggesting the existence of an “optimal” hematocrit (Hct) or hemoglobin concentration ([Hb]) value. To assess to what extent erythrocytosis is beneficial in Andean men at high altitude, we examined and discussed optimal [Hb] using a mathematical approach by modeling the mixed (mean) venous Po2 (Pv̄O2) and arterial O2 content, considering for both the relation between [Hb] and arterial Po2. Relations of [Hb] to other physiological variables such as cardiac output and convective arterial O2 transport were also discussed, revealing the importance of Pv̄O2 in this model. Our theoretical analysis suggests that increasing [Hb] allows increase and maintenance of Pv̄O2 with only moderate declines in arterial Po2 as a consequence of moderate increases in altitude, reaching its maximum at the optimal [Hb] of 14.7 g/dl. Our analysis also shows that [Hb] corresponding to high arterial O2 content and O2 transport values is apparently not quite advantageous for improvement of oxygenation. Furthermore, chronic mountain sickness is discussed as an insightful example of the effects of excessive erythrocytosis at high altitude.

Role of the spleen in the exaggerated polycythemic response to hypoxia in chronic mountain sickness in rats

1999 ◽  
Vol 87 (5) ◽  
pp. 1901-1908 ◽  
Author(s):  
H. Y. Kam ◽  
L. C. Ou ◽  
C. D. Thron ◽  
R. P. Smith ◽  
J. C. Leiter
Keyword(s):  
Bone Marrow ◽  
Chronic Hypoxia ◽  
Hypoxic Exposure ◽  
Large Measure ◽  
Chronic Mountain Sickness ◽  
Fe Uptake ◽  
Rat Strain ◽  
Mountain Sickness ◽  
Rapid Appearance

In a rat model of chronic mountain sickness, the excessive polycythemic response to hypoxic exposure is associated with profound splenic erythropoiesis. We studied the uptake and distribution of radioactive iron and red blood cell (RBC) morphology in intact and splenectomized rats over a 30-day hypoxic exposure. Retention of59Fe in the plasma was correlated with59Fe uptake by both spleen and marrow and the appearance of59Fe-labeled RBCs in the blood.59Fe uptake in both the spleen and the marrow paralleled the production of nucleated RBCs. Splenic59Fe uptake was ∼10% of the total marrow uptake under normoxic conditions but increased to 60% of the total marrow uptake during hypoxic exposure. Peak splenic59Fe uptake and splenomegaly occurred at the most intense phase of erythropoiesis and coincided with the rapid appearance of59Fe-labeled RBCs in the blood. The bone marrow remains the most important erythropoietic organ under both resting and stimulated states, but inordinate splenic erythropoiesis in this rat strain accounts in large measure for the excessive polycythemia during the development of chronic mountain sickness in chronic hypoxia.

Ventilation and hypoxic ventilatory responsiveness in Chinese-Tibetan residents at 3,658 m

1997 ◽  
Vol 83 (6) ◽  
pp. 2098-2104 ◽  
Author(s):  
Linda S. Curran ◽  
Jianguo Zhuang ◽  
Shin Fu Sun ◽  
Lorna G. Moore
Keyword(s):  
High Altitude ◽  
Minute Ventilation ◽  
Ambient Air ◽  
Hypoxic Exposure ◽  
Chronic Mountain Sickness ◽  
Air Breathing ◽  
Ventilatory Responses ◽  
Permissive Role

Curran, Linda S., Jianguo Zhuang, Shin Fu Sun, and Lorna G. Moore. Ventilation and hypoxic ventilatory responsiveness in Chinese-Tibetan residents at 3,658 m. J. Appl. Physiol. 83(6): 2098–2104, 1997.—When breathing ambient air at rest at 3,658 m altitude, Tibetan lifelong residents of 3,658 m ventilate as much as newcomers acclimatized to high altitude; they also ventilate more and have greater hypoxic ventilatory responses (HVRs) than do Han (“Chinese”) long-term residents at 3,658 m. This suggests that Tibetan ancestry is advantageous in protecting resting ventilation levels during years of hypoxic exposure and is of interest in light of the permissive role of hypoventilation in the development of chronic mountain sickness, which is nearly absent among Tibetans. The existence of individuals with mixed Tibetan-Chinese ancestry (Han-Tibetans) residing at 3,658 m affords an opportunity to test this hypothesis. Eighteen men born in Lhasa, Tibet, China (3,658 m) to Tibetan mothers and Han fathers were compared with 27 Tibetan men and 30 Han men residing at 3,658 m who were previously studied. We used the same study procedures (minute ventilation was measured with a dry-gas flowmeter during room air breathing and hyperoxia and with a 13-liter spirometer-rebreathing system during the hypoxic and hypercapnic tests). During room air breathing at 3,658 m (inspired O2 pressure = 93 Torr), Han-Tibetans resembled Tibetans in ventilation (12.1 ± 0.6 vs. 11.5± 0.5 l/min btps, respectively) but had HVR that were blunted (63 ± 16 vs. 121 ± 13, respectively, for HVR shape parameter A) and declined with increasing duration of high-altitude residence. During administered hyperoxia (inspired O2 pressure = 310 Torr) at 3,658 m, the paradoxical hyperventilation previously seen in Tibetan but not Han residents at 3,658 m (11.8 ± 0.5 vs. 10.1 ± 0.5 l/min btps) was absent in these Han-Tibetans (9.8 ± 0.6 l/minbtps). Thus, although longer duration of high-altitude residence appears to progressively blunt HVR among Han-Tibetans born and residing at 3,658 m, their Tibetan ancestry appears protective in their maintenance of high resting ventilation levels despite diminished chemosensitivity.

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