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Treatment with 17-Beta Estradiol Attenuates Chronic Hypoxic Pulmonary Hypertension in Male Rats

Tim Lahm

Marjorie Albrecht

Y. Gao

Mary Van Demark

Amanda Fisher

Robert Presson

I Petrache


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Conference: 2010 International PHA Conference and Scientific Sessions

Release Date: 06.24.2010

Presentation Type: Abstracts

Lahm T, Albrecht M, Gao Y, Van Demark M, Fisher A, Presson RG, Petrache I.
Indiana University School of Medicine and Roudebush VA Medical Center, Indianapolis, IN, USA

BACKGROUND: The protection observed in females against hypoxic pulmonary hypertension (HPH) has been attributed to protective effects of 17-beta estradiol (E2), since E2 withdrawal in females (by ovariectomy; OVX) eliminates this protection, and E2 supplementation in OVX animals restores it. However, it remains unknown if E2 supplementation in male animals attenuates HPH and if so, by which mechanism. We therefore hypothesized that chronic treatment with E2 attenuates the development of HPH in male rats, and studied the role of E2 conversion to methoxyestradiols (ME) as mediators of protective E2 effects.

METHODS: Adult male Sprague-Dawley rats were exposed to chronic hypobaric hypoxia (barometric pressure 362 mmHg; equivalent to 10% FiO2 for 2-4 weeks). Age-matched control animals were exposed to ambient barometric pressure (~760 mmHg; 21% FiO2). All animals were maintained on a 12:12-h light-dark cycle. E2 (75 μg/kg/day via subcutaneously implanted osmotic minipumps) or vehicle were administered continuously for one week prior to hypoxia and for the entire duration of the hypoxia exposure. In a subgroup of animals, E2 conversion to ME was inhibited by the catechol-O-methyl-transferase (COMT) inhibitor OR-486 (1.5 mg/kg/d intraperitoneally). Endpoints assessed were 1) hemodynamics (right ventricular systolic pressure [RVSP; measured via right jugular vein Millar catheter]), cardiac output (CO; measured via flow probe placed around aortic arch), and systemic blood pressure (SBP; measured via left carotid arterial line), 2) RV remodeling (RV/LV+septum ratio), 3) hematocrit levels, and 4) oxygenation status. Measurements were obtained at 21% FiO2 in absence of alkalosis or acidosis. P<0.05 was considered statistically significant. Values are expressed as mean±SEM.

RESULTS: As expected, hypoxia led to a robust increase in RVSP, which peaked at 2 weeks and then plateaued. Similarly, after 2 weeks of hypoxia there was a significant decrease in CO, and a significant increase in the RVSP/CO ratio, accompanied by significant RV remodeling and increased blood hematocrit levels compared to normoxic animals. Rats tolerated the E2 delivered by osmotic minipumps well. E2 treatment markedly attenuated hypoxia-induced RVSP (47.7±2.4 [E2] vs 64.7±4.8 mmHg [untreated]; p<0.05) and RV/LV+S changes (0.4±0.01 vs 0.48±0.04; p<0.05). E2 also tended to decrease RVSP/CO (0.93±0.03 vs 1.34±0.2; p=0.08) and hypoxia-induced erythrocytosis (55.6±2.4 vs 62.3±0.3%; p=0.07). SBP and oxygenation were not affected, indicating lack of ventilation/perfusion mismatch. Interestingly, the beneficial effect of E2 treatment was maintained despite concomitant treatment with the COMT inhibitor.

CONCLUSIONS: Treatment with E2 is associated with improvements in hematologic, hemodynamic and right ventricular remodeling parameters in male rats with hypoxic pulmonary hypertension. The lack of E2 effect on CO may be due to the relatively short treatment interval. Alternatively, higher E2 doses may be necessary to significantly alter cardiac function. It appears that the conversion of E2 to methoxymetabolites is not necessary for its beneficial effects, as evidenced by maintained E2 protection after COMT-inhibition. A better understanding of the effects of E2 on the hypoxic pulmonary vasculature may allow for the development of targeted non-hormonal therapies that may ultimately benefit all pulmonary hypertension patients.