Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

Abstract

Pulmonary artery (PA) hypertension was studied in a chronic hypoxic-pulmonary hypertension model (7-21 days) in the rat. Increase in PA pressure (measured by catheterism), cardiac right ventricle hypertrophy (determined by echocardiography), and PA remodeling (evaluated by histology) were almost entirely prevented after oral dehydroepiandrosterone (DHEA) administration (30 mg͞kg every alternate day). Furthermore, in hypertensive rats, oral administration, or intravascular injection (into the jugular vein) of DHEA rapidly decreased PA hypertension. In PA smooth muscle cells, DHEA reduced the level of intracellular calcium (measured by microspectrofluorimetry). The effect of DHEA appears to involve a large conductance Ca 2؉ -activated potassium channel (BK Ca)-dependent stimulatory mechanism, at both function and expression levels (isometric contraction and Western blot), via a redox-dependent pathway. Voltage-gated potassium (Kv) channels also may be involved because the antagonist 4-amino-pyridine blocked part of the DHEA effect. The possible pathophysiological and therapeutic significance of the results is discussed.hypoxia ͉ potassium channels E xposure of animals to chronic hypoxia leads to the development of chronic hypoxic-pulmonary hypertension (CH-PHT). In human beings CH-PHT is frequently associated with severe pulmonary diseases. CH-PHT involve pulmonary arterial vasoconstriction and remodeling (1). Although the endothelium is involved in the pathogenesis of CH-PHT, the role of vascular smooth muscle cells (SMCs) is increasingly recognized (2).Both the contractile status and the proliferative status of SMCs are regulated by the levels of intracellular Ca 2ϩ ([Ca 2ϩ ] i ). The [Ca 2ϩ ] i levels are determined in part by the influx of Ca 2ϩ through the voltage-gated, L-type Ca 2ϩ channels. In pulmonary artery (PA) SMCs, the membrane potential is regulated by large conductance Ca 2ϩ -activated channels (BK Ca ) (3) and voltagegated K ϩ channels (Kv), including shaker family Kv (4, 5). K channel (BK Ca and Kv) function and expression are downregulated with development and maintenance of CH-PHT (6, 7). CH reduces K current density in PASMCs, resulting in a state of depolarization (8, 9), followed by elevation of [Ca 2ϩ ] i , which induces contraction and proliferation (10).The mechanism for K channel down-regulation is unclear, but recent work suggests that it is related to the altered redox state induced by CH (8). Lungs of rats with CH-PHT are in a more reduced redox state than those of normoxic controls, as indicated by increased levels of reduced glutathione (8). A reduced redox state has potential for both short-term effects through modulation of K ϩ channels function (11) and long-term effects by activating several oxygen-responsive genes including hypoxiainducible factor (HIF) (12).We sought to enhance expression and function of BK Ca by using DHEA, a BK Ca opener in hypoxic human pulmonary cells (13), which can shift the redox balance toward an oxidized state leading to both BK Ca and Kv activatio...

The Effects of Endogenous Sex Hormones and Acute Hypoxia on Vasoconstriction in Isolated Rat Pulmonary Artery Rings

“…One study has shown that exogenous estrogen exposure protected pulmonary hypertensive rats from pulmonary vascular remodeling and right ventricular hypertrophy [28]. Also, DHEA, a testosterone precursor, has been shown to prevent and reverse pulmonary artery remodeling [31].…”

Fraktalkine Produced by Airway Smooth Muscle Cells Contributes to Mast Cell Recruitment in Asthma

“…Changes in HMC-1 intracellular calcium concentration were assessed using the Ca 2ϩ -sensitive probe indo-1 as described previously (13,16). Briefly, cells were loaded with indo-1 (Calbiochem) and mounted in a perfusion chamber continuously perfused.…”

Beneficial effect of dehydroepiandrosterone on pulmonary hypertension in a rodent model of pulmonary hypertension in infants

“…The active dose of DHEA used in our experiments is identical to that given in our previous studies (9,21). This chronic oral protocol yields a circulating concentration of DHEA in the range of ≥10 −7 mol/l, similar to that commonly used in in vitro studies.…”

“…In different models of adult rats with PH, we (9) and others (10,11) have shown that DHEA prevents and reverses PH and the resulting right-ventricular (RV) hypertrophy as well as small PA remodeling. However, similar studies have not been performed in newborn or infant animals.…”

“…Our present model aimed to mimic hypoxic PH secondary to chronic or acute respiratory disease in children such as bronchopulmonary dysplasia, acute viral bronchiolitis, or severe pulmonary infection. Second, because our aim was to evaluate the effect of DHEA in PH, we did not include an additional group of healthy juvenile rats treated with DHEA only, because we have previously demonstrated the absence of modification of pulmonary and systemic hemodynamic in air-exposed adult rats treated with DHEA (9).The active dose of DHEA used in our experiments is identical to that given in our previous studies (9,21). This chronic oral protocol yields a circulating concentration of DHEA in the range of ≥10 −7 mol/l, similar to that commonly used in in vitro studies.…”