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(DHEA) Prevents and Reverses Chronic Hypoxic Pulmonary Hypertension

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(DHEA) Prevents and Reverses Chronic Hypoxic Pulmonary Hypertension Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension Se´ bastien Bonnet*†, Eric Dumas-de-La-Roque*†, Hugues Be´ gueret*, Roger Marthan*, Michael Fayon*, Pierre Dos Santos‡, Jean-Pierre Savineau*, and Etienne-Emile Baulieu§¶ *Institut National de la Sante´et de la Recherche Me´dicale, EMI 0356, Physiologie Cellulaire Respiratoire, Universite´de Bordeaux II, 146, Rue Le´o Saignat, 33076 Bordeaux Cedex, France; ‡Institut National de la Sante´et de la Recherche Me´dicale, U441, Athe´roscle´rose, Avenue du Haut-Le´ve` que, 33604 Pessac, France; and §Institut National de la Sante´et de la Recherche Me´dicale, U488, Ste´roı¨deset Syste`me Nerveux, Hoˆpital de Biceˆtre, 94276 Le Kremlin-Biceˆtre Cedex, France Contributed by Etienne-Emile Baulieu, June 17, 2003 Pulmonary artery (PA) hypertension was studied in a chronic of the PASMCs membrane potential and its effects on the [Ca 2ϩ hypoxic-pulmonary hypertension model (7–21 days) in the rat. ]i. In vivo PA pressure (PAP) as well as right ventricular (RV) Increase in PA pressure (measured by catheterism), cardiac right wall thickness were measured in closed-chest rats undergoing ventricle hypertrophy (determined by echocardiography), and PA CH. Remodeling was determined in small and medium pulmo- 2ϩ remodeling (evaluated by histology) were almost entirely pre- nary arteries. In addition, the effect of DHEA on [Ca ]i and the vented after oral dehydroepiandrosterone (DHEA) administration possible involvement of the potassium channels were measured (30 mg͞kg every alternate day). Furthermore, in hypertensive rats, by microspectrofluorimetry, isometric contraction measure- oral administration, or intravascular injection (into the jugular ment, and Western blot analysis. vein) of DHEA rapidly decreased PA hypertension. In PA smooth muscle cells, DHEA reduced the level of intracellular calcium (mea- Methods sured by microspectrofluorimetry). The effect of DHEA appears to Chronic Hypoxia and DHEA Treatments. Adult male Wistar rats involve a large conductance Ca2؉-activated potassium channel (220–240 g) were randomized into five groups. Two groups were (BK )-dependent stimulatory mechanism, at both function and housed at normal atmospheric pressure (101 kPa); one group Ca Ϫ expression levels (isometric contraction and Western blot), via a comprised rats treated with DHEA (30 mg⅐kg 1 orally every redox-dependent pathway. Voltage-gated potassium (Kv) chan- alternate day), which induces a circulating DHEA sulfate level Ϸ ␮ nels also may be involved because the antagonist 4-amino-pyridine of 0.2 M after 3 wk (normoxic DHEA group) and another blocked part of the DHEA effect. The possible pathophysiological group did not receive DHEA (normoxic group). Other groups ϭ and therapeutic significance of the results is discussed. were kept in a hypobaric chamber (0.5 atm; 1 atm 101.3 kPa) for 7–21 days: one group received DHEA (CH-DHEA group), hypoxia ͉ potassium channels another did not receive DHEA (CH group) and, in a third group, DHEA was given to the CH rats from day 15 to day 21 to look for CH-PHT regression. Intravascular administration was per- xposure of animals to chronic hypoxia leads to the develop- formed via the catheter inserted in the right jugular vein. Ement of chronic hypoxic-pulmonary hypertension (CH- PHT). In human beings CH-PHT is frequently associated with Hemodynamic and Echocardiography Measurements. Rats were an- severe pulmonary diseases. CH-PHT involve pulmonary arterial aesthetized with ketamine 50 mg͞kg and xylazine 10 mg͞kg by vasoconstriction and remodeling (1). Although the endothelium i.p. injection. Mean PAP was measured with 2.5-F catheters is involved in the pathogenesis of CH-PHT, the role of vascular inserted into the right jugular vein in closed-chest rats (14). The smooth muscle cells (SMCs) is increasingly recognized (2). effect of DHEA on the systemic blood pressure was controlled Both the contractile status and the proliferative status of by another catheter placed into the left carotid artery. Through- 2ϩ 2ϩ SMCs are regulated by the levels of intracellular Ca ([Ca ]i). out all the experiments, heart rate and oxygen saturation were 2ϩ 2ϩ The [Ca ]i levels are determined in part by the influx of Ca ϩ monitored. Acute hypoxic stress with fraction of inspired O2 of through the voltage-gated, L-type Ca2 channels. In pulmonary 10% were applied by administration of an air plus nitrogen gas artery (PA) SMCs, the membrane potential is regulated by large mixture. The fraction of inspired O2 was monitored with an 2ϩ conductance Ca -activated channels (BKCa) (3) and voltage- ϩ oxygen analyzer (Servomex, Crowborough, Great Britain), and gated K channels (Kv), including shaker family Kv (4, 5). K the effects on the PAP were measured over 10–15 min. channel (BKCa and Kv) function and expression are down- Echocardiography measurements were made in anaesthetized regulated with development and maintenance of CH-PHT (6, 7). rats. After thorax epilation, the animals were placed in the left CH reduces K current density in PASMCs, resulting in a state of lateral decubitus position. Resting echocardiography measure- 2ϩ depolarization (8, 9), followed by elevation of [Ca ]i, which ments were performed at ambient conditions by using a SONOS induces contraction and proliferation (10). 5500 (Philips) echocardiograph and a 12-MHz sector scare The mechanism for K channel down-regulation is unclear, but transducer. Right and left ventricle wall thickness was measured recent work suggests that it is related to the altered redox state on M-mode tracings following the recommendations of the induced by CH (8). Lungs of rats with CH-PHT are in a more American Society of Echocardiology as described by Jones et al. reduced redox state than those of normoxic controls, as indi- (15). Right cardiac output was evaluated by measuring the cated by increased levels of reduced glutathione (8). A reduced electrical R-R delay, the PA diameter, and the velocity time redox state has potential for both short-term effects through modulation of Kϩ channels function (11) and long-term effects Abbreviations: DHEA, dehydroepiandrosterone; Kv, voltage-gated Kϩ channels; HT, by activating several oxygen-responsive genes including hypoxia- 2ϩ hypertension; PA, pulmonary artery; BKCa, large conductance Ca -activated channels; 2ϩ 2ϩ inducible factor (HIF) (12). [Ca ]i, intracellular Ca ; CH-PHT, chronic hypoxic-pulmonary HT; IPA, intrapulmonary We sought to enhance expression and function of BKCa by artery; PAP, PA pressure; RV, right ventricular; 4-AP, 4-amino-pyridine; PASMC, PA small muscle cell; IbTx, iberiotoxin. using DHEA, a BKCa opener in hypoxic human pulmonary cells (13), which can shift the redox balance toward an oxidized state †S.B. and E.D.-d.-L.-R. contributed equally to this work. ¶ leading to both BKCa and Kv activation and thus repolarization To whom correspondence should be addressed. E-mail: [email protected]. 9488–9493 ͉ PNAS ͉ August 5, 2003 ͉ vol. 100 ͉ no. 16 www.pnas.org͞cgi͞doi͞10.1073͞pnas.1633724100 Downloaded by guest on October 2, 2021 integral (VTI) of PA flux. Of note, all the echocardiography Chemicals and Drugs. Collagenase (type CLS1) was from Worth- measurements were measured by investigators blinded to the ington. Pronase (type E), elastase (type 3), BSA, iberiotoxin treatment groups. (IbTx) (BKCa inhibitor), DHEA (prasterone), 1H-[1,2,4]oxadia- zolol [4,3,-a]quinoxalin-1-one (ODQ) (GMPc pathway inhibi- Tissue and Cell Preparations. Heart and lungs were removed en tor), Genistein (tyrosine kinase inhibitor), ‘‘476485’’ a PKA bloc. Intrapulmonary arteries (IPAs) (150–300 ␮m of internal inhibitor, 4-amino-pyridine (4-AP), DTT (a reducing agent), diameter) were then dissected under binocular control, and the and agitoxin-2 (K shaker family blocker) were from Sigma. adventicial and intimal layers were removed. For contraction Indo-1 was from Calbiochem. DHEA, Indo-1, and (476485) were experiments, rings (3 mm in length) were prepared. PASMCs dissolved in DMSO or in ethanol. The maximal concentration of were isolated by using an enzymatic protocol described (14). DMSO and ethanol used in our experiments was Ͻ0.1% and had no effect on the mechanical activity of rings and the resting value 2ϩ Histology. A section of lung was formalin-fixed for histology of the [Ca ]i. studies. PA external diameter (PAED), PA internal diameter (PAID), and percentage vessel wall thickness (PAED Ϫ PAID)͞ Analysis of Data. Values were expressed as mean Ϯ SEM. Con- PAED ϫ 100) were measured in small- and medium-sized PAs tractions were expressed as a percentage of Kϩ-rich (80 mM) (80–150 ␮m). Each group was comprised of four rats, and 10 solution-induced contractions. Statistical analyses were per- measures were made per rat by an investigator blinded to the formed by using NCSS 5.0 software (NCSS, Kaysville, UT). treatment groups. Intergroup differences were assessed by a repeated-measures ANOVA or factorial ANOVA, as appropriate. Post hoc analysis 2؉ 2ϩ [Ca ]i Measurements. To assess the dynamic changes in [Ca ]i of used a Fisher multiple comparison test. For some comparisons, 2ϩ individual PASMC, we used the [Ca ]i-sensitive fluorophore the Pearson product moment correlation coefficient between indo-1. PASMCs were loaded with indo-1 by incubation in pairs of variables was used as indicated (ORIGIN 5.0, OriginLab, physiological salt solution (139.6 mM NaCl͞6.2 mM KCl͞1mM Northampton, MA). Regarding the number of experiments, (n) ͞ ͞ ␮ MgCl2 12.1 mM glucose 10 mM Hepes) containing 1 M indo-1 refers to the number of rings or cells and (N) to the number of penta-acetoxymethyl ester (Indo-1 a.m.) for 25 min at room animals. Differences were considered significant when P Ͻ 0.05. temperature. The recording system included a Nikon Diaphot inverted microscope fitted with epifluorescence. The studied cell Results was illuminated at 360 nm and counted simultaneously at 405 nm DHEA Prevents CH-PHT.
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