Rationale : Studies have demonstrated that angiotensin-converting enzyme 2 (ACE2) plays a protective role against lung diseases, including pulmonary hypertension (PH). Recently, an antitrypanosomal drug, diminazene aceturate (DIZE), was shown to exert an "offtarget" effect of enhancing the enzymatic activity of ACE2 in vitro. Objectives: To evaluate the pharmacological actions of DIZE in experimental models of PH. Methods: PH was induced in male Sprague Dawley rats by monocrotaline, hypoxia, or bleomycin challenge. Subsets of animals were simultaneously treated with DIZE. In a separate set of experiments, DIZE was administered after 3 weeks of PH induction to determine whether the drug could reverse PH. Measurements and Main Results: DIZE treatment significantly prevented the development of PH in all of the animal models studied. The protective effects were associated with an increase in the vasoprotective axis of the lung renin-angiotensin system, decreased inflammatory cytokines, improved pulmonary vasoreactivity, and enhanced cardiac function. These beneficial effects were abolished by C-16, an ACE2 inhibitor. Initiation of DIZE treatment after the induction of PH arrested disease progression. Endothelial dysfunction represents a hallmark of PH pathophysiology, and growing evidence suggests that bone marrow-derived angiogenic progenitor cells contribute to endothelial homeostasis. We observed that angiogenic progenitor cells derived from the bone marrow of monocrotaline-challenged rats were dysfunctional and were repaired by DIZE treatment. Likewise, angiogenic progenitor cells isolated from patients with PH exhibited diminished migratory capacity toward the key chemoattractant stromal-derived factor 1a, which was corrected by in vitro DIZE treatment. Conclusions: Our results identify a therapeutic potential of DIZE in PH therapy.Keywords: pulmonary hypertension; ACE2; angiogenic progenitor cells; diminazene Pulmonary hypertension (PH) is a life-threatening disease characterized by elevated pressure in the pulmonary arteries and What This Study Adds to the FieldWe show that diminazene, an antitrypanosomal drug, attenuates hemodynamic changes, prevents maladaptive right ventricular remodeling, and enhances pulmonary vasorelaxation in experimental models of PH through activation of ACE2. Furthermore, diminazene improves the functions of APCs obtained from experimental animals and patients with PH. This study identifies a new application for an existing drug, which could be successfully developed for PH therapeutics.

1. The stability of gaze was measured in nine normal subjects during 30-s epochs of standing, walking in place, and running in place. The angle of gaze and head rotations in horizontal and vertical planes were measured using the magnetic search coil technique. Subjects visually fixed on a stationary object located at a distance of 100 m; thus measurements of gaze indicated the stability of images on the retina. 2. During standing, walking, or running in place, the standard deviation of the angle of gaze was less than 0.4 degrees, both horizontally and vertically. During standing and walking in place, peak gaze velocity (Gp) was less than 3.0 degrees/s. During running in place, Gp was less than 3.0 degrees/s horizontally but ranged up to 9.3 degrees/s vertically. 3. Visual acuity was measured during standing, walking, and running in place. During walking in place, five of nine subjects showed a small but significant (P = 0.03) decline in visual acuity compared with standing. During running in place, all nine subjects showed a small but significant (P = 0.002) decline in visual acuity compared with standing. 4. Stability of gaze was also measured during vigorous, voluntary head rotations in the horizontal (yaw) or vertical (pitch) planes, for 15-s epochs. Gp ranged as high as 70 degrees/s horizontally and 41 degrees/s vertically. All subjects reported illusory movement of the seen environment during these head rotations. 5. The suitability of linear systems techniques for analysis of the horizontal and vertical vestibuloocular reflex (VOR) during walking and running in place was assessed using coherence spectral analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Because of the oscillatory pattern of upper airway resistance and breathing during sleep in patients with obstructive sleep apnea (OSA), we hypothesized that OSA patients have an underlying instability of ventilatory drive to inspiratory muscles. To assess the stability of ventilatory drive in OSA patients and controls, we used the pseudorandom binary stimulation (PRBS) test and examined the closed-and open-loop responses to hyperoxic hypercapnia. The closed-loop response is produced by interactions of dynamic gain in controller, plant, and ventilatory feedback. The open-loop response reflects controller dynamic gain or frequency-dependent chemosensitivity. As compared with 16 nonapneic, nonobese control subjects, a group of nine obese OSA patients had a higher peak response and a more rapid and irregular recovery phase of the closed-loop CO 2 response in the PRBS test. The two groups had similar open-loop responses in the PRBS test, suggesting that central dynamic CO 2 chemosensitivity was not abnormal in OSA. We conclude that the differences between OSA patients and controls in the closed-loop response in the PRBS test are not due to differences in dynamic controller gain, but are related to differences in dynamic plant gain and/or negative ventilatory feedback. In addition to OSA, obesity may affect these variables and may have been responsible for our findings. Hudgel DW, Gordon EA, Thanakitcharu S, Bruce EN. Instability of ventilatory control in patients with obstructive sleep apnea.