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The Novel Soluble Guanylate Cyclase Activator PPCA Reverses Acute Hypoxia‐induced Pulmonary Hypertension in Dogs
Author(s) -
Wang Tao,
McCefferty Gerald P.,
Schnackenberg Christine G.,
Jucker Beat M,
Willette Robert N.,
Behm David J.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1023.12
Subject(s) - hypoxic pulmonary vasoconstriction , pulmonary hypertension , medicine , beagle , hypoxia (environmental) , nitric oxide , blood pressure , hemodynamics , endocrinology , pharmacology , cardiology , chemistry , oxygen , organic chemistry
Nitric oxide (NO) plays a critical role in regulating pulmonary vascular tone. Impaired bioavilability of the NO receptor, soluble guanylate cyclase (sGC), and/or response to endogeneous NO has been implicated in the pathogenesis of pulmonary hypertension (PH). We hypothesize that activating sGC in a NO‐independent manner will provide a valuable therapy for patients with PH. We generated a novel NO‐independent type 2 sGC activator, PPCA, and tested it in a canine model of hypoxia‐induced pulmonary hypertension. Under normoxic conditions PPCA dose‐dependently (3–100 μg/kg, IV) decreased mean arterial pressure (MAP) and pulmonary arterial pressure (PAP) in anesthetized and catheterized beagle dogs (n=5). Following 20 minutes of hypoxia (10% O 2 ), either saline or PPCA (15μg/kg, IV) was administered. PPCA significantly decreased PAP (−25.1±4.1%) vs. vehicle (−7.6±1.4%, P < 0.05), MAP (−16.1± 0.1%) vs. vehicle (−2.7±0.1%, P <0.05), PCWP and LVEDP. In addition, PPCA improved SaO 2 and relieved labored breathing as compared to vehicle controls. In contrast, renal blood flow, LV d P/ d tmax and cardiac output were not altered by PPCA. Early administration of PPCA (30μg/kg, IV) at 5 minutes after hypoxia completely blocked the hypoxic pulmonary vasoconstriction for over 80 minutes. These data suggest that activation of sGC by PPCA improves pulmonary hemodynamics and function in hypoxia‐induced pulmonary hypertension.