Abstract
Cardiac hypertrophy often causes impairment of cardiac function. Xenon (Xe), a naturally occurring noble gas, is known to provide neurological and myocardial protection without side effects. The conventional method of Xe delivery by inhalation is not feasible on a chronic basis. We have developed an orally deliverable, effective Xe formulation for long-term administration. We employed 2-hydroxypropyl)-β-cyclodextrin (HPCD), which was dissolved in water to increase the Xe concentration in solution. The beneficial effects of long-term oral administration of Xe-enriched solutions on cardiovascular function were evaluated in vivo. HPCD increased Xe solubility from 0.22 mM to 0.67 mM (3.8-fold). Aged ApoE knockout mice fed high-fat diet for 6 weeks developed hypertension, and myocardial hypertrophy with impaired cardiac function. Oral Xe prevented this ischemic damage, preserving normal blood pressure, while maintaining normal left ventricular mass and wall thickness. This novel formulation allows for gastrointestinal delivery and cardiovascular stabilization.
Highlights
Cardiovascular disease (CVD) is a common, and severe medical problem[1]
We developed a formulation of cyclodextrin-encapsulated Xe and demonstrated cardioprotective benefits in an aged ApoE knockout (KO) mouse model
We demonstrated a potential mechanism of Xe blood pressure lowing may be related to regulation of coupled endothelial NOS (eNOS)/Nitric oxide (NO). 4
Summary
Cardiovascular disease (CVD) is a common, and severe medical problem[1]. Attempts to mitigate CVD complications by management of risk factors, include optimization of dietary patterns and components that have cardiac protective effects. Xe helps sustain release of hypoxia inducible factor 1α (HIF-1α) and other modulators of inflammatory processes[7] such as heme oxygenase-18 and high mobility group protein B19. As many cardiovascular diseases result from chronic pathologic progression, there is a need to develop safe orally-administered formulations for long-term use. We produced a Xe-enriched solution for oral administration through encapsulation of Xe into cyclodextrin. As beneficial effects have been produced by oral administration of gas-enriched liquids[15,16,17,18,19], we hypothesize that therapeutic amounts of Xe can be incorporated into a liquid formation for oral delivery. We developed a formulation of cyclodextrin-encapsulated Xe and demonstrated cardioprotective benefits in an aged ApoE knockout (KO) mouse model
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