Abstract
Background: Established therapies against chronic heart failure (CHF) like beta-blockade or renin-angiotensin inhibition still remain insufficient to conquer CHF, mainly because of the presence of non-responder or intolerability because of extremely low cardiac output. Recent report including ours revealed that transient administration of phosphodiesterase- 3 (PDE-III) inhibitor and subsequent PKA activation mimic preconditioning, reduce infarct size and restore cardiac function after myocardial infarction. Since PDE-III inhibition increases cardiac output, we tested whether intermittent transient PDE-III inhibition is also applicable to preventing non-ischemic cardiac remodeling and failure.
Methods and Results: Male Wistar-Kyoto rats underwent inhibition of nitric oxide synthase by L-NAME for 8 weeks, in the presence or absence of PDE-III inhibitor olprinone by gavage once a day, 3 times a week. L-NAME specifically increased blood pressure, promoted LV hypertrophy and remodeling. Hydralazine totally canceled blood pressure increase but unaffected LV remodeling and reduced contraction, as reported previously. Olprinone was well tolerated and reduced LV hypertrophy, fibrosis and wet lung weight/body weight ratio but unchanged high blood pressure afforded by L-NAME, suggesting that olprinone inhibited the progression of cardiac remodeling and failure beyond blood pressurelowering. Furthermore, LV infiltration of polymorphic neutrophils induced by L-NAME was eliminated by olprinone.
Conclusion: The intermittent transient PDE-III inhibition elicits cardioprotection against non-ischemic heart failure beyond hemodynamic effects, and the inhibition of inflammatory change might be involved in pathophysiology. Since PDE-III inhibition provides positive inotropic effect, this therapy might be a widely acceptable option for patients even with poor response to conventional therapies or severely low cardiac output.
Keywords: Cardiac hypertrophy, fibrosis, heart failure, inflammation, inodilator, intermittent, L-NAME, low output, nitric oxide, phosphodiesterase, polymorphonuclear neutrophils, preconditioning, remodeling
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