Abstract | BACKGROUND:
Adenosine elicits cardioprotection through A1-receptor activation. Therapy with adenosine A1-receptor agonists, however, is limited by undesirable actions of full agonism, such as bradycardia. This study examined the effects of capadenoson (CAP), a partial adenosine A1-receptor agonist, on left ventricular (LV) function and remodeling in dogs with heart failure. METHODS AND RESULTS: Twelve dogs with microembolization-induced heart failure were randomized to 12 weeks oral therapy with CAP (7.5 mg BID; n=6) or to no therapy (control; n=6). LV end-diastolic and end-systolic volumes, ejection fraction, plasma norepinephrine, and n-terminal pro- brain natriuretic peptide were measured before (pre) and 1 and 12 weeks after therapy (post). LV tissue obtained at post was used to assess volume fraction of interstitial fibrosis, sarcoplasmic reticulum calcium ATPase-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, end-diastolic and end-systolic volumes increased and ejection fraction decreased significantly from pre to post (ejection fraction, 30±2 versus 27±1%; P<0.05). In CAP-treated dogs, end-diastolic volume was unchanged; ejection fraction increased significantly after 1 week (36±2 versus 27±2%; P<0.05) with a further increase at post (39±2%; P<0.05), whereas end-systolic volume decreased. CAP significantly decreased volume fraction of interstitial fibrosis, normalized sarcoplasmic reticulum calcium ATPase-2a activity and expression of UCP-2 and UCP-3, and GLUT-1 and GLUT-2 and significantly decreased plasma norepinephrine and n-terminal pro- brain natriuretic peptide. CONCLUSIONS: In heart failure dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial adenosine A1-receptor agonists for the treatment of chronic heart failure.
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Authors | Hani N Sabbah, Ramesh C Gupta, Smita Kohli, Mengjun Wang, Sharad Rastogi, Kefei Zhang, Katja Zimmermann, Nicole Diedrichs, Barbara E Albrecht-Küpper |
Journal | Circulation. Heart failure
(Circ Heart Fail)
Vol. 6
Issue 3
Pg. 563-71
(May 2013)
ISSN: 1941-3297 [Electronic] United States |
PMID | 23564604
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adenosine A1 Receptor Agonists
- Aminopyridines
- Thiazoles
- capadenoson
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Topics |
- Adenosine A1 Receptor Agonists
(pharmacology, therapeutic use)
- Aminopyridines
(pharmacology)
- Animals
- Dogs
- Echocardiography, Doppler
- Heart Failure
(diagnostic imaging, drug therapy, physiopathology)
- Hemodynamics
(drug effects)
- Stroke Volume
(drug effects)
- Thiazoles
(pharmacology)
- Ventricular Function, Left
(drug effects, physiology)
- Ventricular Pressure
(drug effects, physiology)
- Ventricular Remodeling
(drug effects, physiology)
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