Abstract
Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers have been demonstrated to improve symptoms and prognosis in heart failure (HF). We compared the effects of ACE inhibition and AT1 receptor blockade on myocardial β-adrenoceptor desensitization in rabbits with HF established 3 weeks after myocardial infarction (MI) with left circumflex coronary artery ligation. Rabbits with MI were randomized to no treatment, the ACE inhibitor temocapril (0.5 mg/kg/day) or AT1 receptor blocker valsartan (3 mg/kg/day). Echocardiographic examinations showed that, relative to rabbits with untreated MI, rabbits receiving temocapril or valsartan had a limitation of cardiac remodeling and prevention of the development of systolic dysfunction. Circulating plasma norepinephrine levels that were markedly elevated in MI animals were strongly inhibited by temocapril or valsartan therapy. β-Adrenoceptor density, β-adrenoceptor proportion showing high-affinity agonist binding, and basal and isoproterenol-stimulated adenylate cyclase activities were significantly reduced in MI rabbits. These defects were similarly reversed by temocapril or valsartan. Importantly, as found in human HF, myocardial protein levels of β-adrenoceptor kinase 1 and Giα were significantly elevated in MI rabbits, suggesting that these molecules are contributing to the defects in myocardial β-adrenoceptor signaling. The expression levels of these molecules were normalized equally by both treatments. The results suggest that pharmacologically different interventions in the renin-angiotensin system can equivalently improve the derangements in the β-adrenoceptor signaling system in the failing heart. This may be important for the beneficial effects of these agents in HF.
Footnotes
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DOI: 10.1124/jpet.102.040956
- Abbreviations:
- HF
- heart failure
- βARK1
- β-adrenoceptor kinase 1
- Gi
- inhibitory G protein
- Gs
- stimulatory G protein
- RAS
- renin-angiotensin system
- ACE
- angiotensin-converting enzyme
- AT1
- angiotensin II type 1
- MI
- myocardial infarction
- LCX
- left circumflex coronary artery
- LV
- left ventricle
- LVDd
- LV endo-diastolic dimension
- LVDs
- LV endo-systolic dimension
- ICYP
- iodocyanopindolol
- GppNHp
- 5′-guanylyl imidodiphosphate
- PBS
- phosphate-buffered saline
- Received August 10, 2002.
- Accepted September 30, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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