RGD Reference Report - The myocardial beta-adrenergic system in spontaneously hypertensive heart failure (SHHF) rats. - Rat Genome Database

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The myocardial beta-adrenergic system in spontaneously hypertensive heart failure (SHHF) rats.

Authors: Anderson, KM  Eckhart, AD  Willette, RN  Koch, WJ 
Citation: Anderson KM, etal., Hypertension. 1999 Jan;33(1 Pt 2):402-7.
RGD ID: 1625790
Pubmed: PMID:9931137   (View Abstract at PubMed)

-Responsiveness to beta-adrenergic stimulation is reduced in the failing human myocardium. This results principally from reduced beta-adrenergic receptor (betaAR) density, elevated beta-adrenergic receptor kinase 1 (betaARK1) levels, and functional uncoupling of remaining receptors. The temporal nature of changes in the human myocardial beta-adrenergic system relative to onset of symptomatic heart failure (HF) has been difficult to discern. A relatively new model of HF, the spontaneously hypertensive heart failure (SHHF) rat spontaneously and reproducibly develops left ventricular hypertrophy (LVH) and progresses to HF, thus enabling longitudinal studies to examine the cellular and molecular bases for hypertension-induced cardiac hypertrophy and subsequent HF. The purpose of this study was to examine age-dependent changes in the betaAR system in this model. Lean male SHHF rats at 3, 7, 14, and 20 months were compared with age-matched Sprague-Dawley (SD) control rats ([C]; 4 animals/group). At all ages the SHHF rats had elevated blood pressures and left ventricular end-diastolic pressure relative to the SD control rats (P<0.05). Compared with age-matched SD control rats, LVH was evident by 3 months in SHHF rats; 20-month-old SHHF rats had significantly greater LVH compared with the other SHHF rat groups. beta-adrenergic responsiveness (maximal heart rate to isoproterenol) was reduced only in 20-month-old SHHF rats. betaARK1 protein levels and activity were elevated at 14 months (162+/-10% and 195+/-20% C, respectively), and betaARK1 protein remained elevated at 20 months (140+/-14% C). In contrast, G protein-coupled receptor kinase 5, a second receptor kinase in the heart, remained unchanged at all ages. betaAR density did not change with age in the SD control rats and was similar in the SHHF rats until 20 months of age when the receptor number was reduced (30+/-1%). These data indicate that cardiac dysfunction is coincident with reduced betaAR density. Importantly, cardiac dysfunction was preceded by elevated betaARK1 levels and activity, thus suggesting that betaARK1 may be a precipitating factor in the transition from hypertension-induced compensatory cardiac hypertrophy to HF. Furthermore, these results indicate that the SHHF rat is a powerful model for use in examination of the mechanisms involved in alterations of beta-adrenergic signaling that occur in human HF.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
congestive heart failure  ISOGrk2 (Rattus norvegicus)1625790; 1625790associated with Hypertrophy more ...RGD 
congestive heart failure  IEP 1625790associated with Hypertrophy more ...RGD 
congestive heart failure  IAGP 1625790compared to Sprague Dawley controlsRGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
decreased cardiac muscle contractility  IAGP 1625790compared to Sprague Dawley controlsRGD 
heart left ventricle hypertrophy  IAGP 1625790compared to Sprague Dawley controlsRGD 
hypertension  IAGP 1625790compared to Sprague Dawley controlsRGD 
increased left ventricle developed pressure  IAGP 1625790compared to Sprague Dawley controlsRGD 
Objects Annotated

Genes (Rattus norvegicus)
Grk2  (G protein-coupled receptor kinase 2)

Genes (Mus musculus)
Grk2  (G protein-coupled receptor kinase 2)

Genes (Homo sapiens)
GRK2  (G protein-coupled receptor kinase 2)

Strains
SHHFcp/+/Mcc  (NA)


Additional Information