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

Responsiveness to beta-adrenergic stimulation is reduced in the failing human myocardium. This results principally from reduced beta-adrenergic receptor (beta AR) density, elevated beta-adrenergic receptor kinase 1 (beta ARK1) 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 beta AR 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. beta ARK1 protein levels and activity were elevated at 14 months (162+/-10% and 195+/-20% C, respectively), and beta ARK1 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. beta AR 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 beta AR density. Importantly, cardiac dysfunction was preceded by elevated beta ARK1 levels and activity, thus suggesting that beta ARK1 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.