β-adrenergic receptor responsiveness in aging heart and clinical implications (original) (raw)
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Experimental Gerontology, 2021
Ageing is associated with a progressive reduction in physical capacity reducing quality of life. One key physiological limitation of physical capacity that deteriorates in a progressive age-dependent manner, is cardiac reserve. Peak cardiac output falls progressively with advancing age such that in extreme old age there is limited ability to enhance cardiac output beyond basal function as is required to support the increased metabolic needs of physical activity. This loss of dynamic range in cardiac output associates with a progressive reduction in the heart's response to adrenergic stimulation. A combination of decreases in the expression and functioning of beta1 adrenergic receptors partially underly this change. Changes in end effector proteins also have a role to play in this decline. Alterations in the efficiency of excitationcontraction coupling contribute to the reduced chronotropic, inotropic and lusitropic responses of the aged heart. Moderate to vigorous endurance exercise training however has some potential to counter elements of these changes. Further studies are required to fully elucidate the key pivotal mechanisms involved in the age-related loss of response to adrenergic signalling to allow targeted therapeutic strategies to be developed with the aim of preserving physical capacity in advanced old age.
Adrenergic signaling in heart failure and cardiovascular aging
Both cardiovascular disease and aging are associated with changes in the sympathetic nervous system. Indeed, mounting evidence indicates that adrenergic receptors are functionally involved in numerous processes underlying both aging and cardiovascular disorders, in particular heart failure. This article will review the pathophysiological role of the sympathetic nervous system in heart failure and cardiovascular aging.
AJP: Heart and Circulatory Physiology, 2007
adrenergic receptor (-AR) signaling and left ventricular (LV) responses to -AR stimulation are impaired with aging. It is shown that exercise and -AR blockade have a favorable effect on cardiac and vascular -AR signaling in several cardiovascular diseases. In the present study, we examined the effects of these two different strategies on -AR dysregulation and LV inotropic reserve in the aging heart. Forty male Wistar-Kyoto aged rats were randomized to sedentary, exercise (12 wk treadmill training), metoprolol (250 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 for 4 wk), and exercise plus metoprolol treatment protocols. Ten male Wistar-Kyoto sedentary young rats were also used as a control group. Old trained, old metoprolol-treated, and old trained plus metoprololtreated rats showed significantly improved LV maximal and minimal first derivative of the pressure rise responses to -AR stimulation (isoproterenol) compared with old untrained animals. We found a significant reduction in cardiac sarcolemmal membrane -AR density and adenylyl cyclase activity in old untrained animals compared with young controls. Exercise training and metoprolol, alone or combined, restored cardiac -AR density and G-protein-dependent adenylyl cyclase activation in old rats. Although cardiac membrane G-proteinreceptor kinase 2 levels were not upregulated in untrained old compared with young control rats, both exercise and metoprolol treatment resulted in a dramatic reduction of G-protein-receptor kinase 2 protein levels, which is a further indication of -AR signaling amelioration in the aged heart induced by these treatment modalities. In conclusion, we demonstrate for the first time that exercise and -AR blockade can similarly ameliorate -AR signaling in the aged heart, leading to improved -AR responsiveness and corresponding LV inotropic reserve.
Cardiac -adrenergic receptor ( -AR) signaling and left ventricular (LV) responses to -AR stimulation are impaired with aging. It is shown that exercise and -AR blockade have a favourable effect on cardiac and vascular -AR signaling in several cardiovascular diseases. In the present study, we examined the effects of these two different strategies on AR dysregulation and LV inotropic reserve in the aging heart. Forty male Wistar-Kyoto (WKY) aged rats were randomized to sedentary, exercise (12 wks treadmill training), metoprolol (250 mg/Kg/d for 4 wks), and exercise plus metoprolol treatment protocols. Ten male WKY sedentary young rats were also used as control group. Old trained, old metoprolol, and old trained plus metoprolol-treated rats showed significantly improved LV +dP/dt and -dP/dt responses to -AR stimulation (isoproterenol) compared to old untrained animals. We found a significant reduction in cardiac sarcolemmal membrane AR density and adenylyl cyclase (AC) activity in old untrained animals compared to young control ones. Exercise training as well as metoprolol, alone or combined, restored cardiac AR density and G-protein dependent AC activation in old rats. Although cardiac membrane Gprotein receptor kinase-2 (GRK2) levels were not upregulated in untrained old compared to young control rats, both exercise and metoprolol, resulted in a dramatic reduction of GRK2 protein levels, which is a further indication of AR signaling amelioration in the aged heart induced by these treatment modalities. In conclusion, we demonstrate for the first time that exercise and -AR blockade can similarly ameliorate AR signaling in the aged heart leading to improved AR responsiveness and corresponding LV inotropic reserve.
Mitigation of beta 1- and/or beta 2-adrenoceptor function in human heart failure
British Journal of Clinical Pharmacology, 1990
Patients with congestive heart failure (CHF) have an elevated activity of the sympathoadrenal system. We have investigated several aspects of P-adrenoceptor desensitization in such patients. 2 The positive inotropic response to isoprenaline was attenuated in CHF patients, and the pD2-values for isoprenaline's positive inotropic effect gradually decreased in more severe forms of the disease. Stimulation of adenylate cyclase by isoprenaline was also mitigated in cardiac membranes from patients with CHF.
The Adrenergic System in Cardiovascular Metabolism and Aging
The adrenergic (sympathetic) nervous system exerts numerous effects on the cardiovascular system, including increase in cardiac contractility (positive inotropy), heart rate acceleration (positive chronotropy), hastened cardiac relaxation (positive lusitropy), and accelerated atrioventricular conduction (positive dromotropy). Most of these effects are mediated by adrenergic receptors(also known as adrenoceptors, ARs), which belong to the guanine nucleotide-binding G protein-coupled receptor (GPCR) superfamily . GPCRs are heptahelical trans-membrane sensors, accounting for approximately 4 % of the entire protein-coding genome, widely considered the most important drug targets in physiology and medicine . These receptors consist of seven membrane-spanning domains, three intra-and three extracellular loops, one extracellular N-terminal domain, and one intracellular C-terminal tail . GPCR signaling is terminated by phosphorylation of the intracellular domains of the receptor by the family of G-protein-coupled receptor kinases (GRKs) . GRK-mediated phosphorylation increases the affinity of GPCRs for the arrestin class of proteins, which uncouples the phosphorylated receptor from the G-protein and subsequently targets the receptor for internalization . Downregulation of GPCRs has been shown to reduce the functional activity of classical signaling paradigms up to 80 % [69].
Circulation Research, 1990
The contractile response of the aged adult heart to beta-adrenergic stimulation is known to be reduced compared with the young adult heart. Since endogenous adenosine exerts an antiadrenergic action in the heart, this study was undertaken to determine if the basal endogenous level of myocardial adenosine increases with age and whether this increase mediates the reduced responsiveness of aged heart to beta-adrenergic stimulation. Young (3-5 months) and aged (12-22 months) Sprague-Dawley adult rat hearts of CD and SD stock were perfused at constant pressure and paced at 270 contractions/min. The two age groups had a similar level of +dP/dtmax (index of contractility) under control conditions. Adenosine release into the coronary effluent was 30 +/- 3 nmol/min/g dry wt from young and 54 +/- 9 nmol/min/g dry wt from aged hearts. Inosine release was also greater from the aged hearts. Isoproterenol (10(-8) M) stimulation increased contractile state by 113% in young hearts and only 69% in a...
2007
293:H1596-H1603, 2007. First published 8 June 2007; Am J Physiol Heart Circ Physiol Walter J. Koch and Franco Rengo Marchese, Giovanni Esposito, Antonio Rapacciuolo, Barbara Rinaldi, Nicola Ferrara, Lymperopoulos, Carmela Zincarelli, Francesca Fortunato, Luca Golino, Massimo Dario Leosco, Giuseppe Rengo, Guido Iaccarino, Amelia Filippelli, Anastasios adrenergic stimulation signaling and enhance cardiac responsiveness to -adrenergic receptor β age-dependent impairment of -blocker treatment ameliorate β Exercise training and
Journal of Cardiovascular Pharmacology, 2006
Objectives: To determine if centrally reducing sympathetic tone with clonidine will reverse the downregulation in the alpha-adrenergic (aAR) and beta-adrenergic (bAR) responses seen with normal aging. Methods: Twelve rigorously screened young adult (mean age, 26 years) and 15 older adult (mean age, 69 years) subjects were studied before and after using the clonidine patch (TTS-2) for 2 weeks. bAR (isoproterenol at 35 ng/kg/min) and aAR (phenylephrine at 1.0 mg/kg/min) were assessed using radionuclide measures of end diastolic, end systolic, and stroke volume indices, cardiac index, and ejection fraction. Results: Clonidine reduced resting plasma norepinephrine and this reduction was greater in older subjects (247 6 3 versus 226 6 6%, P = 0.001). After 2 weeks of clonidine patch, upregulation of the bAR was significantly higher in young subjects for heart rate (+10.7 6 1.5 versus +4.6 6 1.5 bpm; P = 0.01). There was no significant age-associated difference in the upregulation of the aAR with clonidine for systolic, diastolic, and mean blood pressure or systemic vascular resistance. Conclusions: With aging, there is an impaired resensitization of the chronotropic bAR response with central sympathetic downregulation that is not seen with the aAR.