Age-related changes in beta-adrenergic neuroeffector systems in the human heart.

White, Michel; Roden, Robert L.; Minobe, Wayne; Khan, Muneer; Larrabee, Patricia S.; Wollmering, Mary M.; Port, J. David; Anderson, Fred; Campbell, David; Feldman, Arthur M.

doi:10.1161/01.cir.90.3.1225

Cited by 255 publications

(132 citation statements)

References 83 publications

(10 reference statements)

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…31,32 However, ADRB2 density has not changed with age in a number of studies on human tissues including heart and lung. [33][34][35] Our results show that age selectively modulates the density of lymphocyte ADRB2 because only haplotype 1 carriers had a significant (48%) age-associated decline in ADRB2 density. When these same data were examined without considering the ADRB2 haplotype (ie, grouping only according to age), there was no age difference in ADRB2 density.…”

Section: Discussionmentioning

confidence: 60%

Interactive Effects of Common β ₂ -Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function

et al. 2005

View full text Add to dashboard Cite

Abstract-Few studies have examined to what extent genetic variants of the ␤ 2 -adrenoceptor (ADRB2) are involved in the development of hypertension with age, although ␤ 2 -adrenergic receptor responsiveness declines in older subjects. To investigate this, 10 common single-nucleotide polymorphisms (SNPs) in the promoter and coding regions of the ADRB2 gene were genotyped in an unrelated population consisting of 2 ethnic groups: European American (EA; nϭ610) and African American (AA; nϭ420). ADRB2 haplotypes were estimated by expectation maximization (EM) algorithmbased methods. In the general population for EAs and AAs, the variants of the ADRB2 gene, including the individual SNPs and their haplotypes, were not associated with hypertension. However, there was a significant interaction between age and one of the common haplotypes (haplotype 1) in EAs (Pϭ0.01). Haplotype 1 was associated with protection against hypertension in young (Յ50 years of age) but not in old (Ͼ50 years of age) EAs (odds ratio, 0.5; 95% confidence interval, 0.27 to 0.91; Pϭ0.02). This age-specific effect was further supported by the observations that young subjects carrying Ն1 copy of haplotype 1 had significantly lower diastolic blood pressure and nearly 2-fold higher ADRB2 binding density than the noncarriers (PϽ0.05). With aging, their ADRB2 numbers decreased to the level of the noncarriers, along with increased body mass index (7%; PϽ0.05) and decreased heart rate (7%; PϽ0.001). Our study suggests that age is an important modifier for the effects of ADRB2 polymorphisms on ADRB2 function and the development of hypertension.

show abstract

Section: Discussionmentioning

confidence: 60%

Interactive Effects of Common β ₂ -Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function

et al. 2005

View full text Add to dashboard Cite

show abstract

“…It has been suggested that the increase in MABP with age is a normal age-dependent process that may be a compensatory mechanism for loss of arterial compliance (4). Similarly, the decrease in HR is usually attributed to a diminution in the efficacy of ␤-adrenergic stimulation of the heart, which again is normal and an age-dependent process (41,43) The depressed MABP and HR in diabetic rats observed in the present study is in agreement with many other studies in STZ diabetic rats (9,14,18,20,23,31,39,44). Previous studies from our own laboratory have shown lower HR and reduced systolic blood pressure in conscious STZ-induced diabetic rats (44).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

Nagareddy¹,

Xia²,

McNeill³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

138

View full text Add to dashboard Cite

(MABP) and heart rate (HR), endothelial dysfunction, and attenuated pressor responses to vasoactive agents. We investigated whether these abnormalities are due to diabetes-associated activation of inducible nitric oxide synthase (iNOS). In addition, the effect of the duration of diabetes on these abnormalities was also evaluated. Diabetes was induced by administration of 60 mg/kg STZ via the tail vein. One, 3, 9, or 12 wk after STZ injection, MABP, HR, and endothelial function were measured in conscious unrestrained rats. Pressor response curves to bolus doses of methoxamine (MTX) and angiotensin II (ANG II) were constructed in the presence of N- [3(aminomethyl)benzyl]-acetamidine, dihydrochloride (1400W), a specific inhibitor of iNOS. Depressed MABP and HR and impairment of endothelial function were observed as early as 3 wk after induction of diabetes. Acute inhibition of iNOS with 1400W (3 mg/kg iv) restored the attenuated pressor responses to both MTX and ANG II without affecting the basal MABP and HR. Immunohistochemical and Western analysis blot studies in cardiovascular tissues revealed decreased expression of endothelial nitric oxide synthase (eNOS) concomitant with increased expression of iNOS and nitrotyrosine with the progression of diabetes. Our findings suggest that induction of iNOS in cardiovascular tissues is dependent on the duration of diabetes and contributes significantly to the depressed pressor responses to vasoactive agents and potentially to endothelial dysfunction. inducible nitric oxide synthase; nitric oxide; cardiovascular abnormalities CHRONIC HYPERGLYCEMIA has been shown to directly affect the composition and structure of cardiac, vascular, and renal tissues, the progressive modification of which results in a deranged cardiovascular homeostasis (8). Cardiovascular depression, characterized by depressed mean arterial blood pressure (MABP), heart rate (HR), and attenuated pressor responses to vasoactive agents is one of the most notable manifestations of this derangement, particularly in animal models of Type 1 diabetes. Although the exact mechanisms by which diabetes contributes to cardiovascular depression are currently unknown, it is likely that hyperglycemia may initiate this abnormality through the activation of protein kinase C, increased activity of the polyol pathway, formation of nonenzymatic advanced glycosylation end products, oxidative stress, and/or possibly by induction of nitric oxide (NO) synthase (NOS) (19,42).The role of NO in the regulation of hemodynamics under hyperglycemic conditions has been controversial. Despite an impairment of endothelial function and reduced bioavailability of endothelium-derived NO, streptozotocin (STZ)-induced diabetic rats are not hypertensive but instead are normotensive or hypotensive (9,14,18,20,23,31,39,44). In addition, an increased dependence on a functional NO system at the onset of diabetes has been reported to prevent the development of hypertension in STZ diabetic rats (12). It has been suggested that increased NO synthesis m...

show abstract

“…This decrease in uptake-1 results in increased noradrenaline concentrations at the receptor site that can further contribute to βAR desensitization and down-regulation. In aging, it is not clear whether the reduced βAR function is due to a decrease in β 1 AR density [as found in ventricular myocardium (43)] or due to a decrease in the catalytic unit of the adenylyl cyclase [as found in atria (44)]; however, both settings finally result in a diminished cyclic AMP formation upon βAR stimulation. In addition, also in the aging human heart, uptake-1 is reduced and the resulting increase in noradrenaline concentration at the receptor site might contribute to βAR desensitization.…”

Section: Changes In β-Adrenoceptor Functionmentioning

confidence: 99%

Cardiac Adrenoceptors: Physiological and Pathophysiological Relevance

Brodde¹,

Bruck²,

Leineweber³

2006

J Pharmacol Sci

212

161

View full text Add to dashboard Cite

Abstract. At present, nine adrenoceptor (AR) subtypes have been identified: α 1A -, α 1B -, α 1D -, α 2A -, α 2B -, α 2C -, β 1 -, β 2 -, and β 3 AR. In the human heart, β 1 -and β 2 AR are the most powerful physiologic mechanism to acutely increase cardiac performance. Changes in βAR play an important role in chronic heart failure (CHF). Thus, due to increased sympathetic activity in CHF, βAR are chronically (over)stimulated, and that results in β 1 AR desensitization and alterations of down-stream mechanisms. However, several questions remain open: What is the role of β 2 AR in CHF? What is the role of increases in cardiac G i -protein in CHF? Do increases in G-protein-coupled receptor kinase (GRK)s play a role in CHF? Does βAR-blocker treatment cause its beneficial effects in CHF, at least partly, by reducing GRK-activity? In this review these aspects of cardiac AR pharmacology in CHF are discussed. In addition, new insights into the functional importance of β 1 -and β 2 AR gene polymorphisms are discussed. At present it seems that for cardiovascular diseases, βAR polymorphisms do not play a role as disease-causing genes; however, they might be risk factors, might modify disease, and / or might influence progression of disease. Furthermore, βAR polymorphisms might influence drug responses. Thus, evidence has accumulated that a β 1 AR polymorphism (the Arg389Gly β 1 AR) may affect the response to βAR-blocker treatment.

show abstract

Age-related changes in beta-adrenergic neuroeffector systems in the human heart.

Cited by 255 publications

References 83 publications

Interactive Effects of Common β ₂ -Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function

Interactive Effects of Common β ₂ -Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

Cardiac Adrenoceptors: Physiological and Pathophysiological Relevance

Contact Info

Product

Resources

About

Age-related changes in beta-adrenergic neuroeffector systems in the human heart.

Cited by 255 publications

References 83 publications

Interactive Effects of Common β 2 -Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function

Interactive Effects of Common β 2 -Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

Cardiac Adrenoceptors: Physiological and Pathophysiological Relevance

Contact Info

Product

Resources

About

Interactive Effects of Common β ₂ -Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function

Interactive Effects of Common β ₂ -Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function