Mechanisms of preserved baseline cardiac systolic function in rats with adrenergic inotropic downregulation

Osadchii, Oleg E.; Woodiwiss, Angela J.; Alves, Nélson; Norton, Gavin R.

doi:10.1016/j.lfs.2005.04.047

Cited by 15 publications

(11 citation statements)

References 39 publications

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“…LV relative wall thickness was calculated as a ratio between LV end-diastolic posterior wall thickness and internal LV end-diastolic radius. Measurements were made from three consecutive beats to determine LV endocardial (FS end ) and midwall (FS mid ) fractional shortening as previously described [20][21][22]. LV FS end and FS mid were utilized as load-dependent indexes of chamber and intrinsic myocardial function, respectively.…”

Section: Echocardiographymentioning

confidence: 99%

“…LV FS end and FS mid were utilized as load-dependent indexes of chamber and intrinsic myocardial function, respectively. Isolated, perfused heart preparations Load-independent measures of systolic chamber, intrinsic myocardial function, and contractile responses to inotropic agents were determined ex vivo under controlled conditions as previously outlined [20][21][22]36]. The rats were anesthetized with intraperitoneal injections of ketamine and xylazine (75 and 15 mg/kg, respectively).…”

Section: Echocardiographymentioning

confidence: 99%

“…Load-independent measures of systolic chamber function were determined from the slope of the linear portion of the LV developed pressure-volume relations. Load-independent measures of intrinsic myocardial systolic function were assessed by constructing LV developed stress-strain relations and comparing the slopes of these relationships [20][21][22]. LV developed stress and strain values were calculated using previously described equations [35].…”

Section: Echocardiographymentioning

confidence: 99%

“…It is important to note that cardiac norepinephrine spillover rate is a strong prognostic marker for adverse clinical outcomes in patients with heart failure [16]. Sustained sympathetic activation promotes systolic cardiac dysfunction via chamber dilatation [17,31,36], myocyte loss due to apoptosis and necrosis [2,24,28,29], depleted myocardial norepinephrine stores [4,7], and attenuated β-adrenoreceptor (β-AR)-cAMP-mediated inotropic responses [3,[21][22][23]. The relative importance of these mechanisms in the progression of cardiac failure nevertheless remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

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Temporal changes in myocardial adrenergic regulation with the progression to pump dysfunction after chronic β-adrenoreceptor activation in rats

Osadchii

Woodiwiss

Deftereos

et al. 2007

Pflugers Arch - Eur J Physiol

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We evaluated the relationship between myocardial norepinephrine release or inotropic responsiveness to adrenergic stimulation and intrinsic myocardial function after the progression to pump dysfunction induced by chronic beta-adrenoreceptor activation (isoproterenol [ISO], 0.1 mg/kg/day for 1 month or 6 months) in rats. Left ventricular (LV) systolic chamber dysfunction occurred after 6 months, but not after 1 month of beta-adrenoreceptor activation, as evidenced by reduced LV endocardial fractional shortening determined by echocardiography and a decrease in the slope of the LV systolic pressure-volume relations assessed in isolated, perfused heart preparations. A reduced pump function at 6 months of ISO administration was associated with chamber dilatation, while LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relations (isolated heart preparations), indices of intrinsic myocardial function, were unchanged. After 1 month of ISO administration, reduced beta1- and beta2-adrenoreceptor-mediated and sustained alpha-adrenoreceptor-mediated inotropic responses were noted. Nevertheless, increased inotropic potency of beta-adrenoreceptor agonists and upregulation of alpha-adrenoreceptor-mediated contractile responses were noted after 6 months of ISO administration. Increased adrenergic-inotropic responsiveness after 6 months of ISO administration was associated with depleted LV norepinephrine stores, as evidenced by reduced desipramine-stimulated norepinephrine concentrations in the coronary effluent. In conclusion, in the progression from compensated cardiac hypertrophy to pump dysfunction after chronic sympathetic activation, a preserved intrinsic myocardial contractility is accounted for by paradoxical upregulation of adrenergic-mediated contractile responses.

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Section: Echocardiographymentioning

confidence: 99%

Section: Echocardiographymentioning

confidence: 99%

Section: Echocardiographymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Temporal changes in myocardial adrenergic regulation with the progression to pump dysfunction after chronic β-adrenoreceptor activation in rats

Osadchii

Woodiwiss

Deftereos

et al. 2007

Pflugers Arch - Eur J Physiol

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“…In patients with coronary artery disease, tissue Doppler assessments revealed lower density of β-adrenoceptors in LV regions with impaired systolic function as compared to normal myocardial segments [57]. In the meantime, downregulation of β-adrenoceptor signaling pathway has been revealed in animal models of compensated cardiac hypertrophy [7,43,49,50] and in patients with hypertrophic obstructive cardiomyopathy or aortic stenosis with preserved contractile function [36,55,56]. These findings suggest that impaired β-adrenoceptor-mediated signaling is not necessarily a consequence of systolic pump failure, and it may initially develop at compensated stage of cardiac disease.…”

Section: Introductionmentioning

confidence: 99%

Chronic sympathetic activation promotes downregulation of β-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction

Soltysinska

Thiele

Olesen

et al. 2011

Pflugers Arch - Eur J Physiol

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It is uncertain if downregulation of β-adrenoceptor signaling pathway is promoted by an enhanced adrenergic tone at an early stage of cardiac disease, or it develops secondary to detrimental local myocardial changes in advanced heart failure. We examined the integrity of β-adrenoceptor signaling pathway upon chronic infusion of isoproterenol, a β-adrenoceptor agonist, at a dose producing no structural left ventricular (LV) remodeling and systolic dysfunction. Subcutaneous isoproterenol infusion (400 μg kg(-1) h(-1) over 16 days) to guinea pigs using osmotic minipumps produced no change in cardiac weights, LV internal dimensions, myocyte cross-sectional area, extent of interstitial fibrosis, and basal contractile function. Isolated, perfused heart preparations from isoproterenol-treated guinea pigs exhibited attenuated responsiveness to acute β-adrenoceptor stimulation, as evidenced by reduced LV developed pressure increase, less shortening of LV epicardial monophasic action potential and effective refractory period, and less myocardial cyclic adenosine monophosphate elevation, in response to isoproterenol exposure, when compared to saline-treated controls. Pharmacological responses to forskolin, an activator of the adenylate cyclase catalytic subunit, were well preserved in isoproterenol-treated hearts. Downregulation of β-adrenoceptor-mediated effects upon chronic isoproterenol infusion was associated with markedly reduced stimulatory G-protein α-subunit (G(sα)) myocardial expression levels. No change in expression levels of β-adrenoceptors, G-protein-coupled receptor kinase 2, inhibitory G-protein α-subunit (G(iα2)), and Ca(v)1.2 and K(v)7.1 ion channels was determined in isoproterenol-treated hearts. We therefore conclude that sustained adrenergic overstimulation may promote downregulation of myocardial β-adrenoceptor-mediated effects independently of structural LV remodeling and systolic failure, an effect attributed to β-adrenoceptor uncoupling from adenylate cyclase due to reduced G(sα)-protein expression.

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Dofetilide Promotes Repolarization Abnormalities in Perfused Guinea-pig Heart

Osadchii

2012

Cardiovasc Drugs Ther

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Mechanisms of preserved baseline cardiac systolic function in rats with adrenergic inotropic downregulation

Cited by 15 publications

References 39 publications

Temporal changes in myocardial adrenergic regulation with the progression to pump dysfunction after chronic β-adrenoreceptor activation in rats

Temporal changes in myocardial adrenergic regulation with the progression to pump dysfunction after chronic β-adrenoreceptor activation in rats

Chronic sympathetic activation promotes downregulation of β-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction

Dofetilide Promotes Repolarization Abnormalities in Perfused Guinea-pig Heart

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