Chronic activation of the low affinity site of beta -adrenoceptors stimulates haemodynamics but exacerbated pressure-overload cardiac remodelling

Helen Kiriazis, Naquita Tugiono, Qi Xu, Xiao-Ming Gao, Nicole Jennings, Ziqui Ming, Yidan Su, Paul Klenowski, Roger James Summers, Alberto Kaumann, Peter Molenaar, Xiao-Jun Du

Research output: Contribution to journalArticleResearchpeer-review

Abstract

BACKGROUND AND PURPOSE: The beta1 -adrenoceptor has at least two binding sites, high and low affinity sites (beta1H and beta1L , respectively), which mediate cardiostimulation. While beta1H - adrenoceptor can be blocked by all clinically used beta-blockers, beta1L -adrenoceptor is relatively resistant to blockade. Thus, chronic beta1L -adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of beta1H -adrenoceptors. It is important to determine the potential significance of beta1L -adrenoceptors in vivo, particularly in the setting of disease. EXPERIMENTAL APPROACH: C57Bl/6 male mice were used. Chronic (4 or 8 weeks) beta1L -adrenoceptor activation was achieved by treatment, via osmotic minipumps, with (-)-CGP12177 (10 mg kg-1 day-1 ). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS: (-)-CGP12177 treatment in healthy mice increased heart rate and left ventricular (LV) contractility. In mice subjected to transverse aorta constriction (TAC), (-)-CGP12177 treatment during 4-8 or 4-12 weeks, respectively, after TAC led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment to mice with TAC exacerbated myocardial expression of hypertrophic, fibrogenic and inflammatory genes (all P
Original languageEnglish
Pages (from-to)352 - 365
Number of pages14
JournalBritish Journal of Pharmacology
Volume170
Issue number2
DOIs
Publication statusPublished - 2013

Cite this

Kiriazis, Helen ; Tugiono, Naquita ; Xu, Qi ; Gao, Xiao-Ming ; Jennings, Nicole ; Ming, Ziqui ; Su, Yidan ; Klenowski, Paul ; Summers, Roger James ; Kaumann, Alberto ; Molenaar, Peter ; Du, Xiao-Jun. / Chronic activation of the low affinity site of beta -adrenoceptors stimulates haemodynamics but exacerbated pressure-overload cardiac remodelling. In: British Journal of Pharmacology. 2013 ; Vol. 170, No. 2. pp. 352 - 365.
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abstract = "BACKGROUND AND PURPOSE: The beta1 -adrenoceptor has at least two binding sites, high and low affinity sites (beta1H and beta1L , respectively), which mediate cardiostimulation. While beta1H - adrenoceptor can be blocked by all clinically used beta-blockers, beta1L -adrenoceptor is relatively resistant to blockade. Thus, chronic beta1L -adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of beta1H -adrenoceptors. It is important to determine the potential significance of beta1L -adrenoceptors in vivo, particularly in the setting of disease. EXPERIMENTAL APPROACH: C57Bl/6 male mice were used. Chronic (4 or 8 weeks) beta1L -adrenoceptor activation was achieved by treatment, via osmotic minipumps, with (-)-CGP12177 (10 mg kg-1 day-1 ). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS: (-)-CGP12177 treatment in healthy mice increased heart rate and left ventricular (LV) contractility. In mice subjected to transverse aorta constriction (TAC), (-)-CGP12177 treatment during 4-8 or 4-12 weeks, respectively, after TAC led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment to mice with TAC exacerbated myocardial expression of hypertrophic, fibrogenic and inflammatory genes (all P",
author = "Helen Kiriazis and Naquita Tugiono and Qi Xu and Xiao-Ming Gao and Nicole Jennings and Ziqui Ming and Yidan Su and Paul Klenowski and Summers, {Roger James} and Alberto Kaumann and Peter Molenaar and Xiao-Jun Du",
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Chronic activation of the low affinity site of beta -adrenoceptors stimulates haemodynamics but exacerbated pressure-overload cardiac remodelling. / Kiriazis, Helen; Tugiono, Naquita; Xu, Qi; Gao, Xiao-Ming; Jennings, Nicole; Ming, Ziqui; Su, Yidan; Klenowski, Paul; Summers, Roger James; Kaumann, Alberto; Molenaar, Peter; Du, Xiao-Jun.

In: British Journal of Pharmacology, Vol. 170, No. 2, 2013, p. 352 - 365.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Chronic activation of the low affinity site of beta -adrenoceptors stimulates haemodynamics but exacerbated pressure-overload cardiac remodelling

AU - Kiriazis, Helen

AU - Tugiono, Naquita

AU - Xu, Qi

AU - Gao, Xiao-Ming

AU - Jennings, Nicole

AU - Ming, Ziqui

AU - Su, Yidan

AU - Klenowski, Paul

AU - Summers, Roger James

AU - Kaumann, Alberto

AU - Molenaar, Peter

AU - Du, Xiao-Jun

PY - 2013

Y1 - 2013

N2 - BACKGROUND AND PURPOSE: The beta1 -adrenoceptor has at least two binding sites, high and low affinity sites (beta1H and beta1L , respectively), which mediate cardiostimulation. While beta1H - adrenoceptor can be blocked by all clinically used beta-blockers, beta1L -adrenoceptor is relatively resistant to blockade. Thus, chronic beta1L -adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of beta1H -adrenoceptors. It is important to determine the potential significance of beta1L -adrenoceptors in vivo, particularly in the setting of disease. EXPERIMENTAL APPROACH: C57Bl/6 male mice were used. Chronic (4 or 8 weeks) beta1L -adrenoceptor activation was achieved by treatment, via osmotic minipumps, with (-)-CGP12177 (10 mg kg-1 day-1 ). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS: (-)-CGP12177 treatment in healthy mice increased heart rate and left ventricular (LV) contractility. In mice subjected to transverse aorta constriction (TAC), (-)-CGP12177 treatment during 4-8 or 4-12 weeks, respectively, after TAC led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment to mice with TAC exacerbated myocardial expression of hypertrophic, fibrogenic and inflammatory genes (all P

AB - BACKGROUND AND PURPOSE: The beta1 -adrenoceptor has at least two binding sites, high and low affinity sites (beta1H and beta1L , respectively), which mediate cardiostimulation. While beta1H - adrenoceptor can be blocked by all clinically used beta-blockers, beta1L -adrenoceptor is relatively resistant to blockade. Thus, chronic beta1L -adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of beta1H -adrenoceptors. It is important to determine the potential significance of beta1L -adrenoceptors in vivo, particularly in the setting of disease. EXPERIMENTAL APPROACH: C57Bl/6 male mice were used. Chronic (4 or 8 weeks) beta1L -adrenoceptor activation was achieved by treatment, via osmotic minipumps, with (-)-CGP12177 (10 mg kg-1 day-1 ). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS: (-)-CGP12177 treatment in healthy mice increased heart rate and left ventricular (LV) contractility. In mice subjected to transverse aorta constriction (TAC), (-)-CGP12177 treatment during 4-8 or 4-12 weeks, respectively, after TAC led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment to mice with TAC exacerbated myocardial expression of hypertrophic, fibrogenic and inflammatory genes (all P

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DO - 10.1111/bph.12272

M3 - Article

VL - 170

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EP - 365

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 1476-5381

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ER -