scholarly journals The β3 Adrenergic Receptor Antagonist L-748,337 Attenuates Dobutamine-Induced Cardiac Inefficiency While Preserving Inotropy in Anesthetized Pigs

2021 ◽  
pp. 107424842110487
Author(s):  
Lars Rødland ◽  
Leif Rønning ◽  
Anders Benjamin Kildal ◽  
Ole-Jakob How
Keyword(s):  
Adrenergic Receptor ◽  
Myocardial Metabolism ◽  
Combined Treatment ◽  
Left Ventricular ◽  
Dobutamine Infusion ◽  
Cardiac Energetics ◽  
Adrenergic Stimulation ◽  
Cardiac Efficiency ◽  
Drug Infusion ◽  
Cardiac Inotropy

Excessive myocardial oxygen consumption (MVO2) is considered a limitation for catecholamines, termed oxygen cost of contractility. We hypothesize that increased MVO2 induced by dobutamine is not directly related to contractility but linked to intermediary myocardial metabolism. Furthermore, we hypothesize that selective β3 adrenergic receptor (β3AR) antagonism using L-748,337 prevents this. In an open-chest pig model, using general anesthesia, we assessed cardiac energetics, hemodynamics and arterial metabolic substrate levels at baseline, ½ hour and 6 hours after onset of drug infusion. Cardiac efficiency was assessed by relating MVO2 to left ventricular work (PVA; pressure–volume area). Three groups received dobutamine (5 μg/kg/min), dobutamine + L-748,337 (bolus 50 μg/kg), or saline for time-matched controls. Cardiac efficiency was impaired over time with dobutamine infusion, displayed by persistently increased unloaded MVO2 from ½ hour and 47% increase in the slope of the PVA–MVO2 relation after 6 hours. Contractility increased immediately with dobutamine infusion ( dP/ dt max; 1636 ± 478 vs 2888 ± 818 mmHg/s, P < 0.05) and persisted throughout the protocol (2864 ± 1055 mmHg/s, P < 0.05). Arterial free fatty acid increased gradually (0.22 ± 0.13 vs 0.39 ± 0.30 mM, P < 0.05) with peak levels after 6 hours (1.1 ± 0.4 mM, P < 0.05). By combining dobutamine with L-748,337 the progressive impairment in cardiac efficiency was attenuated. Interestingly, this combined treatment effect occurred despite similar alterations in cardiac inotropy and substrate supply. We conclude that the extent of cardiac inefficiency following adrenergic stimulation is dependent on the duration of drug infusion, and β3AR blockade may attenuate this effect.

β-blockade abolishes the augmented cardiac tPA release induced by transactivation of heterodimerised bradykinin receptor-2 and β2-adrenergic receptor in vivo

2014 ◽  
Vol 112 (11) ◽  
pp. 951-959 ◽  
Author(s):  
Morten Eriksen ◽  
Arnfinn Ilebekk ◽  
Alessandro Cataliotti ◽  
Cathrine Rein Carlson ◽  
Torstein Lyberg ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Sympathetic Nerves ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Adrenergic Stimulation ◽  
Β2 Adrenergic Receptor ◽  
Β Blocker

SummaryBradykinin (BK) receptor-2 (B2R) and β2-adrenergic receptor (β2AR) have been shown to form heterodimers in vitro. However, in vivo proofs of the functional effects of B2R-β2AR heterodimerisation are missing. Both BK and adrenergic stimulation are known inducers of tPA release. Our goal was to demonstrate the existence of B2R-β2AR heterodimerisation in myocardium and to define its functional effect on cardiac release of tPA in vivo. We further investigated the effects of a non-selective β-blocker on this receptor interplay. To investigate functional effects of B2R-β2AR heterodimerisation (i. e. BK transactivation of β2AR) in vivo, we induced serial electrical stimulation of cardiac sympathetic nerves (SS) in normal pigs that underwent concomitant BK infusion. Both SS and BK alone induced increases in cardiac tPA release. Importantly, despite B2R desensitisation, simultaneous BK infusion and SS (BK+SS) was characterised by 2.3 ± 0.3-fold enhanced tPA release compared to SS alone. When β-blockade (propranolol) was introduced prior to BK+SS, tPA release was inhibited. A persistent B2R-β2AR heterodimer was confirmed in BK-stimulated and nonstimulated left ventricular myocardium by immunoprecipitation studies and under non-reducing gel conditions. All together, these results strongly suggest BK transactivation of β2AR leading to enhanced β2AR-mediated release of tPA. Importantly, non-selective β-blockade inhibits both SS-induced release of tPA and the functional effects of B2R-β2AR heterodimerisation in vivo, which may have important clinical implications.

Adrenergic responsiveness is reduced, while baseline cardiac function is preserved in old adult conscious monkeys

1995 ◽  
Vol 269 (5) ◽  
pp. H1664-H1671 ◽  
Author(s):  
N. Sato ◽  
K. Kiuchi ◽  
Y. T. Shen ◽  
S. F. Vatner ◽  
D. E. Vatner
Keyword(s):  
Adrenergic Receptor ◽  
Left Atrial ◽  
Pressure Gauge ◽  
Left Ventricular ◽  
Peripheral Vascular ◽  
Adrenergic Stimulation ◽  
First Derivative ◽  
Old Adult ◽  
Vascular Responsiveness ◽  
Isovolumic Relaxation

To examine the physiological deficit to adrenergic stimulation with aging, five younger adult (3 +/- 1 yr old) and nine older adult (17 +/- 1 yr old) healthy monkeys were studied after instrumentation with a left ventricular (LV) pressure gauge, aortic and left atrial catheters, and aortic flow probes to measure cardiac output directly. There were no significant changes in baseline hemodynamics in conscious older monkeys. For example, an index of contractility, the first derivative of LV pressure (LV dP/dt) was similar (3,191 +/- 240, young vs. 3,225 +/- 71 mmHg/s, old) as well as in isovolumic relaxation, tau (24.3 +/- 1.7 ms, young vs. 23.0 +/- 1.0 ms, old) was similar. However, inotropic, lusitropic, and chronotropic responses to isoproterenol (Iso; 0.1 micrograms/kg), norepinephrine (NE; 0.4 micrograms/kg), and forskolin (For; 75 nmol/kg) were significantly (P < 0.05) depressed in older monkeys. For example. Iso increased LV dP/dt by by 146 +/- 14% in younger monkeys and by only 70 +/- 5% in older monkeys. Iso also reduced tau more in younger monkeys (-28 +/- 7%) compared with older monkeys (-13 +/- 3%). Furthermore, peripheral vascular responsiveness to Iso, NE, For, and phenylephrine (PE; 5 micrograms/kg) was significantly (P < 0.05) reduced in older monkeys. For example, phenylephrine (5 micrograms/kg) increased total peripheral resistence by 69 +/- 4% in younger monkeys and by only 45 +/- 3% in older monkeys. Thus in older monkeys without associated cardiovascular disease, baseline hemodynamics are preserved, but adrenergic receptor responsiveness is reduced systemically, not just in the heart.

Greater glycogen utilization during β1- than β2-adrenergic receptor stimulation in the isolated perfused rat heart

2007 ◽  
Vol 293 (6) ◽  
pp. E1828-E1835 ◽  
Author(s):  
Patrick McConville ◽  
Edward G. Lakatta ◽  
Richard G. Spencer
Keyword(s):  
Rat Heart ◽  
Adrenergic Receptor ◽  
Left Ventricular ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Adrenergic Stimulation ◽  
Functional Responses ◽  
Perfused Rat Heart ◽  
Phosphorylation Potential ◽  
Isolated Perfused Rat Heart

Differences in energy metabolism during β1- and β2-adrenergic receptor (AR) stimulation have been shown to translate to differences in the elicited functional responses. It has been suggested that differential access to glycogen during β1- compared with β2-AR stimulation may influence the peak functional response and modulation of the response during sustained adrenergic stimulation. Interleaved 13C- and 31P-NMR spectroscopy was used during β1- and β2-AR stimulation at matched peak workload (2.5 times baseline) in the isolated perfused rat heart to monitor glycogen levels, phosphorylation potential, and intracellular pH. Simultaneous measurements of left ventricular (LV) function [LV developed pressure (LVDP)], heart rate (HR), and rate-pressure product (RPP = LVDP × HR) were also performed. The heart was perfused under both substrate-free (SF) conditions and with exogenous glucose (G). The greater glycogenolysis was observed during β1- than β2-AR stimulation with G (54% vs. 38% reduction, P = 0.006) and SF (92% vs. 79% reduction, P = 0.04) perfusions. The greater β1-AR-mediated glycogenolysis was correlated with greater ability to sustain the initial contractile response. However, with SF perfusion, the duration of this ability was limited: excessive early glycogen depletion caused an earlier decline in LVDP and phosphorylation potential during β1- than β2-AR stimulation. Therefore, endogenous glycogen stores are depleted earlier and to a greater extent, despite a slightly weaker overall inotropic response, during β1- than β2-AR stimulation. These findings are consistent with β1-AR-specific PKA-dependent glycogen phosphorylase kinase signaling.

Activation of Hageman Factor by α-Adrenergic Stimulation

1970 ◽  
Vol 23 (03) ◽  
pp. 417-422 ◽  
Author(s):  
D. G McKay ◽  
J.-G Latour ◽  
Mary H. Parrish
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Adrenergic Receptor ◽  
Adrenergic Stimulation ◽  
Hageman Factor ◽  
Intravascular Coagulation ◽  
Receptor Sites ◽  
High Doses ◽  
Stimulation Of

SummaryThe infusion of epinephrine in high doses produces disseminated intravascular coagulation by activation of Hageman factor. The effect is blocked by phenoxybenz-amine and is therefore due to stimulation of α-adrenergic receptor sites.

scholarly journals Cardiac Autonomic Dysfunction in Myasthenia Gravis and Relapsing-Remitting Multiple Sclerosis—A Pilot Study

2021 ◽  
Vol 10 (10) ◽  
pp. 2173
Author(s):  
Łukasz Rzepiński ◽  
Monika Zawadka-Kunikowska ◽  
Julia L. Newton ◽  
Paweł Zalewski
Keyword(s):  
Multiple Sclerosis ◽  
Myasthenia Gravis ◽  
Autonomic Dysfunction ◽  
Left Ventricular ◽  
High Frequency Component ◽  
Cardiac Inotropy ◽  
Cardiac Autonomic Dysfunction ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

This study assessed cardiac autonomic response to head-up tilt test (HUTT) in 23 myasthenia gravis (MG) and 23 relapsing-remitting multiple sclerosis (RRMS) patients compared to 30 healthy controls (HC). Task Force® Monitor was used to evaluate cardiac inotropy parameters, baroreflex sensitivity (BRS), heart rate (HRV), and blood pressure variability (BPV) during HUTT. MG patients were characterized by reduced BRS (p < 0.05), post-HUTT decrease in high-frequency component (p < 0.05) and increase in sympathovagal ratio of HRV (p < 0.05) when compared to controls indicating parasympathetic deficiency with a shift of sympathovagal balance toward sympathetic predominance. Compared to HC, MG patients also showed lower cardiac inotropy parameters, specifically, left ventricular work index (LVWI) during supine rest (p < 0.05) as well as LVWI and cardiac index values in response to orthostatic stress (p < 0.01 and p < 0.05, respectively). Compared to controls, RRMS patients were characterized by lower HRV delta power spectral density (p < 0.05) and delta low-frequency HRV (p < 0.05) in response to HUTT suggesting combined sympathetic and parasympathetic dysfunction. There were no differences in cardiac autonomic parameters between MG and MS patients (p > 0.05). Our study highlights the possibility of cardiac and autonomic dysfunction in patients with MG and RRMS which should be considered in the pharmacological and rehabilitation approach to managing these conditions.

Abstract 15848: Restoration of Normal Cardiomyocyte Basal and β-Adrenergic Receptor (AR) Subtype Modulation in Heart Failure by Chronic Phosphodiesterase Type 5 Inhibition With Sildenafil

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Tiankai Li ◽  
Heng-Jie Cheng ◽  
Shadi A Qasem ◽  
Michael Callahan ◽  
Wei-Min Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptor ◽  
Pde5 Inhibitor ◽  
Left Ventricular ◽  
Cell Contractility ◽  
Lv Dysfunction ◽  
Myocyte Function ◽  
Phosphodiesterase Type ◽  
Β Adrenergic Receptors ◽  
Mini Pump

Background: We have shown that Sildenafil (SIL), a selective PDE5 inhibitor reversed left ventricular (LV) dysfunction and β- adrenergic receptors (AR) desensitization in heart failure (HF). However the mechanism is not yet clear. Recent evidence suggests that normal myocardial performance depend on the balance in cardiomyocyte β 3 -, β 1 -, and β 2 -AR. Pivotal restructuring of β-AR system resulting in decline of β-adrenergic reserve plays a crucial role in the development of HF. We assessed the hypothesis that chronic SIL would prevent HF-induced abnormalities of β-AR subtype-stimulated regulation on intrinsic LV myocyte function and [Ca 2+ ] i regulation, thus restoring cardiac function. Methods: Studies were conducted in 3 groups (10/group) of rats: 1) HF, 12 weeks (W) after receiving isoproterenol (ISO) (170 mg/kg sq for 2 days); 2) HF/SIL, 8W after receiving ISO, SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and 3) controls. After 12W, we compared LV myocyte contractile and [Ca 2+ ] iT responses to β-AR subtype stimulation by random exposure of myocytes to ISO (10 -8 M) or a selective β 1 -, β 2 -, or β 3 -agonist, Norepinephrine (NE, 10 -7 M), Zinterol (ZIN, 10 -5 M) and BRL-37,344 (BRL, 10 -8 M), respectively, during drug superfusion. Results: Only ISO-treated rats had HF showed 46% decreased LV contractility (E ES ) and extensive LV myocardium fibrosis. Compared with normal myocytes (N), in HF myocytes, basal cell contractility (dL/dt max , HF: 77 vs N: 136 μm/s), relaxation and [Ca 2+ ] iT all significantly decreased. ISO-stimulated dL/dt max (31% vs 67%) was attenuated accompanied by a diminished NE-mediated increase in dL/dt max (13% vs 49%), but enhanced BRL-induced decreases in dL/dt max (-29% vs -16%).The response of dL/dt max (25% vs 15%) to ZIN was increased. Importantly, in HF/SIL myocytes, the basal dL/dt max (139 μm/s) and [Ca 2+ ] iT remained close to control values with preserved β-stimulated positive modulation on cell contraction. The increases in dL/dt max in response to ISO (70%) and NE (44%) were similar as in normal myocytes, but repose to ZIN (27%) was enhanced. Conclusions: Chronic SIL reverses β-adrenergic signaling defects, resensitizing the β-AR subtype system modulation on LV myocytes function, thus playing a salutary role in HF.

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