In vivo and in vitro cardiac responses to beta-adrenergic stimulation in volume-overload heart failure

beta-Adrenergic stimulation of salmonid red cells results in a rapid decrease (within 5 min) in the nucleotide triphosphate:haemoglobin ratio (NTP:Hb), which is thereafter maintained at a constant level, presumably through increased ATP turnover via matched aerobic metabolism and energy-consuming processes. Addition of the beta-adrenergic agonist isoproterenol to rainbow trout red cells in vitro leads to a rise in intracellular pH (pHi), a corresponding decrease in extracellular pH (pHe) and an increase in red cell oxygen consumption (MO2). Moreover, the extent to which red cell pHi is maintained constant in the face of an acute extracellular acidosis in vitro or in vivo is proportional to the adrenergically stimulated increase in red cell MO2. In the absence of oxygen, these red cells remain capable of pH regulation, but cannot maintain NTP:Hb constant. As a result, membrane and metabolic functions become uncoupled in the stimulated deoxygenated cells.

Download Full-text

Inhibition of nitric oxide synthase augments myocardial contractile responses to beta-adrenergic stimulation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.6.h2646 ◽

1996 ◽

Vol 271 (6) ◽

pp. H2646-H2652 ◽

Cited By ~ 12

Author(s):

J. F. Keaney ◽

J. M. Hare ◽

J. L. Balligand ◽

J. Loscalzo ◽

T. W. Smith ◽

...

Keyword(s):

Nitric Oxide ◽

Myocardial Contractility ◽

Adrenergic Stimulation ◽

Maximum Increase ◽

Beta Adrenergic ◽

Before And After ◽

Nos Inhibitor ◽

Oxide Synthase

Recent in vitro evidence suggests a role for nitric oxide (NO) in the modulation of myocardial contractility. The specific role of NO in the control of cardiac function in vivo, however, remains unclear. We investigated the effect of NO synthase (NOS) inhibition on myocardial contractility in response to beta-adrenergic stimulation in autonomically blocked dogs. Intracoronary infusions of dobutamine (1-50 micrograms/min) and isoproterenol (0.1 and 0.5 microgram/min) were performed before and after the intracoronary administration of the specific NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Intracoronary dobutamine resulted in a dose-dependent increase in peak first derivative of pressure (dP/dtmax) to a maximum of 195 +/- 10% (P < 0.001). After inhibition of NOS with intracoronary L-NAME at rates of 0.1 and 1 mg/min, the response to dobutamine was significantly enhanced with dP/dtmax, increasing 276 +/- 17 and 317 +/- 26%, respectively (P < 0.001). Intracoronary isoproterenol resulted in a maximum increase in dP/dtmax of 116 +/- 15% (P < 0.001) that further increased to 154 +/- 17 and 157 +/- 18% after NOS inhibition with 0.1 and 1 mg/min L-NAME, respectively (both P < 0.002). L-NAME had no effect on baseline dP/dtmax but did produce a reduction in myocardial guanosine 3',5'-cyclic monophosphate content. These results suggest a role for NO in the control of myocardial contractility in response to beta-adrenergic stimulation in vivo.

Download Full-text

Early activation of the cardiac CX3CL1/CX3CR1 axis delays β-adrenergic-induced heart failure

Scientific Reports ◽

10.1038/s41598-021-97493-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

M. Flamant ◽

N. Mougenot ◽

E. Balse ◽

L. Le Fèvre ◽

F. Atassi ◽

...

Keyword(s):

Heart Failure ◽

Protective Role ◽

Cardiomyocyte Hypertrophy ◽

Adrenergic Stimulation ◽

Intramyocardial Injection ◽

In Vivo Experiments ◽

Concentric Hypertrophy

AbstractWe recently highlighted a novel potential protective paracrine role of cardiac myeloid CD11b/c cells improving resistance of adult hypertrophied cardiomyocytes to oxidative stress and potentially delaying evolution towards heart failure (HF) in response to early β-adrenergic stimulation. Here we characterized macrophages (Mφ) in hearts early infused with isoproterenol as compared to control and failing hearts and evaluated the role of upregulated CX3CL1 in cardiac remodeling. Flow cytometry, immunohistology and Mφ-depletion experiments evidenced a transient increase in Mφ number in isoproterenol-infused hearts, proportional to early concentric hypertrophy (ECH) remodeling and limiting HF. Combining transcriptomic and secretomic approaches we characterized Mφ-enriched CD45+ cells from ECH hearts as CX3CL1- and TNFα-secreting cells. In-vivo experiments, using intramyocardial injection in ECH hearts of either Cx3cl1 or Cx3cr1 siRNA, or Cx3cr1−/− knockout mice, identified the CX3CL1/CX3CR1 axis as a protective pathway delaying transition to HF. In-vitro results showed that CX3CL1 not only enhanced ECH Mφ proliferation and expansion but also supported adult cardiomyocyte hypertrophy via a synergistic action with TNFα. Our data underscore the in-vivo transient protective role of the CX3CL1/CX3CR1 axis in ECH remodeling and suggest the participation of CX3CL1-secreting Mφ and their crosstalk with CX3CR1-expressing cardiomyocytes to delay HF.

Download Full-text

Secretion of lingual lipase and amylase from rat lingual serous glands

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1987.253.2.g217 ◽

1987 ◽

Vol 253 (2) ◽

pp. G217-G225 ◽

Cited By ~ 1

Author(s):

R. B. Field ◽

A. R. Hand

Keyword(s):

Protein Secretion ◽

Major Salivary Gland ◽

Adrenergic Stimulation ◽

Adrenergic Agonist ◽

Beta Adrenergic ◽

Cholinergic Agonist ◽

Significant Difference ◽

The Media

The effects of various secretagogues on the release of lingual lipase and amylase from rat lingual serous glands was examined in vitro and in vivo. After incubation, the media and tissues were assayed for lingual lipase and amylase activity to determine percent of secretion. In vitro secretion of lingual lipase and amylase stimulated by the cholinergic agonist, carbamylcholine chloride (carbachol), was 28.3 +/- 1.7, 48.0 +/- 3.2, and 55.9 +/- 2.4% and 18.1 +/- 1.7, 26.4 +/- 3.0, and 28.0 +/- 2.5%, respectively, for 30-, 60-, and 90-min incubations. The beta-adrenergic agonist, isoproterenol, and the adenylate cyclase activator, forskolin, elicited very little secretion in vitro; the 90-min values with isoproterenol were 16.8 +/- 7.1% lingual lipase and 6.0 +/- 2.6% amylase. The alpha-adrenergic agonist, phenylephrine, did not stimulate enzyme secretion. Morphological assessment of incubated tissues revealed that carbachol induced a rapid and extensive degranulation of the acinar cells, while isoproterenol caused only minimal exocytosis. In vivo stimulation by the cholinergic agonist, pilocarpine, caused rapid secretion, with maximal secretion occurring by 1 h. In vivo secretion stimulated by isoproterenol was slow, but by 4 h secretion was comparable to that induced by pilocarpine. In vitro, there was a significant difference between the percentages of lingual lipase and amylase secreted, which could not be accounted for by the presence of proteases or microbial products or the lack of stability of the enzymes during the incubation period. Neurotransmitter regulation of protein secretion by the lingual serous (minor salivary) glands appears to be principally cholinergic in contrast to the beta-adrenergic stimulation of protein secretion by the parotid (major salivary) gland.

Download Full-text

Abstract 26: Myocardial Phosphodiesterase-2A Is Upregulated in Human and Experimental Heart Failure and Blunts Cardiac β-Adrenergic Inotropic Responsiveness

Circulation Research ◽

10.1161/res.111.suppl_1.a26 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Christiane Vettel ◽

Hind Mehel ◽

Julius Emons ◽

Katrin Wittkoepper ◽

Danilo Seppelt ◽

...

Keyword(s):

Heart Failure ◽

Cyclic Nucleotide ◽

Defense Mechanism ◽

Large Animal ◽

Adrenergic Stimulation ◽

Isolated Cardiomyocytes ◽

Beta Adrenergic ◽

Protein Levels ◽

Hydrolyzing Enzymes

Augmented cGMP- and diminished cAMP-signaling within cardiomyocytes is characteristic for failing hearts. Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of cyclic-nucleotide hydrolyzing enzymes, controlling cAMP and cGMP levels. Among them the PDE-2A isoform has the unique property to be stimulated by cGMP but primarily hydrolyzing cAMP. This appears to mediate a negative cross-talk between both signaling pathways. However, a potential role for PDE-2A in the failing heart has not been addressed yet. Here we show that PDE-2A protein levels were ∼2-fold higher in failing human hearts as well as in a large animal heart failure model from dog hearts subjected to rapid-pacing (n≥6, p<0.05). Intriguingly, PDE-2A protein levels were normal in hypertrophied hearts from patients with preserved cardiac function who underwent aortic valve replacement. Chronic beta-adrenergic stimulation by catecholamine infusions enhanced cAMP hydrolyzing activity of PDE-2A by four-fold (n≥6, p<0.05) in rat hearts in vivo and in isolated cardiomyocytes (measured by radioimmunoassay and FRET-based sensors, respectively) and correlated with blunted beta-adrenergic responsiveness. Consistent with this observation, overexpressed PDE-2A, which localized to the sarcomeric Z-line, blunted the rise in cAMP by 70% (n≥6, p<0.05) and abolished the positive inotropic effect after acute beta-adrenergic stimulation by 70% (n≥6, p<0.05) in isolated cardiomyocytes. Notably, those cardiomyocytes also showed marked protection from norepinephrine-induced hypertrophic responses, e. g. 40% less increase in cell surface area (n≥10, p<0.05). In summary, PDE-2A is markedly upregulated in human and experimental failing hearts. This may constitute an important defense mechanism during cardiac stress, by antagonizing the cAMP-mediated toxic effects. Thus, activating myocardial PDE-2A may represent a new intracellular anti-adrenergic therapeutic strategy in heart failure.

Download Full-text

The effects of forced activity on circulating catecholamines and pH and water content of erythrocytes in the toad

Journal of Experimental Biology ◽

10.1242/jeb.128.1.411 ◽

1987 ◽

Vol 128 (1) ◽

pp. 411-418

Author(s):

B. L. Tufts ◽

D. C. Mense ◽

D. J. Randall

Keyword(s):

Water Content ◽

Adrenergic Stimulation ◽

Adrenergic Agonist ◽

Beta Adrenergic ◽

In Vivo Experiments ◽

Beta Adrenergic Agonist ◽

Toad Bufo ◽

Adrenergic Effects

In vivo experiments were carried out to determine the effect of forced activity on circulating catecholamine levels, haematocrit, and the pH and water content of erythrocytes in the toad, Bufo marinus. In addition, the effect of the beta-adrenergic agonist isoproterenol on erythrocyte pH and water content was examined in vitro. Forced activity caused a significant decrease in both whole blood and erythrocyte pH, while haematocrit and circulating adrenaline and noradrenaline levels increased. Erythrocyte water content did not change following forced activity. Addition of isoproterenol to toad blood in vitro had no effect on either erythrocyte pH or water content. The apparent absence of beta-adrenergic effects on erythrocyte pH and water content in the toad is in sharp contrast to the response of teleost fish erythrocytes to beta-adrenergic stimulation. The significance of these differences is discussed.

Download Full-text

Effect of exercise on lipolytic sensitivity in endurance-trained athletes

Journal of Applied Physiology ◽

10.1152/jappl.1995.78.6.2201 ◽

1995 ◽

Vol 78 (6) ◽

pp. 2201-2206 ◽

Cited By ~ 15

Author(s):

S. Klein ◽

E. F. Coyle ◽

R. R. Wolfe

Keyword(s):

High Intensity ◽

Lipolytic Activity ◽

Whole Body ◽

Adrenergic Stimulation ◽

Epinephrine Infusion ◽

Beta Adrenergic ◽

Ergometer Exercise ◽

Plasma Ffa

Studies performed in vitro suggest that an acute bout of exercise increases the lipolytic response to beta-adrenergic stimulation. We evaluated the effect of exercise on lipolytic sensitivity in vivo in five endurance-trained athletes. The rate of appearance (Ra) of glycerol in plasma, an index of whole body lipolysis, was determined during 60 min of epinephrine infusion (0.015 microgram.kg-1.min-1) on two occasions: 1) at basal resting conditions and 2) 90 min after completing 1 h of high-intensity (70% O2 uptake) cycle ergometer exercise. Total glycerol Ra during epinephrine infusion in the basal state (352 +/- 35 mumol.kg-1. 60 min-1) was not significantly different from the value obtained after high-intensity exercise (439 +/- 58 mumol.kg-1. 60 min-1). However, the increase in glycerol Ra above baseline during epinephrine infusion was lower after (30 +/- 16 mumol.kg-1. 60 min-1) than before (148 +/- 28 mumol.kg-1. 60 min-1) exercise because of the high postexercise baseline value (P < 0.05). Mean plasma free fatty acid (FFA) concentration was lower during exercise than during epinephrine infusion despite a greater rate of lipolysis during exercise. The slope of change in plasma FFA with respect to glycerol RA was lower during exercise (0.0171 +/- 0.006) than during epinephrine infusion (0.0835 +/- 0.018) (P < 0.05). We conclude that a single bout of intense exercise does not increase in vivo lipolytic sensitivity to beta-adrenergic stimulation in endurance-trained athletes. In addition, plasma FFA concentration represents the balance between plasma FFA inflow and tissue uptake and cannot be used as an index of lipolytic activity during certain physiological conditions, such as exercise.

Download Full-text

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

Thrombosis and Haemostasis ◽

10.1160/th14-01-0059 ◽

2014 ◽

Vol 112 (11) ◽

pp. 951-959 ◽

Cited By ~ 1

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.

Download Full-text

Abstract 285: Cardiac Inflammation and Fibrosis Induced by Heart Failure Are Reversed by Short-Duration Estrogen Therapy

Circulation Research ◽

10.1161/res.111.suppl_1.a285 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Andrea Iorga ◽

Rangarajan Nadadur ◽

Salil Sharma ◽

Jingyuan Li ◽

Mansoureh Eghbali

Keyword(s):

Heart Failure ◽

Estrogen Therapy ◽

Pressure Overload ◽

Decompensated Heart Failure ◽

Left Ventricular ◽

Neonatal Rat ◽

In Vivo Model ◽

Anti Inflammatory

Heart failure is generally characterized by increased fibrosis and inflammation, which leads to functional and contractile defects. We have previously shown that short-term estrogen (E2) treatment can rescue pressure overload-induced decompensated heart failure (HF) in mice. Here, we investigate the anti-inflammatory and anti-fibrotic effects of E2 on reversing the adverse remodeling of the left ventricle which occurs during the progression to heart failure. Trans-aortic constriction procedure was used to induce HF. Once the ejection fraction reached ∼30%, one group of mice was sacrificed and the other group was treated with E2 (30 αg/kg/day) for 10 days. In vitro, co-cultured neonatal rat ventricular myocytes and fibroblasts were treated with Angiotensin II (AngII) to simulate cardiac stress, both in the presence or absence of E2. In vivo RT-PCR showed that the transcript levels of the pro-fibrotic markers Collagen I, TGFβ, Fibrosin 1 (FBRS) and Lysil Oxidase (LOX) were significantly upregulated in HF (from 1.00±0.16 to 1.83±0.11 for Collagen 1, 1±0.86 to 4.33±0.59 for TGFβ, 1±0.52 to 3.61±0.22 for FBRS and 1.00±0.33 to 2.88±0.32 for LOX) and were reduced with E2 treatment to levels similar to CTRL. E2 also restored in vitro AngII-induced upregulation of LOX, TGFβ and Collagen 1 (LOX:1±0.23 in CTRL, 6.87±0.26 in AngII and 2.80±1.5 in AngII+E2; TGFβ: 1±0.08 in CTRL, 3.30±0.25 in AngII and 1.59±0.21 in AngII+E2; Collagen 1: 1±0.05 in CTRL.2±0.01 in AngII and 0.65±0.02 (p<0.05, values normalized to CTRL)). Furthermore, the pro-inflammatory interleukins IL-1β and IL-6 were upregulated from 1±0.19 to 1.90±0.09 and 1±0.30 to 5.29±0.77 in the in vivo model of HF, respectively, and reversed to CTRL levels with E2 therapy. In vitro, IL-1β was also significantly increased ∼ 4 fold from 1±0.63 in CTRL to 3.86±0.14 with AngII treatment and restored to 1.29±0.77 with Ang+E2 treatment. Lastly, the anti-inflammatory interleukin IL-10 was downregulated from 1.00±0.17 to 0.49±0.03 in HF and reversed to 0.67±0.09 in vivo with E2 therapy (all values normalized to CTRL). This data strongly suggests that one of the mechanisms for the beneficial action of estrogen on left ventricular heart failure is through reversal of inflammation and fibrosis.

Download Full-text