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Lothar A. Blatter - One of the best experts on this subject based on the ideXlab platform.
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Beta-Adrenergic Stimulation Increases the Intra-SR Ca Termination Threshold for Spontaneous Ca Release in Cardiac Myocytes
Biophysical Journal, 2013Co-Authors: Joshua T. Maxwell, Timothy L. Domeier, Lothar A. BlatterAbstract:In the heart, Beta-Adrenergic Stimulation is associated with pro-arrhythmic Ca waves that occur as the result of the sarcoplasmic reticulum (SR) Ca content reaching a critical threshold level. Recently, we have shown that Beta-Adrenergic Stimulation increases the intra-SR Ca threshold for Ca wave initiation, potentially serving as a protective mechanism against pro-arrhythmic Ca release during Beta-Adrenergic Stimulation (Domeier et al., 2012). However, data regarding the termination of such release and details on the regulation of this process have yet to be elucidated. In this study we directly and dynamically measured the intra-SR Ca level ([Ca]SR) at which spontaneous Ca waves terminate (termination threshold) under control conditions and during Beta-Adrenergic Stimulation. Application of the Beta-Adrenergic receptor agonist isoproterenol (ISO; 1 μM) resulted in an increase in basal [Ca]SR. Importantly, in the presence of ISO the [Ca]SR at which spontaneous Ca waves terminated was also increased compared to control conditions. In addition, the depletion amplitude of spontaneous Ca waves was decreased in the presence of ISO compared to control conditions. When [Ca]SR was subsequently lowered in the presence of ISO to that observed under control conditions (by reducing extracellular Ca and partially inhibiting SERCA with cyclopiazonic acid or thapsigargin), the [Ca]SR at which spontaneous release terminated was still increased compared to control conditions. Likewise, the depletion amplitude remained decreased compared to control conditions. These data indicate that during Beta-Adrenergic Stimulation in the heart, both the intra-SR Ca threshold at which spontaneous Ca waves initiate and terminate is increased, while the amount of Ca released during Ca waves is decreased. The Ca wave termination level may represent an important mode of altering diastolic Ca wave amplitude, and thus, the arrhythmogenic potential of the cell during acute Beta-Adrenergic Stimulation.
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Beta-Adrenergic Stimulation Increases the Intra-Sarcoplasmic Reticulum Ca Threshold for Spontaneous Ca Waves
Biophysical Journal, 2011Co-Authors: Timothy L. Domeier, Joshua T. Maxwell, Lothar A. BlatterAbstract:Beta-Adrenergic signaling induces positive inotropic effects on the heart that frequently associate with spontaneous arrhythmogenic Ca release events including Ca waves. It remains unclear if the greater incidence of Ca waves is due to increased sarcoplasmic reticulum (SR) Ca content ([Ca]SR) or a change in the function of ryanodine receptors. To address this controversy we utilized dynamic [Ca]SR measurements (fluo-5N) to test if Beta-Adrenergic Stimulation alters the [Ca]SR level where Ca waves initiate (wave threshold) during rest after action potential Stimulation. Under control conditions [Ca]SR was progressively increased to the wave threshold via incremental increases in pacing frequency in a high extracellular Ca (7 mM) environment. In the presence of the Beta-Adrenergic agonist isoproterenol (ISO, 1 microM) [Ca]SR increased and Ca waves were observed. When [Ca]SR was subsequently lowered using low extracellular Ca (1 mM) and SERCA inhibition (3 microM cyclopiazonic acid), Ca waves were no longer observed, even at [Ca]SR levels above the control wave threshold. In parallel experiments we found that resting cytosolic [Ca] (indo-1) was similar between the respective experimental conditions. Indirect assessment of [Ca]SR using the amplitude of the cytosolic Ca transient induced by 10 mM caffeine confirmed our observation that in the presence of ISO Ca waves only occur when [Ca]SR is above the control wave threshold. Furthermore, spontaneous Ca spark measurements (fluo-4) showed a tendency towards spark inhibition in the presence of ISO at experimentally matched [Ca]SR. Together, these data show that acute Beta-Adrenergic Stimulation increases the [Ca]SR threshold for Ca waves, and therefore the primary cause of Ca waves is the robust increase in [Ca]SR above this higher threshold level. Elevation of the [Ca]SR wave threshold may be interpreted as a protective mechanism against pro-arrhythmogenic Ca release during Beta-Adrenergic Stimulation.
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mechanisms of spontaneous calcium wave generation during Beta Adrenergic Stimulation in rabbit ventricular myocytes
Biophysical Journal, 2010Co-Authors: Timothy L. Domeier, Lothar A. BlatterAbstract:The Beta-Adrenergic signaling pathway represents the principal positive inotropic mechanism of the heart. While the effects of Beta-Adrenergic Stimulation on L-type Ca channel Ca influx and SERCA-mediated sarcoplasmic reticulum (SR) Ca uptake are well established, the effects on SR Ca release through ryanodine receptor (RyR) release clusters remains highly controversial. Here, we examine SR Ca release in rabbit ventricular myocytes in the form of spontaneous Ca waves during Beta-Adrenergic Stimulation with isoproterenol under controlled cytosolic and SR [Ca]. Cytosolic Ca was monitored using high-affinity Ca indicators indo-1 or rhod-2, while SR Ca was measured directly using the low-affinity Ca indicator fluo-5N or indirectly using the amplitude of the cytosolic Ca transient in response to 10 mM caffeine. Under control conditions, Ca waves were not observed following rest from 0.75 Hz pacing. In the presence of isoproterenol (500 nM), SR Ca content increased by 34% and spontaneous Ca waves were observed in 67% of cells during rest after pacing. However, when post-rest cytosolic Ca and SR Ca content were experimentally matched to control conditions using low extracellular Ca (100 uM versus 2 mM) and SERCA inhibition (7.5 uM cyclopiazonic acid), spontaneous Ca waves were never observed in the presence of isoproterenol. In contrast, pharmacological sensitization of the RyR with 250 uM caffeine induced Ca waves under control conditions (8/12 cells) and in the presence of isoproterenol at matched cytosolic Ca and SR Ca content (7/12). Together, these data suggest that spontaneous Ca release during Beta-Adrenergic Stimulation is a result of increased RyR sensitivity in response to increased SR Ca content, and is not due to direct alterations in RyR function by the Beta-Adrenergic signaling cascade.
Ellen E. Blaak - One of the best experts on this subject based on the ideXlab platform.
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hsl serine phosphorylation and glycerol exchange across skeletal muscle in lean and obese subjects effect of Beta Adrenergic Stimulation
Diabetes, 2008Co-Authors: Johan W E Jocken, Wilhelmus Hermanus Maria Saris, Gijs H Goossens, Marleen A Van Baak, Carsten Roepstorff, Paula Van Der Baan, Bente Kiens, Ellen E. BlaakAbstract:Abstract Objective: Increased intramuscular triacylglycerol (IMTG) storage is a characteristic of the obese insulin resistant state. We aimed to investigate whether a blunted fasting or Beta-Adrenergically mediated lipolysis contributes to this increased IMTG storage in obesity. Research design and Methods: Forearm skeletal muscle (SM) lipolysis was investigated in thirteen lean and ten obese men using [ 2 H 5 ]-glycerol combined with the measurement of arterio-venous differences before and during Beta-Adrenergic Stimulation using the non-selective Beta-agonist isoprenaline (ISO). Muscle biopsies were taken from the vastus lateralis muscle before and during ISO to investigate hormone-sensitive lipase (HSL) protein expression and serine phosphorylation. Results: Baseline total glycerol release across the forearm was significantly blunted in obese compared with lean subjects (P=0.045). This was accompanied by lower HSL protein expression (P=0.004), and HSL phosphorylation on PKA sites Ser 563 (P=0.041) and Ser 659 (P=0.09) and on the AMPK site Ser 565 (P=0.007), suggesting a blunted skeletal muscle lipolysis in obesity. Total forearm glycerol uptake during baseline did not differ significantly between groups while higher net fatty acid uptake across the forearm was observed in the obese (P=0.064). ISO induced an increase in total glycerol release from SM, which was not significantly different between groups. Interestingly, this was accompanied by an increase in HSL Ser 659 phosphorylation in obese subjects during ISO compared with baseline (P=0.008). Conclusions: Obesity is accompanied by impaired fasting glycerol release, lower HSL protein expression and serine phosphorylation. It remains to be determined whether this is a primary factor or an adaptation to the obese insulin resistant state.
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endocrine role of the renin angiotensin system in human adipose tissue and muscle effect of Beta Adrenergic Stimulation
Hypertension, 2007Co-Authors: Gijs H Goossens, Ellen E. Blaak, Wilhelmus Hermanus Maria Saris, Johan W E Jocken, Paul M H Schiffers, Marleen A Van BaakAbstract:The renin-angiotensin system has been implicated in obesity-related hypertension and insulin resistance. We examined whether locally produced components of the renin-angiotensin system in adipose tissue and skeletal muscle play an endocrine role in vivo in humans. Furthermore, the effects of Beta-Adrenergic Stimulation on plasma concentrations and tissue release of renin-angiotensin system components were investigated. Systemic renin-angiotensin system components and arteriovenous differences of angiotensin II (Ang II) and angiotensinogen (AGT) across abdominal subcutaneous adipose tissue and skeletal muscle were assessed in combination with measurements of tissue blood flow before and during systemic Beta-Adrenergic Stimulation in 13 lean and 10 obese subjects. Basal plasma Ang II and AGT concentrations were not significantly different between lean and obese subjects. Ang II concentrations were increased in obese compared with lean subjects during Beta-Adrenergic Stimulation (12.6+/-1.5 versus 8.1+/-1.0 pmol/L; P=0.04), whereas AGT concentrations remained unchanged. Plasma renin activity increased to a similar extent in lean and obese subjects during Beta-Adrenergic Stimulation (both P<0.01). No net Ang II release across adipose tissue and skeletal muscle could be detected in both groups of subjects. However, AGT was released from adipose tissue and muscle during Beta-Adrenergic Stimulation in obese subjects (both P<0.05). In conclusion, locally produced Ang II in adipose tissue and skeletal muscle exerts no endocrine role in lean and obese subjects. In contrast, AGT is released from adipose tissue and muscle in obese subjects during Beta-Adrenergic Stimulation, which may contribute to the increased plasma Ang II concentrations during Beta-Adrenergic Stimulation in obese subjects.
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Endocrine role of the renin-angiotensin system in human adipose tissue and muscle: effect of Beta-Adrenergic Stimulation.
Hypertension (Dallas Tex. : 1979), 2007Co-Authors: Gijs H Goossens, Ellen E. Blaak, Wilhelmus Hermanus Maria Saris, Johan W E Jocken, Paul M H Schiffers, Marleen A Van BaakAbstract:The renin-angiotensin system has been implicated in obesity-related hypertension and insulin resistance. We examined whether locally produced components of the renin-angiotensin system in adipose tissue and skeletal muscle play an endocrine role in vivo in humans. Furthermore, the effects of Beta-Adrenergic Stimulation on plasma concentrations and tissue release of renin-angiotensin system components were investigated. Systemic renin-angiotensin system components and arteriovenous differences of angiotensin II (Ang II) and angiotensinogen (AGT) across abdominal subcutaneous adipose tissue and skeletal muscle were assessed in combination with measurements of tissue blood flow before and during systemic Beta-Adrenergic Stimulation in 13 lean and 10 obese subjects. Basal plasma Ang II and AGT concentrations were not significantly different between lean and obese subjects. Ang II concentrations were increased in obese compared with lean subjects during Beta-Adrenergic Stimulation (12.6+/-1.5 versus 8.1+/-1.0 pmol/L; P=0.04), whereas AGT concentrations remained unchanged. Plasma renin activity increased to a similar extent in lean and obese subjects during Beta-Adrenergic Stimulation (both P
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Beta-Adrenergic Stimulation of energy expenditure and forearm skeletal muscle metabolism in lean and obese men
American Journal of Physiology-endocrinology and Metabolism, 1994Co-Authors: Ellen E. Blaak, M. T. W. Pakbiers, Guido A. K. Heidendal, Gerrit J. Kemerink, Marleen A Van Baak, Wilhelmus Hermanus Maria SarisAbstract:The effect of Beta-Adrenergic Stimulation on whole body energy expenditure and forearm skeletal muscle metabolism was investigated in lean and obese men. Whole body energy expenditure was determine...
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Beta-Adrenergic Stimulation of energy expenditure and forearm skeletal muscle metabolism in lean and obese men.
The American journal of physiology, 1994Co-Authors: Ellen E. Blaak, M. T. W. Pakbiers, Guido A. K. Heidendal, Gerrit J. Kemerink, Marleen A Van Baak, Wilhelmus Hermanus Maria SarisAbstract:The effect of Beta-Adrenergic Stimulation on whole body energy expenditure and forearm skeletal muscle metabolism was investigated in lean and obese men. Whole body energy expenditure was determined during rest and during intravenous infusion of increasing doses of the nonselective Beta-agonist isoprenaline (Iso). Forearm skeletal muscle metabolism was investigated with Iso infusion with and without simultaneous infusion of the Beta 1-blocker atenolol (AT) by measuring skeletal muscle blood flow (SMBF) and arteriovenous concentration differences of various metabolites. The changes in SMBF were estimated from forearm total (venous occlusion plethysmography), skin (laser doppler), and fat tissue blood flow (133Xe washout). The increase in whole body energy expenditure with Iso was similar in lean and obese subjects. With Iso, the rise in arterial or arterialized glycerol and nonesterified fatty acids (NEFA) was lower in obese than lean subjects, which may reflect a lower Beta-Adrenergically mediated lipolysis in obesity. During infusion of increasing doses of Iso, the respiratory exchange ratio decreased significantly in lean subjects but not in the obese subjects, which indicates a more pronounced increase in fat oxidation in lean subjects. This is confirmed by the data on skeletal muscle metabolism, where NEFA uptake was increased in lean subjects, whereas the obese subjects showed a tendency toward an increased glucose uptake and a significantly increased lactate release. With Iso plus AT (mainly Beta 2-Adrenergic Stimulation), both groups showed an increased skeletal muscle lactate release. In conclusion, although the thermogenic response to Iso was similar in lean and obese subjects, the utilization of fat seems to be impaired in obesity.
Wilhelmus Hermanus Maria Saris - One of the best experts on this subject based on the ideXlab platform.
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hsl serine phosphorylation and glycerol exchange across skeletal muscle in lean and obese subjects effect of Beta Adrenergic Stimulation
Diabetes, 2008Co-Authors: Johan W E Jocken, Wilhelmus Hermanus Maria Saris, Gijs H Goossens, Marleen A Van Baak, Carsten Roepstorff, Paula Van Der Baan, Bente Kiens, Ellen E. BlaakAbstract:Abstract Objective: Increased intramuscular triacylglycerol (IMTG) storage is a characteristic of the obese insulin resistant state. We aimed to investigate whether a blunted fasting or Beta-Adrenergically mediated lipolysis contributes to this increased IMTG storage in obesity. Research design and Methods: Forearm skeletal muscle (SM) lipolysis was investigated in thirteen lean and ten obese men using [ 2 H 5 ]-glycerol combined with the measurement of arterio-venous differences before and during Beta-Adrenergic Stimulation using the non-selective Beta-agonist isoprenaline (ISO). Muscle biopsies were taken from the vastus lateralis muscle before and during ISO to investigate hormone-sensitive lipase (HSL) protein expression and serine phosphorylation. Results: Baseline total glycerol release across the forearm was significantly blunted in obese compared with lean subjects (P=0.045). This was accompanied by lower HSL protein expression (P=0.004), and HSL phosphorylation on PKA sites Ser 563 (P=0.041) and Ser 659 (P=0.09) and on the AMPK site Ser 565 (P=0.007), suggesting a blunted skeletal muscle lipolysis in obesity. Total forearm glycerol uptake during baseline did not differ significantly between groups while higher net fatty acid uptake across the forearm was observed in the obese (P=0.064). ISO induced an increase in total glycerol release from SM, which was not significantly different between groups. Interestingly, this was accompanied by an increase in HSL Ser 659 phosphorylation in obese subjects during ISO compared with baseline (P=0.008). Conclusions: Obesity is accompanied by impaired fasting glycerol release, lower HSL protein expression and serine phosphorylation. It remains to be determined whether this is a primary factor or an adaptation to the obese insulin resistant state.
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endocrine role of the renin angiotensin system in human adipose tissue and muscle effect of Beta Adrenergic Stimulation
Hypertension, 2007Co-Authors: Gijs H Goossens, Ellen E. Blaak, Wilhelmus Hermanus Maria Saris, Johan W E Jocken, Paul M H Schiffers, Marleen A Van BaakAbstract:The renin-angiotensin system has been implicated in obesity-related hypertension and insulin resistance. We examined whether locally produced components of the renin-angiotensin system in adipose tissue and skeletal muscle play an endocrine role in vivo in humans. Furthermore, the effects of Beta-Adrenergic Stimulation on plasma concentrations and tissue release of renin-angiotensin system components were investigated. Systemic renin-angiotensin system components and arteriovenous differences of angiotensin II (Ang II) and angiotensinogen (AGT) across abdominal subcutaneous adipose tissue and skeletal muscle were assessed in combination with measurements of tissue blood flow before and during systemic Beta-Adrenergic Stimulation in 13 lean and 10 obese subjects. Basal plasma Ang II and AGT concentrations were not significantly different between lean and obese subjects. Ang II concentrations were increased in obese compared with lean subjects during Beta-Adrenergic Stimulation (12.6+/-1.5 versus 8.1+/-1.0 pmol/L; P=0.04), whereas AGT concentrations remained unchanged. Plasma renin activity increased to a similar extent in lean and obese subjects during Beta-Adrenergic Stimulation (both P<0.01). No net Ang II release across adipose tissue and skeletal muscle could be detected in both groups of subjects. However, AGT was released from adipose tissue and muscle during Beta-Adrenergic Stimulation in obese subjects (both P<0.05). In conclusion, locally produced Ang II in adipose tissue and skeletal muscle exerts no endocrine role in lean and obese subjects. In contrast, AGT is released from adipose tissue and muscle in obese subjects during Beta-Adrenergic Stimulation, which may contribute to the increased plasma Ang II concentrations during Beta-Adrenergic Stimulation in obese subjects.
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Endocrine role of the renin-angiotensin system in human adipose tissue and muscle: effect of Beta-Adrenergic Stimulation.
Hypertension (Dallas Tex. : 1979), 2007Co-Authors: Gijs H Goossens, Ellen E. Blaak, Wilhelmus Hermanus Maria Saris, Johan W E Jocken, Paul M H Schiffers, Marleen A Van BaakAbstract:The renin-angiotensin system has been implicated in obesity-related hypertension and insulin resistance. We examined whether locally produced components of the renin-angiotensin system in adipose tissue and skeletal muscle play an endocrine role in vivo in humans. Furthermore, the effects of Beta-Adrenergic Stimulation on plasma concentrations and tissue release of renin-angiotensin system components were investigated. Systemic renin-angiotensin system components and arteriovenous differences of angiotensin II (Ang II) and angiotensinogen (AGT) across abdominal subcutaneous adipose tissue and skeletal muscle were assessed in combination with measurements of tissue blood flow before and during systemic Beta-Adrenergic Stimulation in 13 lean and 10 obese subjects. Basal plasma Ang II and AGT concentrations were not significantly different between lean and obese subjects. Ang II concentrations were increased in obese compared with lean subjects during Beta-Adrenergic Stimulation (12.6+/-1.5 versus 8.1+/-1.0 pmol/L; P=0.04), whereas AGT concentrations remained unchanged. Plasma renin activity increased to a similar extent in lean and obese subjects during Beta-Adrenergic Stimulation (both P
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Beta-Adrenergic Stimulation of energy expenditure and forearm skeletal muscle metabolism in lean and obese men
American Journal of Physiology-endocrinology and Metabolism, 1994Co-Authors: Ellen E. Blaak, M. T. W. Pakbiers, Guido A. K. Heidendal, Gerrit J. Kemerink, Marleen A Van Baak, Wilhelmus Hermanus Maria SarisAbstract:The effect of Beta-Adrenergic Stimulation on whole body energy expenditure and forearm skeletal muscle metabolism was investigated in lean and obese men. Whole body energy expenditure was determine...
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Beta-Adrenergic Stimulation of energy expenditure and forearm skeletal muscle metabolism in lean and obese men.
The American journal of physiology, 1994Co-Authors: Ellen E. Blaak, M. T. W. Pakbiers, Guido A. K. Heidendal, Gerrit J. Kemerink, Marleen A Van Baak, Wilhelmus Hermanus Maria SarisAbstract:The effect of Beta-Adrenergic Stimulation on whole body energy expenditure and forearm skeletal muscle metabolism was investigated in lean and obese men. Whole body energy expenditure was determined during rest and during intravenous infusion of increasing doses of the nonselective Beta-agonist isoprenaline (Iso). Forearm skeletal muscle metabolism was investigated with Iso infusion with and without simultaneous infusion of the Beta 1-blocker atenolol (AT) by measuring skeletal muscle blood flow (SMBF) and arteriovenous concentration differences of various metabolites. The changes in SMBF were estimated from forearm total (venous occlusion plethysmography), skin (laser doppler), and fat tissue blood flow (133Xe washout). The increase in whole body energy expenditure with Iso was similar in lean and obese subjects. With Iso, the rise in arterial or arterialized glycerol and nonesterified fatty acids (NEFA) was lower in obese than lean subjects, which may reflect a lower Beta-Adrenergically mediated lipolysis in obesity. During infusion of increasing doses of Iso, the respiratory exchange ratio decreased significantly in lean subjects but not in the obese subjects, which indicates a more pronounced increase in fat oxidation in lean subjects. This is confirmed by the data on skeletal muscle metabolism, where NEFA uptake was increased in lean subjects, whereas the obese subjects showed a tendency toward an increased glucose uptake and a significantly increased lactate release. With Iso plus AT (mainly Beta 2-Adrenergic Stimulation), both groups showed an increased skeletal muscle lactate release. In conclusion, although the thermogenic response to Iso was similar in lean and obese subjects, the utilization of fat seems to be impaired in obesity.
Timothy L. Domeier - One of the best experts on this subject based on the ideXlab platform.
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Beta-Adrenergic Stimulation Increases the Intra-SR Ca Termination Threshold for Spontaneous Ca Release in Cardiac Myocytes
Biophysical Journal, 2013Co-Authors: Joshua T. Maxwell, Timothy L. Domeier, Lothar A. BlatterAbstract:In the heart, Beta-Adrenergic Stimulation is associated with pro-arrhythmic Ca waves that occur as the result of the sarcoplasmic reticulum (SR) Ca content reaching a critical threshold level. Recently, we have shown that Beta-Adrenergic Stimulation increases the intra-SR Ca threshold for Ca wave initiation, potentially serving as a protective mechanism against pro-arrhythmic Ca release during Beta-Adrenergic Stimulation (Domeier et al., 2012). However, data regarding the termination of such release and details on the regulation of this process have yet to be elucidated. In this study we directly and dynamically measured the intra-SR Ca level ([Ca]SR) at which spontaneous Ca waves terminate (termination threshold) under control conditions and during Beta-Adrenergic Stimulation. Application of the Beta-Adrenergic receptor agonist isoproterenol (ISO; 1 μM) resulted in an increase in basal [Ca]SR. Importantly, in the presence of ISO the [Ca]SR at which spontaneous Ca waves terminated was also increased compared to control conditions. In addition, the depletion amplitude of spontaneous Ca waves was decreased in the presence of ISO compared to control conditions. When [Ca]SR was subsequently lowered in the presence of ISO to that observed under control conditions (by reducing extracellular Ca and partially inhibiting SERCA with cyclopiazonic acid or thapsigargin), the [Ca]SR at which spontaneous release terminated was still increased compared to control conditions. Likewise, the depletion amplitude remained decreased compared to control conditions. These data indicate that during Beta-Adrenergic Stimulation in the heart, both the intra-SR Ca threshold at which spontaneous Ca waves initiate and terminate is increased, while the amount of Ca released during Ca waves is decreased. The Ca wave termination level may represent an important mode of altering diastolic Ca wave amplitude, and thus, the arrhythmogenic potential of the cell during acute Beta-Adrenergic Stimulation.
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Beta-Adrenergic Stimulation Increases the Intra-Sarcoplasmic Reticulum Ca Threshold for Spontaneous Ca Waves
Biophysical Journal, 2011Co-Authors: Timothy L. Domeier, Joshua T. Maxwell, Lothar A. BlatterAbstract:Beta-Adrenergic signaling induces positive inotropic effects on the heart that frequently associate with spontaneous arrhythmogenic Ca release events including Ca waves. It remains unclear if the greater incidence of Ca waves is due to increased sarcoplasmic reticulum (SR) Ca content ([Ca]SR) or a change in the function of ryanodine receptors. To address this controversy we utilized dynamic [Ca]SR measurements (fluo-5N) to test if Beta-Adrenergic Stimulation alters the [Ca]SR level where Ca waves initiate (wave threshold) during rest after action potential Stimulation. Under control conditions [Ca]SR was progressively increased to the wave threshold via incremental increases in pacing frequency in a high extracellular Ca (7 mM) environment. In the presence of the Beta-Adrenergic agonist isoproterenol (ISO, 1 microM) [Ca]SR increased and Ca waves were observed. When [Ca]SR was subsequently lowered using low extracellular Ca (1 mM) and SERCA inhibition (3 microM cyclopiazonic acid), Ca waves were no longer observed, even at [Ca]SR levels above the control wave threshold. In parallel experiments we found that resting cytosolic [Ca] (indo-1) was similar between the respective experimental conditions. Indirect assessment of [Ca]SR using the amplitude of the cytosolic Ca transient induced by 10 mM caffeine confirmed our observation that in the presence of ISO Ca waves only occur when [Ca]SR is above the control wave threshold. Furthermore, spontaneous Ca spark measurements (fluo-4) showed a tendency towards spark inhibition in the presence of ISO at experimentally matched [Ca]SR. Together, these data show that acute Beta-Adrenergic Stimulation increases the [Ca]SR threshold for Ca waves, and therefore the primary cause of Ca waves is the robust increase in [Ca]SR above this higher threshold level. Elevation of the [Ca]SR wave threshold may be interpreted as a protective mechanism against pro-arrhythmogenic Ca release during Beta-Adrenergic Stimulation.
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mechanisms of spontaneous calcium wave generation during Beta Adrenergic Stimulation in rabbit ventricular myocytes
Biophysical Journal, 2010Co-Authors: Timothy L. Domeier, Lothar A. BlatterAbstract:The Beta-Adrenergic signaling pathway represents the principal positive inotropic mechanism of the heart. While the effects of Beta-Adrenergic Stimulation on L-type Ca channel Ca influx and SERCA-mediated sarcoplasmic reticulum (SR) Ca uptake are well established, the effects on SR Ca release through ryanodine receptor (RyR) release clusters remains highly controversial. Here, we examine SR Ca release in rabbit ventricular myocytes in the form of spontaneous Ca waves during Beta-Adrenergic Stimulation with isoproterenol under controlled cytosolic and SR [Ca]. Cytosolic Ca was monitored using high-affinity Ca indicators indo-1 or rhod-2, while SR Ca was measured directly using the low-affinity Ca indicator fluo-5N or indirectly using the amplitude of the cytosolic Ca transient in response to 10 mM caffeine. Under control conditions, Ca waves were not observed following rest from 0.75 Hz pacing. In the presence of isoproterenol (500 nM), SR Ca content increased by 34% and spontaneous Ca waves were observed in 67% of cells during rest after pacing. However, when post-rest cytosolic Ca and SR Ca content were experimentally matched to control conditions using low extracellular Ca (100 uM versus 2 mM) and SERCA inhibition (7.5 uM cyclopiazonic acid), spontaneous Ca waves were never observed in the presence of isoproterenol. In contrast, pharmacological sensitization of the RyR with 250 uM caffeine induced Ca waves under control conditions (8/12 cells) and in the presence of isoproterenol at matched cytosolic Ca and SR Ca content (7/12). Together, these data suggest that spontaneous Ca release during Beta-Adrenergic Stimulation is a result of increased RyR sensitivity in response to increased SR Ca content, and is not due to direct alterations in RyR function by the Beta-Adrenergic signaling cascade.
Marc Leeman - One of the best experts on this subject based on the ideXlab platform.
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effect of Beta Adrenergic Stimulation on pulse wave velocity in black and white subjects
Journal of Hypertension, 2004Co-Authors: Daniel Lemogoum, Luc M Van Bortel, Wouter Van Den Abeele, Agnieszka Ciarka, Jeanpaul Degaute, Philippe Van De Borne, Marc LeemanAbstract:BACKGROUND: Reduced Beta-Adrenergic sensitivity has been reported in black subjects. We hypothesized that Beta-Adrenergic Stimulation by isoproterenol would affect pulse wave velocity (PWV), a marker of arterial stiffness, differently in black and white subjects. METHODS: Healthy normotensive black subjects (n = 21) matched for age, gender, height and body mass index with healthy normotensive white subjects (n = 20), participated in a randomized, double-blind, placebo-controlled cross-over study. The PWV was determined using an automated device at baseline and after 30 min of an equal volume infusion of isoproterenol (8 mug/kg per min) or placebo (dextrose 5%), separated by a washout period of 25 min. RESULTS: At baseline, heart rate (HR), systolic and diastolic blood pressure (SBP, DBP) and PWV were comparable in black and in white subjects. Placebo had no significant effect on haemodynamic variables. Isoproterenol increased HR, SBP and pulse pressure and decreased DBP with a comparable magnitude in both groups. Compared with placebo, isoproterenol decreased carotid-femoral PWV in white (from 5.9 +/- 1.2 to 5.7 +/- 1.1 m/s, means +/- SD, P = 0.05), but not in black subjects (from 6.2 +/- 1.3 to 6.6 +/- 1.7 m/s, P = 0.1). The difference in response between black and white subjects was significant (P = 0.04). Isoproterenol decreased carotid-radial PWV only significantly in white subjects. CONCLUSION: These results are compatible with the hypothesis of an altered Beta-Adrenergic sensitivity, which is expressed by a blunted effect of isoproterenol on arterial stiffness in black subjects.
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Effect of Beta-Adrenergic Stimulation on pulse wave velocity in black and white subjects.
Journal of hypertension, 2004Co-Authors: Daniel Lemogoum, Agnieszka Ciarka, Jeanpaul Degaute, Luc M. Van Bortel, Wouter Van Den Abeele, Philippe Van De Borne, Marc LeemanAbstract:BACKGROUND Reduced Beta-Adrenergic sensitivity has been reported in black subjects. We hypothesized that Beta-Adrenergic Stimulation by isoproterenol would affect pulse wave velocity (PWV), a marker of arterial stiffness, differently in black and white subjects. METHODS Healthy normotensive black subjects (n = 21) matched for age, gender, height and body mass index with healthy normotensive white subjects (n = 20), participated in a randomized, double-blind, placebo-controlled cross-over study. The PWV was determined using an automated device at baseline and after 30 min of an equal volume infusion of isoproterenol (8 mug/kg per min) or placebo (dextrose 5%), separated by a washout period of 25 min. RESULTS At baseline, heart rate (HR), systolic and diastolic blood pressure (SBP, DBP) and PWV were comparable in black and in white subjects. Placebo had no significant effect on haemodynamic variables. Isoproterenol increased HR, SBP and pulse pressure and decreased DBP with a comparable magnitude in both groups. Compared with placebo, isoproterenol decreased carotid-femoral PWV in white (from 5.9 +/- 1.2 to 5.7 +/- 1.1 m/s, means +/- SD, P = 0.05), but not in black subjects (from 6.2 +/- 1.3 to 6.6 +/- 1.7 m/s, P = 0.1). The difference in response between black and white subjects was significant (P = 0.04). Isoproterenol decreased carotid-radial PWV only significantly in white subjects. CONCLUSION These results are compatible with the hypothesis of an altered Beta-Adrenergic sensitivity, which is expressed by a blunted effect of isoproterenol on arterial stiffness in black subjects.