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A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins.

ABSTRACT: Classical numerical models have attributed the regulation of normal cardiac automaticity in sinoatrial node cells (SANCs) largely to G protein-coupled receptor (GPCR) modulation of sarcolemmal ion currents. More recent experimental evidence, however, has indicated that GPCR modulation of SANCs automaticity involves spontaneous, rhythmic, local Ca(2+) releases (LCRs) from the sarcoplasmic reticulum (SR). We explored the GPCR rate modulation of SANCs using a unique and novel numerical model of SANCs in which Ca(2+)-release characteristics are graded by variations in the SR Ca(2+) pumping capability, mimicking the modulation by phospholamban regulated by cAMP-mediated, PKA-activated signaling. The model faithfully predicted the entire range of physiological chronotropic modulation of SANCs by the activation of beta-adrenergic receptors or cholinergic receptors only when experimentally documented changes of sarcolemmal ion channels are combined with a simultaneous increase/decrease in SR Ca(2+) pumping capability. The novel numerical mechanism of GPCR rate modulation is based on numerous complex synergistic interactions between sarcolemmal and intracellular processes via membrane voltage and Ca(2+). Major interactions include changes of diastolic Na(+)/Ca(2+) exchanger current that couple earlier/later diastolic Ca(2+) releases (predicting the experimentally defined LCR period shift) of increased/decreased amplitude (predicting changes in LCR signal mass, i.e., the product of LCR spatial size, amplitude, and number per cycle) to the diastolic depolarization and ultimately to the spontaneous action potential firing rate. Concomitantly, larger/smaller and more/less frequent activation of L-type Ca(2+) current shifts the cellular Ca(2+) balance to support the respective Ca(2+) cycling changes. In conclusion, our model simulations corroborate recent experimental results in rabbit SANCs pointing to a new paradigm for GPCR heart rate modulation by a complex system of dynamically coupled sarcolemmal and intracellular proteins.

SUBMITTER: Maltsev VA

PROVIDER: S-EPMC2886657 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins.

Maltsev Victor A VA Lakatta Edward G EG

American journal of physiology. Heart and circulatory physiology 20100312 6

Classical numerical models have attributed the regulation of normal cardiac automaticity in sinoatrial node cells (SANCs) largely to G protein-coupled receptor (GPCR) modulation of sarcolemmal ion currents. More recent experimental evidence, however, has indicated that GPCR modulation of SANCs automaticity involves spontaneous, rhythmic, local Ca(2+) releases (LCRs) from the sarcoplasmic reticulum (SR). We explored the GPCR rate modulation of SANCs using a unique and novel numerical model of SAN ...[more]

PMID: 20228256

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Project description:Obesity leads to an imbalance in the autonomic nervous system, especially in increased sympathetic modulation and decreased vagal tone, and some anthropometric, metabolic, and lifestyle variables may increase the risk of developing cardiovascular disease. Objective. To analyze the association between cardiovascular autonomic modulation and biochemical and anthropometric markers, food intake, and physical activity level in severely obese individuals. Methodology. The present study is a cutout of a randomized clinical trial "Effect of nutritional intervention and olive oil in severe obesity" (DieTBra Trial), where the baseline data were analyzed. Anthropometric data, biochemical exams, heart rate variability (HRV), accelerometry, and 24?h recall (R24H) of obese patients (body mass index BMI ?35?kg/m2) were collected. Results. 64 obese patients were analyzed, with a mean age of 39.10?±?7.74 years (27 to 58 years). By HRV analysis, in the frequency domain, the obese had a higher predominance of sympathetic autonomic modulation (low frequency (LF) 56.44?±?20.31?nu) and lower parasympathetic modulation (high frequency (HF) 42.52?±?19.18?nu). A negative association was observed between the variables Homeostasis Evaluation Model (HOMA-IR) and HF (p = 0.049). In the physical activity analysis, there was a negative association between moderate to vigorous physical activity and the sympathetic component (p = 0.043), and for sedentary time (ST), there was a negative association with HF (p = 0.049) and LF/HF (p = 0.036) and a positive association with LF (p = 0.014). For multiple linear regression, waist circumference (WC) and HOMA-IR values were negatively associated with HF (??=?-0.685, p = 0.010; ??=?-14.989, p = 0.010; respectively). HOMA-IR (??=?0.141, p = 0.003) and the percentage of lipids ingested (??=?-0.030, p = 0.043) were negatively associated with LF/HF. Conclusion. Among the cardiovascular risk variables studied, insulin resistance and central adiposity showed the greatest influence on cardiac autonomic modulation of obese, increasing the risk for cardiovascular disease.

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A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins.

Publications

A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins.

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