Beta-, Not Alpha-Adrenergic Stimulation Enhances Conduction Velocity in Cultures of Neonatal Cardiomyocytes

Abstract

n the mature circulatory system, -adrenergic stimulation predominantly affects vessel diameter whereas 1-adrenergic stimulation determines the adaptation of heart rate and contractility to changing demands. In the immature stages of heart development, postnatal maturation coincides with in-growth of sympathetic neurons, elevated levels of released catecholamines and enhanced expression of -adrenoreceptors. 1 Shortly after birth, hyperplasia of the cardiomyocytes ceases and is followed by hypertrophic growth and maturation. 2 During maturation, cardiac rhythm becomes slower, while conduction velocity (CV) of the electrical impulse, which is initially slow, 3 increases. Several factors contribute to cell-to-cell propagation of the cardiac electrical impulse, which is enabled by specialized membrane structures named gap junctions. Gap junctions are agglomerates of intercellular channels composed of hexagonally arranged connexin (Cx) proteins. The Circulation Journal Vol.71, June 2007Cxs form a large family of transmembrane proteins, and are expressed in virtually all vertebrate cells. 4 Three isoforms, Cx40, -43 and -45, are expressed by mammalian cardiomyocytes. Expression of the isoforms is not uniform within cardiac tissue, differs between the species and is subject to developmental changes. [5][6][7][8] Cx43, as expressed between all working myocardial cells, is predominant. Intercellular gap junctional communication is determined by the number and distribution of expressed gap junction channels (n), the open probability of each channel (Po) and the single-channel conductance ( j). Po and j differ between gap junction isoforms and are subject to post-translational modulation (eg, by phosphorylation). 9 Propagation further depends on the level of expression of the protein subunits that constitute the ion channels responsible for the electrical make-up of the action potential (AP). In adult hearts, sodium channel availability in particular determines the upstroke velocity of the AP. In immature hearts, availability of the L-type calcium channel is most important in this respect. The higher the upstroke velocity, the faster a depolarized myocyte is able to trigger adjacent myocytes. Within the syncytium of all connected cardiomyocytes, changes in upstroke velocity thereby reflect on CV.A third factor that affects propagation is the geometry of the tissue. Differences in cell size and shape affect the conCirc J 2007; 71: 973 -981 (Received September 11, 2006; revised manuscript received March 6, 2007; accepted March 19, 2007 Background During both cardiac maturation and myopathy, elevated levels of circulating catecholamines coincide with alterations in impulse propagation. An in vitro model of cultured cardiomyocytes was used to study the effects of adrenergic stimulation on the conduction characteristics of immature heart cells. Methods and ResultsNeonatal rat cardiomyocytes were cultured on preparations designed to measure conduction velocity (CV). CV was measured on the same preparation twice at t=0 and at t...

Beta-receptor activation increases sodium current in guinea pig heart

“…These results coincided with those of De Boer et al [18] . Namely, betaadrenergic stimulation, and not alpha-adrenergic stimulation, enhances conduction velocity in cultures of neonatal cardiac myocytes.…”

Differential regulation of low and high voltage-activated calcium channels in neonatal rat myocytes following chronic PKA modulation

“…21 Long-term (>2 h) stimulation by the β-adrenergic agonist isoproterenol results in an increase in the expression of Ca v 1.2 as well as auxiliary subunits α 2 δ and β 2 a in myocytes cultured in serum-containing media. [22][23][24] PKA stimulation increases the mRNA levels of Ca v 1.2 and β 2 a in myocytes, an effect that saturated after 8 h. 22,23 Consistent with these findings, we showed that at 7 h of treatment, 8Br-cAMP increased and H89 reduced the HVA calcium current component, suggesting that the channels may be regulated through PKA-dependent mechanisms. Unexpectedly, we observed that long-term treatment with H89 persistently increased both HVA and LVA current densities.…”

“…[22][23][24] PKA phosphorylation of the VDCCs also regulates channel activity. Upon β-adrenergic stimulation, PKA activation increases myocardial contractility (positive inotropy) via upregulation of the HVA Ca v 1.2 channel activity.…”

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

“…The effects of sympathetic excitation include APD shortening via modulation of the slow inward rectifying potassium channel (IK S ), increased repolarization heterogeneity, increased intracellular calcium, and increased afterdepolarizations (5), among other effects. The sodium channel NaV1.4 (encoded by SCN5A) is known to be upregulated and modulated by ␤-adrenergic stimulation (13,31). However, this is on a longer time scale and unlikely to have played a role on the short-term effects of SGS studied here.…”

“…CV anisotropy ϭ CVL/CVT. Impact of ␤-adrenergic receptor activation on GJ conductance from de Boer et al (13). estimate local APD has limitations.…”