Intraventricular and interventricular cellular heterogeneity of inotropic responses to α₁-adrenergic stimulation

Abstract

α1-Adrenergic receptors (α1-ARs) elicit a negative inotropic effect (NIE) in the mouse right ventricular (RV) myocardium but a positive inotropic effect (PIE) in the left ventricular (LV) myocardium. Effects on myofilament Ca(2+) sensitivity play a role, but effects on Ca(2+) handling could also contribute. We monitored the effects of α1-AR stimulation on contraction and Ca(2+) transients using single myocytes isolated from the RV or LV. Interestingly, for both the RV and LV, we found heterogeneous myocyte inotropic responses. α1-ARs mediated either a PIE or NIE, although RV myocytes had a greater proportion of cells manifesting a NIE (68%) compared with LV myocytes (36%). Stimulation of a single α1-AR subtype (α1A-ARs) with a subtype-selective agonist also elicited heterogeneous inotropic responses, suggesting that the heterogeneity arose from events downstream of the α1A-AR subtype. For RV and LV myocytes, an α1-AR-mediated PIE was associated with an increased Ca(2+) transient and a NIE was associated with a decreased Ca(2+) transient, suggesting a key role for Ca(2+) handling. For RV and LV myocytes, α1-AR-mediated decreases in the Ca(2+) transient were associated with increased Ca(2+) export from the cell and decreased Ca(2+) content of the sarcoplasmic reticulum. In contrast, for myocytes with α1-AR-induced increased Ca(2+) transients, sarcoplasmic reticulum Ca(2+) content was not increased, suggesting that other mechanisms contributed to the increased Ca(2+) transients. This study demonstrates the marked heterogeneity of LV and RV cellular inotropic responses to stimulation of α1-ARs and reveals a new aspect of biological heterogeneity among myocytes in the regulation of contraction.

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

“…Cardiac myocyte-specific transgenic overexpression of the a 1 A-subtype at high levels (148-to 170-fold) increases basal contractile function (Lin et al, 2001) and limits pathologic remodeling from pressure overload and ischemic injury (Du et al, 2004(Du et al, , 2006. These results suggest that the a 1 A-subtype mediates positive inotropic responses, in agreement with recent in vitro studies (Mohl et al, 2011;Chu et al, 2013). Conversely, transgenic overexpression of the a 1 B-subtype can be associated with depressed contractile function and pathologic remodeling in the heart (Grupp et al, 1998;Wang et al, 2000;Iaccarino et al, 2001;Lemire et al, 2001).…”

“…However, in mice, the a 1 -AR inotropic response can be negative in a few left ventricular preparations, including isolated papillary muscles and a minority of isolated cardiac myocytes (Hirano et al, 2006;Chu et al, 2013). Interestingly, populations of cardiac myocytes from the right and left ventricle have a fraction of myocytes that have a positive inotropic response to phenylephrine and an increased Ca 2+ transient, prominent in the left ventricle, and a fraction of myocytes that have a negative inotropic response to phenylephrine and a decreased Ca 2+ transient, mainly in the right ventricle (Chu et al, 2013).…”

“…Proposed mechanisms include inhibition of outward K + currents and increased action potential duration (Apkon and Nerbonne, 1988;Fedida et al, 1989Fedida et al, , 1990Fedida et al, , 1991Ravens et al, 1989;Tohse et al, 1990Tohse et al, , 1992Wang et al, 1991Wang et al, , 2001Braun et al, 1992;Sato and Koumi, 1995;Gaughan et al, 1998 ); inhibition of L-type Ca 2+ channel current (Chen et al, 1996;Gaughan et al, 1998;Belevych et al, 2001) or activation (Zhang et al, 1998;Mohl et al, 2011;Chu et al, 2013); activation of the Na + /H + exchanger and intracellular acidification (Gambassi et al, 1992;Terzic et al, 1992); and regulation of myofilament Ca 2+ sensitivity through phosphorylation of myosin light chain and/or cardiac troponin I (Hartmann et al, 1995;Andersen et al, 2002;McCloskey et al, 2003;MacGowan et al, 2005;Wang et al, 2006Wang et al, , 2010.…”

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis

“…49 Finally, β2-adrenoceptors were found highly upregulated in LV, but not RV, in rats with chronic mild stress. 50 Thus, although relatively little is known about interventricular differences in ion channel regulation, presently available data suggest a complex system with chamber-specific remodeling of pre-existing interventricular differences in regulatory signaling pathways, which act upon differences in basal LV versus RV electrophysiology and Ca 2+ handling.…”

Emergency Spatiotemporal Shift: The Response of Protein Kinase D to Stress Signals in the Cardiovascular System

“…Paradoxically, α1-AR stimulation with PE, elicits a triphasic response in both the left ventricle (LV) and right ventricle (RV), but an overall positive inotropic response in LV trabeculae and an overall negative inotropic response in RV trabeculae (Wang et al, 2006). The overall response of each ventricle does not correspond to the response of individual myocytes, however, as α1-AR signaling causes both a positive and negative inotropic effect in individual myocytes of both ventricles that is independent of which α1-AR subtype is stimulated (Chu et al, 2013). In what is likely a compensatory mechanism, heart failure shifts the overall negative response to PE in the RV to a positive one (Wang et al, 2010).…”