Contrasting inotropic responses to α₁-adrenergic receptor stimulation in left versus right ventricular myocardium

Abstract

The left ventricle (LV) and right ventricle (RV) have differing hemodynamics and embryological origins, but it is unclear whether they are regulated differently. In particular, no previous studies have directly compared the LV versus RV myocardial inotropic responses to alpha(1)-adrenergic receptor (alpha(1)-AR) stimulation. We compared alpha(1)-AR inotropy of cardiac trabeculae from the LV versus RV of adult mouse hearts. As previously reported, for mouse RV trabeculae, alpha(1)-AR stimulation with phenylephrine (PE) caused a triphasic contractile response with overall negative inotropy. In marked contrast, LV trabeculae had an overall positive inotropic response to PE. Stimulation of a single subtype (alpha(1A)-AR) with A-61603 also mediated contrasting LV/RV inotropy, suggesting differential activation of multiple alpha(1)-AR-subtypes was not involved. Contrasting LV/RV alpha(1)-AR inotropy was not abolished by inhibiting protein kinase C, suggesting differential activation of PKC isoforms was not involved. However, contrasting LV/RV alpha(1)-AR inotropic responses did involve different effects on myofilament Ca(2+) sensitivity: submaximal force of skinned trabeculae was increased by PE pretreatment for LV but was decreased by PE for RV. For LV myocardium, alpha(1)-AR-induced net positive inotropy was abolished by the myosin light chain kinase inhibitor ML-9. This study suggests that LV and RV myocardium have fundamentally different inotropic responses to alpha(1)-AR stimulation, involving different effects on myofilament function and myosin light chain phosphorylation.

Heart failure switches the RV α1-adrenergic inotropic response from negative to positive

“…3A), consistent with our previous report (33). Moreover, fitting the force-Ca 2ϩ relationship to the Hill equation revealed that PE caused a significant increase in EC 50 (Fig.…”

“…In the nonfailing LV myocardium, ␣ 1 -ARs mediated a positive inotropic response (Fig. 2C), consistent with our previous report (33). Moreover, in the LV myocardium, the inotropic response to ␣ 1 -ARs was similar in nonfailing versus failing hearts (Fig.…”

“…For the nonfailing RV myocardium, stimulation of ␣ 1 -ARs with PE in the presence of a ␤-AR antagonist caused an overall negative inotropic response (Fig. 1A), consistent with our previous report (33). In marked contrast, in heart failure, the response to ␣ 1 -ARs in the RV myocardium was switched to a net positive inotropic response (Fig.…”

“…Stimulation of ␣ 1 -ARs results in MLCK-dependent phosphorylation of cardiac MLC2, which sensitizes the myofilaments to Ca 2ϩ (1,5,33). Therefore, to investigate the role of MLCK in the switch to a positive ␣ 1 -AR inotropic response in the RV myocardium in heart failure, we acutely treated trabeculae with the MLCK inhibitor ML-9 (1).…”

“…Conversely, we (33) reported that the RV and LV have fundamentally different inotropic responses to stimulation of ␣ 1 -adrenergic receptors (ARs), which caused negative inotropic responses in the RV myocardium but positive inotropic responses in the LV myocardium. This and another study (31) have indicated that the RV and LV are categorically different and that RV failure cannot be understood by extrapolating data from LV failure.…”