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

Abstract

Right ventricular (RV) failure is a serious common clinical problem that is poorly understood. Therefore, for failing and nonfailing hearts, we examined the distinctive inotropic responses induced in the RV myocardium after the stimulation of ␣ 1-adrenergic receptors (ARs). In RV trabeculae from nonfailing mouse hearts, ␣ 1-ARs induced a negative inotropic response, consistent with our previous study. In marked contrast, in RV trabeculae from failing hearts, 12 wk after coronary artery ligation, ␣1-ARs induced a positive inotropic response. Mechanistically, experiments with skinned trabeculae showed that ␣1-ARs decreased myofilament Ca 2ϩ sensitivity in the nonfailing RV myocardium, whereas ␣1-ARs increased Ca 2ϩ sensitivity in heart failure. This suggests that a switch in the Ca 2ϩ sensitivity response to ␣1-AR stimulation explained the switch in the RV ␣1-AR inotropic response in heart failure. Myosin light chain kinase (MLCK) can increase myofilament Ca 2ϩ sensitivity, and the smooth muscle isoform (smMLCK), which is also present in cardiomyocytes, was more abundant in the RV myocardium from failing versus nonfailing hearts. Moreover, the MLCK inhibitor ML-9 prevented the switch of the RV myocardium to a positive ␣1-AR inotropic response in heart failure. In the left ventricular myocardium, in contrast, ␣1-AR inotropic responses were not different in failing versus nonfailing hearts, and smMLCK abundance was not increased in heart failure. In relation to human disease, we found that smMLCK mRNA and protein levels were increased in RVs from failing human hearts. We conclude that the RV inotropic response to ␣1-ARs is switched from negative to positive in heart failure, through a pathway involving increased myofilament Ca 2ϩ sensitivity. Since ␣1-AR agonist catecholamines are elevated in heart failure, increased ␣1-AR inotropic responses in the RV myocardium may be adaptive in heart failure by helping the failing RV respond to increased pulmonary pressures. right ventricle; myosin light chain kinase; myofilament calcium sensitivy RIGHT VENTRICULAR (RV) failure is a prevalent cause of cardiovascular collapse and a major public health problem (14,20). RV failure frequently arises in patients with left ventricular (LV) failure and causes markedly worse symptoms and prognosis compared with patients with LV failure without RV dysfunction (9,11,13). Moreover, the prognosis of heart failure patients with pulmonary hypertension is strongly related to RV dysfunction (13).Despite its clinical significance, RV failure is relatively understudied and poorly understood (31). The RV has been viewed merely as a weak LV (14). 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 extrapola...

Different expression of adrenoceptors and GRKs in the human myocardium depends on heart failure ethiology and correlates to clinical variables

“…Although ␣ 1 -ARs are not generally considered to be major regulators of the cardiac contractile function under physiological conditions, they are thought to have more influence under pathological conditions, such as HF (18). The correlation found between the LVEF and mRNA levels for ␣ 1A -AR in the human ventricle, not previously described, suggests that some degree of ␣ 1A activation could be beneficial in this pathology, as previously proposed in mouse (27) and humans (32,39). In addition, previous data have associated ␣ 1A -ARs with cardioprotection, whereas ␣ 1B -ARs are associated with cardiac growth and hypertrophy (16,18,41).…”

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

“…Standard treatments for LVF (ACE inhibitors, ␤-blockers) have shown limited success in RVF (22, 54), suggesting fundamental cellular-level differences between the RV and LV. The two ventricles derive embryologically from different heart fields (19) and manifest differences in calcium handling, inotropy, and patterns of gene expression in response to stress (7,37,67,69). Little is known about the role of the UPS in the RV.…”

Myocardial Alterations in Adrenoreceptors After Ventricular Unloading with a Pulsatile vs a Nonpulsatile Device~!2010-02-15~!2010-05-06~!2010-06-10~!

“…This particular collaboration suggests that not only do beta adrenergic receptors become 'dormant' and then respond to ventricular unloading, but that alpha adrenergic receptors respond in a similar manner, if not to such a great extent, possibly initiating a mechanism to avert inotropic changes [18], be part of the repair and restoration process [19], or become a pharmacologic treatment target [20].…”