| First Author | Cowley PM | Year | 2015 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 309 |
| Issue | 5 | Pages | H888-96 |
| PubMed ID | 26116709 | Mgi Jnum | J:226453 |
| Mgi Id | MGI:5697276 | Doi | 10.1152/ajpheart.00042.2015 |
| Citation | Cowley PM, et al. (2015) The alpha1A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium. Am J Physiol Heart Circ Physiol 309(5):H888-96 |
| abstractText | Dysfunction of the right ventricle (RV) is closely related to prognosis for patients with RV failure. Therefore, strategies to improve failing RV function are significant. In a mouse RV failure model, we previously reported that alpha1-adrenergic receptor (alpha1-AR) inotropic responses are increased. The present study determined the roles of both predominant cardiac alpha1-AR subtypes (alpha1A and alpha1B) in upregulated inotropy in failing RV. We used the mouse model of bleomycin-induced pulmonary fibrosis, pulmonary hypertension, and RV failure. We assessed the myocardial contractile response in vitro to stimulation of the alpha1A-subtype (using alpha1A-subtype-selective agonist A61603) and alpha1B-subtype [using alpha1A-subtype knockout mice and nonsubtype selective alpha1-AR agonist phenylephrine (PE)]. In wild-type nonfailing RV, a negative inotropic effect of alpha1-AR stimulation with PE (force decreased approximately 50%) was switched to a positive inotropic effect (PIE) with bleomycin-induced RV injury. Upregulated inotropy in failing RV occurred with alpha1A-subtype stimulation (force increased approximately 200%), but not with alpha1B-subtype stimulation (force decreased approximately 50%). Upregulated inotropy mediated by the alpha1A-subtype involved increased activator Ca(2+) transients and increased phosphorylation of myosin regulatory light chain (a mediator of increased myofilament Ca(2+) sensitivity). In failing RV, the PIE elicited by the alpha1A-subtype was appreciably less when the alpha1A-subtype was stimulated in combination with the alpha1B-subtype, suggesting functional antagonism between alpha1A- and alpha1B-subtypes. In conclusion, upregulation of alpha1-AR inotropy in failing RV myocardium requires the alpha1A-subtype and is opposed by the alpha1B-subtype. The alpha1A subtype might be a therapeutic target to improve the function of the failing RV. |
