title: Molsidomine Attenuates Ventricular Electrical Remodeling and Arrhythmogenesis in Rats With Chronic β-Adrenergic Receptor Activation Through the NO/cGMP/PKG Pathway.
abstract: This study investigated the effects and associated underlying mechanisms of molsidomine, a nitric oxide (NO) donor, on cardiac electrical remodeling and ventricular tachycardias (VTs) induced by chronic isoprenaline (ISO) stimulation in rats. The rats were randomly divided into groups that were treated with saline (control group), ISO (ISO group), ISO + molsidomine (ISO + M group), and ISO + molsidomine + the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, ISO + M + O group) for 14 days. An electrophysiological study was performed to assess cardiac repolarization, action potential duration restitution, and the induction of action potential duration alternans and VTs in vitro. The properties of the Ca transients, Ca handling-related proteins, and NO/guanosine 3'5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) pathway were examined. Compared with the control group, chronic ISO stimulation prolonged the cardiac repolarization, decreased the Ca transient alternans and action potential duration alternans thresholds, and increased the maximum slope (Smax) of the action potential duration restitution curve and incidence of VTs in vitro. All these effects were attenuated by molsidomine treatment (P < 0.05). Moreover, molsidomine activated cGMP/PKG signaling and stabilized the expression of calcium handling-related proteins compared with the ISO group. However, the protective effects of molsidomine were partially inhibited by ODQ. Our results suggest that molsidomine stabilizes calcium handling and attenuates cardiac electrical remodeling and arrhythmogenesis in rats with chronic β-adrenergic receptor activation. These effects are at least partially mediated by the activation of NO/cGMP/PKG pathway.
authors.affiliation: *Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China; †Cardiovascular Research Institute, Wuhan University, Wuhan, PR China; and ‡Hubei Key Laboratory of Cardiology, Wuhan, PR China.
authors.forename: Yingguang
authors.initials: Y
authors.lastname: Shan
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.forename: Congxin
authors.initials: C
authors.lastname: Huang
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004562:Electrocardiography / Q000187:drug effects; D008297:Male; D008981:Molsidomine / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000819:agonists / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D020030:Nitric Oxide Donors; D011943:Receptors, Adrenergic, beta; D009569:Nitric Oxide; D008981:Molsidomine; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP