title: The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction.
abstract: We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with N(ω)-nitro-l-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 ± 3% vs. 37 ± 2% in Veh-treated rats, P < 0.001) and stroke volume (324 ± 33 vs. 255 ± 15 μl in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 ± 1.1 mmHg) than Veh-treated rats (16.3 ± 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 ± 1.8 vs. 30.9 ± 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload.
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Lennart G
authors.initials: LG
authors.lastname: Bongartz
authors.forename: Branko
authors.initials: B
authors.lastname: Braam
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Verhaar
authors.forename: Maarten Jan M
authors.initials: MJ
authors.lastname: Cramer
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Gaillard
authors.forename: Paul
authors.initials: P
authors.lastname: Steendijk
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008981:Molsidomine / Q000008:administration & dosage / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009392:Nephrectomy; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology*; D019335:Nitroarginine; D051381:Rats; D011917:Rats, Inbred Lew; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D015415:Biomarkers; D002316:Cardiotonic Agents; D020030:Nitric Oxide Donors; D019335:Nitroarginine; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D003404:Creatinine; D008981:Molsidomine