Modulation of iNOS activity in age-related cardiac dysfunction.
Based on the role of inducible nitric oxide synthase (iNOS) in heart failure, we hypothesized that the elevated expression of iNOS compared to young mice in the myocardium contributes to the age-related decline of left ventricular (LV) function. Cardiac iNOS mRNA and protein expression was singularly identified in old, wild type (WT) male mice (I6-month) and not in young WT male mice (6-month). Characterized with in vivo pressure-volume loops analysis, an age-related LV dysfunction was found in the old WT mice. The LV dysfunction of the aged mice was modified to that of the younger mice by the specific iNOS inhibitors, aminoguanidine (AMG, 10 mg/Kg, i.v. or infusion, n = 15) and S-methyl-isothiourea (MITU, 3 mg/Kg, i.v. n = 7), and declined with L-arginine (10 mg/Kg, i.v. n = 7). All three drugs had no effects on the LV function of young WT mice or old iNOS knockout (KO) mice. The NOx and cGMP levels were significantly higher only in the old WT mice (n = 6) and cGMP levels decreased to normal with AMG administration. In conclusion, these results suggested that the iNOS/NO/cGMP pathway may contribute to ventricular dysfunction during the aging process and that inhibition of iNOS activity significantly improved heart function in aged mice.
Yang
Bo
B
University Heart Center and Department of Surgery, the University of Arizona, Room 4402, Tucson, AZ 85724, USA.
Larson
Douglas F
DF
Watson
Ronald R
RR
D000375:Aging / Q000502:physiology*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019084:Fluorescent Antibody Technique, Indirect; D006146:Guanidines / Q000494:pharmacology; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics
D004791:Enzyme Inhibitors; D006146:Guanidines; D012333:RNA, Messenger; D007550:Isothiuronium; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C027744:S-methylisothiopseudouronium; D006152:Cyclic GMP; C004479:pimagedine