Involvement of iNOS in postischemic heart dysfunction of stroke-prone spontaneously hypertensive rats.
We investigated the possible contribution of inducible nitric oxide synthase (iNOS) to postischemic heart dysfunction and injuries in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP, 13-14 wk of age, had significantly higher systolic blood pressure and greater heart weight than age-matched Wistar-Kyoto rats (WKY). Permanent occlusion of the left anterior descending coronary artery (LAD) caused significant and long-lasting increases in the activity and mRNA expression of myocardial iNOS in SHRSP compared with WKY. However, there was no significant difference in the LAD occlusion-induced expression of interleukin-1beta mRNA between SHRSP and WKY. Hemodynamic deterioration and myocardial fibrosis were also observed in SHRSP at 4 wk after LAD occlusion. Continuous administration of 2-amino-5,6-dihydro-6-methyl-4H-1,2-thiazin (AMT) completely blocked the LAD occlusion-induced increase in the myocardial iNOS activity of SHRSP. Moreover, postischemic heart dysfunction and injuries were also significantly ameliorated by 2-amino-5,6-dihydro-6-methyl-4H-1,2-thiazin (AMT). These results suggest that the increased activity of myocardial iNOS plays a pivotal role in the development of postischemic cardiac dysfunction and injuries in SHRSP with the hypertensive and hypertrophic heart.
Abe
K
K
Department of Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan. kohji.abe@shionogi.co.jp
Tokumura
M
M
Ito
T
T
Murai
T
T
Takashima
A
A
Ibii
N
N
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D003326:Coronary Circulation; D003327:Coronary Disease / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005312:Fetal Blood; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007375:Interleukin-1 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020521:Stroke / Q000378:metabolism; D013843:Thiazines / Q000494:pharmacology
C093124:2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013843:Thiazines; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat