Contributions of endothelin-1 and sodium hydrogen exchanger-1 in the diabetic myocardium.
BACKGROUND
Endothelin-1 (ET-1) and sodium hydrogen exchanger-1 (NHE-1) are important mediators of several disease processes affecting the heart, especially relating to myocardial ischemia. There is evidence that their actions may be interrelated. Their contributions to diabetic heart disease have not been extensively documented. Accordingly, the aim of this study was to investigate the interactive roles of ET-1 and NHE-1 in the pathogenesis of diabetic cardiomyopathy, a significant cause of morbidity in diabetic patients.


METHODS
Streptozotocin-induced diabetic Sprague Dawley rats were treated with NHE-1 blocker cariporide or dual ET(A)/ET(B) blocker bosentan and were subsequently studied one, three and six months after induction of diabetes. These animals were compared with nondiabetic rats as well as with diabetic rats on poor blood glucose control.


RESULTS
Diabetes leads to hyperglycemia, reduced body weight gain and increased glycated hemoglobin levels. These animals exhibited focal myocardial fibrosis and increased ejection fraction, in association with a tendency to increased left ventricular wall thickness and heart weight, after six months of follow-up, both bosentan and cariporide prevented these responses. Diabetes also caused significant increases in ET-1 mRNA and protein expression in the heart at all time points, which was further augmented by cariporide treatment for three months. Diabetes did not affect either mRNA or protein expression of NHE-1, although these did decrease in hearts of diabetic animals treated with bosentan for six months.


CONCLUSIONS
These results indicate an important contribution of both ET-1 and NHE-1 in the pathogenesis of diabetic cardiomyopathy. These data suggest that NHE-1 may act as a downstream mediator in the production of ET-induced functional and structural changes in the myocardium in diabetes.
Hileeto
Denise
D
Department of Pathology, The University of Western Ontario, London, Ontario, Canada.
Cukiernik
Mark
M
Mukherjee
Suranjana
S
Evans
Terry
T
Barbin
Yousef
Y
Downey
Donal
D
Karmazyn
Morris
M
Chakrabarti
Subrata
S
D000818:Animals; D001835:Body Weight; D000077300:Bosentan; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019333:Endothelin-2 / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014158:Transcription, Genetic
D019332:Endothelin-1; D019333:Endothelin-2; D006146:Guanidines; D007328:Insulin; D012333:RNA, Messenger; D017923:Sodium-Hydrogen Exchangers; D013449:Sulfonamides; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; C093373:cariporide; D000077300:Bosentan