Chronic endothelin-A receptor antagonism is as protective as angiotensin converting enzyme inhibition against cardiac dysfunction in diabetic rats.
OBJECTIVE
Diabetes mellitus is associated with a specific cardiomyopathy. We compared the cardioprotective effects of an endothelin-A receptor blocker (ET(A)-RB) with those of an angiotensin-converting enzyme inhibitor (ACE-I) in rats with streptozotocin (STZ)-induced diabetes.


METHODS
Diabetic rats were left untreated or received either the ET(A)-RB atrasentan or the ACE-I ramipril (each 3 mg kg(-1) per day) orally for 8 weeks. Isolated isovolumic heart function was studied during normoxia and in response to ischaemia-reperfusion. Cardiac fibrosis, tissue oxidative stress and tissue nitric oxide synthase (NOS) activity were determined.


RESULTS
Basal left ventricular systolic contractility was lower in diabetic compared to nondiabetic hearts and ET(A)-RB or ACE-I treatment significantly antagonised the decline. Following 15 min of no-flow ischaemia, reperfusion systolic function was depressed and left-ventricular end-diastolic pressure (LVEDP) was elevated in diabetic hearts. ET(A)-RB or ACE-I treatment significantly improved recovery of reperfusion systolic and diastolic function, without differences between groups. Hydroxyproline (an index of tissue fibrosis) and malondialdehyde (a measure of tissue oxidative stress) were elevated at the end of reperfusion in diabetic, compared to nondiabetic hearts. Either treatment reduced hydroxyproline and malondialdehyde to control level. Constitutive NOS activity was similar in nondiabetic and diabetic hearts and unaffected by ET(A)-RB or ACE-I treatment.


CONCLUSIONS
These results suggest that in experimental type 1 diabetes ET(A)-RB is as effective as an ACE-I in ameliorating myocardial functions during normoxia and ischaemia-reperfusion. Combining the two treatments neither afforded additive effects, nor diminished any protection effect seen with either drug.
Wölkart
G
G
Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-8010 Graz, Austria.
Pang
X
X
Stessel
H
H
Kirchengast
M
M
Brunner
F
F
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000077868:Atrasentan; D002318:Cardiovascular Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D065130:Endothelin A Receptor Antagonists; D005260:Female; D005355:Fibrosis; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
D000806:Angiotensin-Converting Enzyme Inhibitors; D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D013311:Streptozocin; D019001:Nitric Oxide Synthase; D017257:Ramipril; D000077868:Atrasentan