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Chronic endothelin-A receptor antagonism is as protective as angiotensin converting enzyme inhibition against cardiac
1Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-8010 Graz, Austria.
Background And Purpose:
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.
Experimental Approach:
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.
Key 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 And Implications:
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.
Insights
Endothelin-A receptor blockers (ET(A)-RB) and angiotensin-converting enzyme inhibitors (ACE-I) equally protect diabetic hearts from dysfunction and damage. Combining these treatments offers no additional benefit for diabetic cardiomyopathy in this rat model.
Area of Science:
- Cardiology
- Pharmacology
- Diabetology
Background:
- Diabetes mellitus is linked to distinct cardiac complications, known as diabetic cardiomyopathy.
- Experimental models of diabetes are crucial for understanding and mitigating these cardiac effects.
Purpose of the Study:
- To compare the cardioprotective efficacy of an endothelin-A receptor blocker (ET(A)-RB) against an angiotensin-converting enzyme inhibitor (ACE-I).
- To evaluate these effects in a rat model of streptozotocin (STZ)-induced diabetes.
Main Methods:
- Diabetic rats were treated with either ET(A)-RB (atrasentan) or ACE-I (ramipril) for 8 weeks.
- Isolated heart function was assessed under normoxia and after ischemia-reperfusion.
- Cardiac fibrosis, oxidative stress, and nitric oxide synthase (NOS) activity were measured.
Main Results:
- Both ET(A)-RB and ACE-I treatments prevented declines in systolic contractility in diabetic hearts.
- Both drugs improved recovery of heart function post-ischemia-reperfusion and reduced cardiac fibrosis and oxidative stress.
- No significant differences in efficacy were observed between ET(A)-RB and ACE-I, and no additive benefits were found when combined.
Conclusions:
- ET(A)-RB demonstrates comparable cardioprotective effects to ACE-I in experimental type 1 diabetes.
- These findings suggest ET(A)-RB as a potential therapeutic strategy for diabetic cardiomyopathy.
- Combined therapy did not enhance the protective effects observed with monotherapy.
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