RU28318, an aldosterone antagonist, in combination with an ACE inhibitor and angiotensin receptor blocker attenuates cardiac dysfunction in diabetes.
OBJECTIVE
We evaluated the effects of RU28318 (RU), a selective mineralocorticoid receptor (MR) antagonist, Captopril (Capt), an angiotensin converting enzyme inhibitor, and Losartan (Los), an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R-) induced cardiac dysfunction in hearts obtained from normal and diabetic rats.


METHODS
Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I) followed by a period of 30 min of reperfusion (R). Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple). Recovery of cardiac hemodynamics was evaluated.


RESULTS
Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment.


CONCLUSIONS
RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving -dP/dt (a measure of diastolic function) when administered to diabetic hearts after ischemia.
Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait.
Ibrahim F
IF
Benter
Fawzi
F
Babiker
Ibrahim
I
Al-Rashdan
Mariam
M
Yousif
Saghir
S
Akhtar
D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002216:Captopril / Q000494:pharmacology / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology; D004359:Drug Therapy, Combination; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; C041006:RU 28318; D002216:Captopril; D019808:Losartan