Anti-ischaemic activity of an antioxidant aldose reductase inhibitor on diabetic and non-diabetic rat hearts.
OBJECTIVE
Many observations report the cardioprotective effects of inhibitors of aldose reductase in different models of ischaemia-reperfusion injury in diabetic myocardium. In this paper, the inhibitory effects of the new pyrido[1,2-a]-pyrimidin-4-one derivative PPO, whose aldose reductase-inhibitory and antioxidant effects were shown in a previous study, were evaluated.


METHODS
The effect of PPO was evaluated on aldose reductase from hearts of diabetic and non-diabetic rats, and compared with that of the reference drug epalrestat. Moreover, the two drugs were tested on isolated and Langendorff-perfused diabetic and non-diabetic hearts submitted to ischaemia-reperfusion cycle.


RESULTS
Epalrestat showed equivalent levels of potency in inhibiting the activity of the enzyme in the diabetic and in the non-diabetic hearts. On the contrary, the inhibitory potency of PPO was decreased in the diabetic organs. In the diabetic hearts submitted to ischaemia-reperfusion, an increased level of heart aldose reductase activity was recorded, and both PPO and epalrestat produced cardioprotective effects, suggesting that aldose reductase is deeply involved in the process of ischaemia-reperfusion injury in diabetic myocardium. In non-diabetic hearts, where aldose reductase has a lower activity, epalrestat failed to produce significant protection, while PPO still maintained cardioprotective effects, which may be reasonably attributed to useful 'ancillary' effects - such as antioxidant activity - independent from the aldose reductase inhibition.


CONCLUSIONS
Therefore PPO, a new molecule endowed with both aldose reductase-inhibitory effects and antioxidant activity, may represent the prototype of a new class of multitarget drugs, focused on two different steps deeply involved in the pathogenesis of ischaemic injury of diabetic hearts.
Calderone
Vincenzo
V
Dipartimento di Psichiatria, Neurobiologia, Farmacologia, Biotecnologie, Università di Pisa, Pisa, Italy. calderone@farm.unipi.it
Testai
Lara
L
Martelli
Alma
A
La Motta
Concettina
C
Sartini
Stefania
S
Da Settimo
Federico
F
Breschi
Maria C
MC
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012236:Rhodanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology
C554082:2-(3,4-dihydroxyphenyl)-6-hydroxypyrido(1,2-a)pyrimidin-4-one; D000975:Antioxidants; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; D011744:Pyrimidinones; D053778:Thiazolidines; C038131:epalrestat; D012236:Rhodanine; D000449:Aldehyde Reductase