Effects of newly-developed benzodiazepine ligands on noise-induced mitochondrial damage in the rat.
In this study we measured the ability of three newly-synthesized N-arylalkylindol-3-ylglyoxylylamide derivatives, which have recently been characterized as partial agonists at central benzodiazepine binding sites, to prevent the rat cardiac mitochondrial alterations resulting from acute loud noise exposure. In particular, we evaluated the effects of these new compounds on the ultrastructural damage induced by noise stress on the right atrium and ventricle after 6 and 12 hr of loud noise exposure. In parallel experiments, we measured the affinity of these compounds for peripheral benzodiazepine binding sites. Following a single injection of the test products, we observed a cardioprotective effect which was more marked after 6 hr compared with 12 hr of noise exposure. Confirming our recent data showing that full agonists at benzodiazepine receptors produce cardioprotection, we demonstrate in this study that partial agonists, like indolylglyoxylylamides, can also produce a cardioprotective effect. Based on their greater affinity in binding studies, the protective activity seems to be related more to their action at central than at peripheral benzodiazepine receptors.
Department of Human Morphology and Applied Biology, School of Medicine, University of Pisa, Italy.
M
M
Gesi
A
A
Pellegrini
P
P
Lenzi
F
F
Da Settimo
C
C
Martini
F
F
Salvetti
S
S
Taliani
F
F
Fornai
D000818:Animals; D001570:Benzodiazepinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D002316:Cardiotonic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D006325:Heart Atria; D006352:Heart Ventricles; D007546:Isoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D009622:Noise; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
D001570:Benzodiazepinones; D002316:Cardiotonic Agents; D007546:Isoquinolines; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; C037850:PK 11195