ANNALS OF ANATOMY Effects of newly-developed benzodiazepine ligands on noise-induced mitochondrial damage in the rat Marco Gesi 1, Antonio Pellegrini 1, Paola Lenzi 1, Federico Da Settimo 2, Claudia Martini 3, Francesca Salvetti 3, Sabrina Taliani 2, and Francesco Fornai I 1Department of Human Morphology and Applied Biology, School of Medicine, University of Pisa, via Roma 55, 1-56126 Pisa, Italy, 2Department of Pharmaceutical Sciences and 3Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, Faculty of Pharmacy, University of Pisa, Italy Summary. 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 eva- luated the effects of these new compounds on the ultra- structural damage induced by noise stress on the right atrium and ventricle after 6 and 12 hr of loud noise expo- sure. 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 indo- lylglyoxylylamides, 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 recep- tors. Key words: Noise stress - Heart - Mitochondria - Benzo- diazepine ligands - Transmission electron microscopy - Rat - N-arylalkylindol-,3-ylglyoxylylamide derivatives Correspondence to: Marco Gesi Introduction In previous studies we reported that prolonged exposure to loud noise induces damage to the myocardium and adrenal gland of rodents (Soldani et al. 1997; Pellegrini et al. 1998). In particular, we found that loud noise induces several ultrastructural changes in heart ceils, consisting of enlargement of the endoplasmic reticulum, swelling of the mitochondria, dilution of the mitochondrial matrix and alterations to the cristae (Soldani et al. 1997). These effects are probably induced by increased intracellular calcium concentrations (Matlib et al. 1983; Cox and Matlib 1993) which, in the heart, derive from an in- creased noradrenergic activity (Reuter 1966). In keeping with this, other studies have shown that heart ultrastructural damage induced by noise occurs con- comitantly with an increase in noradrenergic activity (Pel- legrini et al. 1996), and it has been shown that stress induced by loud noise provokes an increased heart nor- adrenergic innervation (Paparelli et al. 1992). Preventing the stressful effects of prolonged noise ex- posure should therefore be regarded as a potential pro- tective mechanism to reduce myocardial damage. In view of these considerations, we evaluated the effects of ben- zodiazepine ligands on loud noise-induced myocardial ul- trastructural damage. In preliminary work limited to atrial tissue, we obtained evidence of a clear protective effect by pre-administering the anxiolytic drug diazepam to rats that subsequently underwent loud noise exposure (Pellegrini et al. 1996). Diazepam was selected as the first test compound because it acts as a full agonist at both peripheral (PBR) and central (CBR) benzodiazepine (BDZ) receptors. Furthermore, in order to clarify whether Ann Anat (2000) 182:311-318 © Urban & FischerVerlag http://www.urbanfischer.de/journals/annanat 0940-9602/00/182/4-311 $12,00•0