The perfusion of cisplatin and cisplatin structural analogues through the isolated rat heart: The effects on coronary flow and cardiodynamic parameters.

The therapeutic use of cisplatin for the treatment of solid tumours is associated with organ toxicity. Amongst those, the cardiotoxicity is an occasional but very serious and severe side effect. To prevent or reduce these negative effects, many cisplatin analogues have been synthesized and evaluated in terms of being a less toxic and more effective agent. In present study, we examined the effects of cisplatin and its three analogues in the isolated rat heart to determine whether changes in the structure of the platinum complexes (changing of carrier ligands - ethylenediamine; 1,2-diaminocyclohexane; 2,2':6',2''-terpyridine) can influence their cardiotoxic effects. The results of our research indicate that the introduction of aromatic rings in the structure of the platinum complexes has a negative influence on the heart function. Conversely, the other two examined complexes had less negative effects on heart function compared to cisplatin. Our findings may be of interest for a possible synthetic strategy of introducing a carrier ligand that will exert a less cardiotoxic effect.

Cisplatin and cisplatin analogues perfusion through isolated rat heart: the effects of acute application on oxidative stress biomarkers.

Drug-induced oxidative stress can occur in numerous tissues and organ systems (liver, kidney, ear, nervous system, and cardiovascular system). Cancer therapy with cisplatin is associated with side effects to which oxidative stress may contribute. We have compared the influences of cisplatin (reference compound) and its' analogues (dichloro(1,2-diaminocyclohexane)platinum(II) and chloro(2,2':6',2″-terpyridine)platinum(II)) in a model of isolated rat heart using the Langendorff technique. The production of oxidative stress biomarkers, antioxidant enzymes, myocardial damage, and expression of Bax, OH-1, and SODs were studied. Cisplatin and the analogues were perfused at concentration of 10-6 and 10-5 M during 30 min. The results of this study showed that examined platinum complexes had different ability to induce oxidative stress of isolated perfused rat heart. Varying the carrier ligands, such as 1,2-diaminocyclohexane and 2,2':6',2″-terpyridine, related to amino ligands (cisplatin) directly influenced the strength to induce production of oxidative stress biomarkers. Introducing 2,2':6',2″-terpyridine ligands provoked the smallest changes in antioxidant enzymes activity, lipid peroxidation, and expression of heme oxygenase-1, that undoubtedly indicated that this complex had the lowest impact on redox status in heart tissue. These findings may be useful in synthesis of novel platinum analogues with lower potential for oxidative stress induction. However, the fact that platinum complexes could induce toxic effects in the heart by other mechanisms should be taken into the consideration.

Platinum Complexes-Induced Cardiotoxicity of Isolated, Perfused Rat Heart: Comparison of Pt(II) and Pt(IV) Analogues Versus Cisplatin.

We have compared the cardiotoxicity of five platinum complexes in a model of isolated rat heart using the Langendorff technique. These effects were assessed via coronary flow (CF) and cardiac functional parameters. cis-Diamminedichloroplatinum(II) (cisplatin, CDDP), dichloro-(1,2-diaminocyclohexane)platinum(II) (Pt((II))DACHCl2), dichloro-(ethylenediamine)platinum(II) (Pt((II))ENCl2), tetrachloro-(1,2-diaminocyclohexane)platinum(IV) (Pt((IV))DACHCl4) and tetrachloro-(ethylenediamine)platinum(IV) (Pt((II))ENCl4) were perfused at increasing concentrations of 10(-8), 10(-7), 10(-6), 10(-5) and 10(-4) M during 30 min. In this paper, we report that cisplatin-induced dose-dependent effects on cardiac contractility and coronary flow both manifested as decrease in cardiac contractile force (dP/dt)max, heart rate and significant reduction in CF. Pt((II))ENCl2, Pt((IV))ENCl2 and Pt((IV))DACHCl4 did induce dose-dependent response only in case of CF. Our results could be also important for better understanding dose-dependent side effects of potential metal-based anticancer drugs.

[Effects of platelet single passage on coronary circulation in the isolated guinea-pig heart: focus on the L-arginine: nitric oxide system]. / Efekat jednokratne pasaze trombocita na koronarnu cirkulaciju izolov anog srca zamorceta: fokus na l-arginin:NO sistem.

INTRODUCTION: In order to evaluate endothelial response to platelet single passage through coronary vascular bed, experiments on isolated guinea-pig hearts perfused by the Langendorff method at constant pressure were performed. MATERIAL AND METHODS: Platelet single passage was performed with platelet-rich plasma obtained from healthy volunteers, as well as from patients with acute myocardial infarction. Hearts, isolated from guinea-pigs of either sex were perfused with Krebs-Hensenleit buffer. After a stabilization period of 30 minutes at 70 cm H2O, coronary perfusion pressure decreased to 30 cm H2O and increased to 120 cm H2O. After basic protocol, hearts were perfused with PRP, PRP-AMI alone or in combination with nitric oxide synthase inhibitor, N(omega)-nitro-L arginine methyl ester (L-NAME)--30 M, and nitrite outflow (NO2-) was measured. RESULTS: Basal (at 70 cm H2O) coronary flow (CF) and NO2- was 4.71+/-0.43 ml/min and 0.55+/-0.13 nmol/min/g wt. PRP induced significant decrease of CF at all values of CPP (from 32% at 30 cm H2O to 27% at 120 cm H2O), with parallel NO2- reduction (from 25% to 28%). When L-NAME, 30 M was added, PRP was much less effective: CF was reduced from 13% to 5%, with parallel changes of NO2- (reduction of 10% at all CPP values). PRP-AMI induced higher degree of CF reduction (from 42% to 44%) with NO2 reduction from 23% to 35%. PRP-AMI after applied L-NAME induced also less CF-reduction (from 18% to 12%), with similar NO2- reduction (from 18% to 12%). CONCLUSION: Our findings show that effects of platelet single passage through coronary vascular bed should be affected by NO in isolated guinea-pig hearts.