Advantages in the use of carvedilol versus propranolol for the protection of cardiac mitochondrial function

BACKGROUND: Carvedilol is a neurohormonal antagonist of multiple action which is used in clinical practice for the treatment of congestive heart failure, mild to moderate hypertension and myocardial infarction. Previous results from our group have demonstrated that one of the main targets for the protective effect of carvedilol is the cardiac mitochondrial network. In-this work, we compare the effect of carvedilol with propranolol in different models of mitochondrial dysfunction and in the generation of transmembrane electric potential (EP). We further tested if carvedilol was able to inhibit the mitochondrial permeability transition (MPT) induced by doxorubicin and calcium-dependent cytochrome c release, a phenomenon frequently associated with apoptotic cell death. METHODS: Cardiac mitochondria were isolated by differential centrifugation. Oxygen consumption and mitochondrial EP were determined using an oxygen electrode and a tetraphenylphosphonium-sensitive electrode, respectively. Changes in mitochondrial volume and the release of cytochrome c were measured with spectrophotometric techniques. RESULTS: Propranolol, compared with carvedilol, had only a marginal effect, not only in protection against MPT induction, but also against oxygen consumption linked to the oxidation of external NADH, a process that is considered by several authors as key in the cardiotoxicity of doxorubicin. Regarding EP generation, propranolol had no effect, in contrast to carvedilol, which was confirmed to act as a protonophore. For the first time we also show that carvedilol inhibits the MPT induced by doxorubicin and calcium-dependent cytochrome c release. CONCLUSIONS: With this work, we further support the notion that carvedilol is effective in several models of mitochondrial dysfunction, particularly those involving oxidative stress. The results demonstrate that for some pathological conditions, carvedilol and propranolol have different mechanisms of action at the sub-cellular level, as propranolol seems to lack effectiveness in the protection of cardiac mitochondria

Carriers for metal complexes on tumour cells: the effect of cyclodextrins vs CNTs on the model guest phenanthroline-5,6-dione trithiacyclononane ruthenium(II) chloride

The complex [Ru[9]aneS(3)(pdon)Cl]Cl (pdon = 1,10-phenanthroline-5,6-dione) was readily obtained from the stoichiometric reaction of Ru[9]aneS(3)(dmso)Cl-2 with pdon. Recrystallisation in ethanol using salicylic acid as a co-crystallisation helper afforded single-crystals suitable for the collection of X-ray diffraction data which afforded a reasonable structural description. Two different kinds of molecular carriers were tested as vehicles for this complex: carbon nanotubes (CNTs) and cyclodextrins. CNTs had an insufficient loading rate for the ruthenium complex at CNT concentrations deemed non-cytotoxic on cultured cells. The cyclodextrin (CD) carriers, beta-CD and TRIMEB (standing for permethylated beta-CD), were able to form two adducts, studied by powder X-ray diffraction, thermogravimetric analysis (TGA), C-13{H-1} CP/MAS NMR and FT-IR spectroscopies. The DNA thermal denaturation studies showed that the complex 1 is able to intercalate with DNA. The in vitro cytotoxicity of the free complex [Ru[9]aneS(3)(pdon)Cl]Cl (1) and of its two CD adducts (2 and 3) was assessed on both rodent and human cell lines. By using the mouse K1735-M2 melanoma cell line and the non-tumour rat H9c2 cardiomyoblasts, the results showed that 1 and 2 significantly inhibited the growth of the tumour cell line while displaying a good safety profile on cardiomyoblasts. Compound 3 at 100 mu M inhibited the proliferation of both cell lines, with a higher activity towards the melanoma cell line. The cytotoxicity of the compounds 1-3 was further assessed on human breast cancer cell lines. Against the MDA-MB-231 line, growth inhibition occurred only with 1 and 3 at the incubation time of 96 h, both with approximate inhibition rates of 50 %; against the MCF-7 line, mild cytotoxicity was observed at 48 h of incubation, with IC50 values calculated above 100 mu M for 1, 2 and 3