Mechanism of Vascular Toxicity in Rats Subjected to Treatment with a Tyrosine Kinase Inhibitor.

Sunitinib (Su) is a tyrosine kinase inhibitor with antiangiogenic and antineoplastic effects that is recommended therapy for renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. Arterial hypertension is one of the adverse effects observed in the treatment with Su. The aim of this work was to deepen our understanding of the underlying mechanisms involved in the development of this side effect. Studies on endothelial function, vascular remodeling and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) system were carried out in thoracic aortas from rats treated with Su for three weeks. Animals subjected to Su treatment presented with increased blood pressure and reduced endothelium-dependent vasodilation, the latter being reverted by NADPH oxidase blockade. Furthermore, vascular remodeling and stronger Masson trichrome staining, together with enhanced immunofluorescence signal for collagen 1 alpha 1 (Col1α1), were observed in aortas from treated animals. These results were accompanied by a significant elevation in superoxide anion production and the activity/protein/gene expression of NADPH oxidase isoforms (NOX1, NOX2, and NOX4), which was also prevented by NOX inhibition. Furthermore, a decrease in nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activation was observed in aortas from Su-treated animals. All these results indicate that endothelial dysfunction secondary to changes in vascular remodeling and oxidative stress might be responsible for the typical arterial hypertension that develops following treatment with Su.

Benefit of tolvaptan in the management of hyponatraemia in patients with diuretic-refractory congestive heart failure: the SEMI-SEC project.

AIMS: Hyponatraemia is an electrolyte disorder that occurs in advanced congestive heart failure (HF) and worsens prognosis. We explored the usefulness of tolvaptan, which has shown promising results in the treatment of this condition. METHODS AND RESULTS: This study is based on a retrospective national registry (2011-15) of patients hospitalized with refractory HF and hyponatraemia who agreed to receive tolvaptan when standard treatment was ineffective. The benefit of tolvaptan was analysed according to the following criteria: normalization ([Na+] ≥ 135 mmol/L) or increased sodium levels [Na+] ≥ 4 mEq/L on completion of treatment, and increase in urine output by 300 or 500 mL at 48 h. Factors associated with tolvaptan benefit were explored. A total of 241 patients were included, 53.9% of whom had ejection fraction <40%. All patients received concomitant loop diuretics. Initial tolvaptan dose was 17.2 ± 6.1 mg, and end dose was 26.4 ± 23.2 mg (duration 7.8 ± 8.6 days). Serum sodium concentrations increased significantly at 24-48 h, from 126.5 ± 6.2 mEq/L at baseline to 134.1 ± 6.1 mEq/L at the end of treatment (P < 0.0001). Weight fell by ~5 kg before discharge (P < 0.0001) and urine output increased 1.3-fold (P < 0.0001). Normal sodium levels and/or increases of 500 mL in urine output were achieved by 90.8% of patients (35.7% achieved both) and 94.8% increased to [Na+] ≥ 4 mEq/L and/or +300 mL in urine output (54.4% both). CONCLUSIONS: An increase in sodium levels and/or improvement in urine output was observed in patients admitted for HF and refractory hyponatraemia under tolvaptan treatment. Tolvaptan may be useful in this setting, in which no effective proven alternatives are available.

Inflammatory and fibrotic processes are involved in the cardiotoxic effect of sunitinib: Protective role of L-carnitine.

Sunitinib (Su) is currently approved for treatment of several malignances. However, along with the benefits of disease stabilization, cardiovascular toxicities have also been increasingly recognized. The aim of this study was to analyze which mechanisms are involved in the cardiotoxicity caused by Su, as well as to explore the potential cardioprotective effects of l-carnitine (LC). To this end, four groups of Wistar rats were used: (1) control; (2) rats treated with 400mg LC/kg/day; (3) rats treated with 25mg Su/kg/day; and (4) rats treated with LC+Su simultaneously. In addition, cultured rat cardiomyocytes were treated with an inhibitor of nuclear factor kappa B (NF-κB), in order to examine the role of this transcription factor in this process. An elevation in the myocardial expression of pro-inflammatory cytokines, together with an increase in the mRNA expression of NF-κB, was observed in Su-treated rats. These results were accompanied by an increase in the expression of pro-fibrotic factors, nitrotyrosine and NOX 2 subunit of NADPH oxidase; and by a decrease in that of collagen degradation factor. Higher blood pressure and heart rate levels were also found in Su-treated rats. All these alterations were inhibited by co-administration of LC. Furthermore, cardiotoxic effects of Su were blocked by NF-κB inhibition. Our results suggest that: (i) inflammatory and fibrotic processes are involved in the cardiac toxicity observed following treatment with Su; (ii) these processes might be mediated by the transcription factor NF-κB; (iii) LC exerts a protective effect against arterial hypertension, cardiac inflammation and fibrosis, which are all observed after Su treatment.

The role of inflammatory markers in the cardioprotective effect of L-carnitine in L-NAME-induced hypertension.

BACKGROUND: The mechanism(s) underlying the effects of L-carnitine (beta-hydroxy-gamma-N-trimethylammonium-butyrate; LC) in cardiovascular diseases are not well clarified. Previous studies have demonstrated that oxidative stress and inflammation contribute to arterial hypertension, and antioxidant and/or anti-inflammatory therapies have been proposed. We hypothesized that LC might attenuate the hypertensive status through an inhibition of inflammation process. METHODS: Heart mRNA expression and plasma levels of inflammatory markers, interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), were measured in rats that were made hypertensive with N(omega)-nitro-L-arginine methyl ester (L-NAME) and subjected to a simultaneous administration of LC. To clarify the role of the renin-angiotensin system (RAS) in this effect of LC, the activity and expression of angiotensin I-converting enzyme (ACE) as well as the expression of angiotensin II type I receptor (AT1R) in the heart were also determined. RESULTS: LC produced a significant, but not complete, reduction of blood pressure in L-NAME-treated rats. Plasma levels and heart expression of IL-1 beta, IL-6, and TNF-alpha showed an increase in the L-NAME group, which was reversed by LC treatment. The plasma ACE activity was not modified between normotensive and hypertensive rats although LC treatment produced a reduction of these values in the latter. Finally, protein and mRNA expression of ACE and AT1R was enhanced in the heart of L-NAME-treated animals, and LC reversed these values. CONCLUSIONS: The chronic administration of LC reduces blood pressure and attenuates the inflammatory process associated with arterial hypertension. LC might produce a partial inactivation in the RAS resulting in a reduction in the production and effects of angiotensin II.