Different distribution of the common HFE variants between western and eastern Spanish populations evidences an independent haplotype gene flow / Diferencias en la distribución de las variantes comunes del gen HFE entre poblaciones del oeste y este de España evidencian un flujo independiente de sus distintos haplotipos

Introduction. Hereditary hemochromatosis is a disease responsible for excess blood iron. The hemochromatosis gene has two predominant variants, H63D and C282Y single nucleotide polymorphisms. Our study aims to analyze the diagnostic utility of genotyping the 63 and 282 loci, and examine the geographic distribution of these mutations in Spain. Methods and materials. Genotyping was performed on 94 healthy control individuals and 324 patients suspected of hereditary hemochromatosis, and also biochemical test to 313 individuals in the patients group. Results. The comparison of allelic frequencies between East and West of Spain, as well as other countries located at a similar longitude, evidenced a west-east distribution gradient of the C282Y allele. In addition, heterogeneous distribution of the H63D mutation in Spain was observed. Patients who carried the 282YY genotype showed significantly higher biochemical parameters (ferritin>300μg/L, Fe>180μg/L, IST>60%, UIBC>355μg/L and CTFH>370μg/dL), which confirmed the correlation between the mutated homozygous genotype and the associated hemochromatosis phenotype. Conclusion. Our results strengthen the importance of executing genetic tests to increase the efficiency of hereditary hemochromatosis diagnosis, which reveal an interesting variability among geographical regions (AU)

Introducción. La hemocromatosis hereditaria es una enfermedad responsable del exceso de hierro en sangre. El gen de la hemocromatosis tiene dos variantes predominantes, los polimorfismos de un solo nucleótido H63D y C282Y. Nuestro estudio trata de analizar la utilidad diagnóstica del genotipado de los loci 282 y 63, y examinar la distribución geográfica de estas mutaciones en España. Material y métodos. Se realizó genotipado en 94 controles sanos y 324 pacientes con sospecha de hemocromatosis hereditaria y además, test bioquímico a 313 individuos del grupo de pacientes. Resultados. La comparación de frecuencias alélicas entre poblaciones del este y el oeste de España, así como de otros países localizados en longitudes similares, evidenció una distribución en gradiente del alelo C282Y. Además se observó una distribución heterogénea de la mutación H63D en España. Los pacientes portadores del genotipo 282YY mostraron parámetros bioquímicos significativamente más elevados (ferritina >300μg/L, Fe > 180μg/L, IST > 60%, UIBC > 355μg/L y CTFH>370μg/dL), confirmando la correlación entre el genotipo homozigoto mutado y el fenotipo característico de hemocromatosis. Conclusión. Nuestros resultados refuerzan la importancia de realizar pruebas genéticas para confirmar el diagnóstico de la hemocromatosis hereditaria, teniendo en cuenta la variabilidad de los datos entre ámbitos geográficos (AU)

The increase in rat ventricular automaticity induced by salbutamol is mediated through ß(1)- but not ß(2)-adrenoceptors: role of phosphodiesterases.

AIMS: While ß(2)-adrenoceptor (AR) agonists are useful bronchodilators, they also produce cardiac arrhythmias. These agents are not fully selective and also activate ß(1)-AR, but the involvement of ß(1)-AR and ß(2)-AR in the observed pro-arrhythmic effect has not been established. We studied the effect of ß(1)-AR and ß(2)-AR activation on ventricular automaticity and the role of phosphodiesterases (PDE) in regulating this effect. MAIN METHODS: Experiments were performed in the spontaneously beating isolated right ventricle of the rat heart. We also measured cAMP production in this tissue. KEY FINDINGS: The ß(2)-AR agonist salbutamol (1-100 µM) produced a concentration-dependent increase in ventricular automaticity that was not affected by 50nM of the ß(2)-AR antagonist ICI 118551. This effect was enhanced by the non-selective PDE inhibitor theophylline (100 µM) and by the selective PDE4 inhibitors rolipram (1 µM) and Ro 201724 (2 µM), but not modified by the selective PDE3 inhibitors cilostamide (0.3 µM) or milrinone (0.2 µM). The effects of salbutamol alone and in the presence of either theophylline or rolipram were virtually abolished by 0.1 µM ß(1)-AR antagonist CGP 20712A. Salbutamol (10 µM) increased the cAMP concentration, and this effect was abolished by CGP 20712A (0.1 µM) but enhanced by theophylline (100 µM) or rolipram (1 µM). Cilostamide (0.3 µM) failed to modify the effect of salbutamol on cAMP concentration. SIGNIFICANCE: These results indicate that the increase of ventricular automaticity elicited by salbutamol was exclusively mediated through ß(1)-AR and enhanced by non-selective PDE inhibition with theophylline or selective PDE4 inhibition. However, PDE3 did not appear to regulate this effect.

Glucagon increases contractility in ventricle but not in atrium of the rat heart.

This study evaluates the inotropic responses to glucagon in electrically driven isolated left and right atria as well as in right ventricular strips of rat heart. For comparison, the contractile effects resulting from stimulating beta-adrenoceptors with isoprenaline in atrial and ventricular tissues were also obtained. Glucagon (0.01-1 microM) produces a concentration-dependent positive inotropic effect in ventricular but not in atrial myocardium. Isoprenaline, however, increases contractility both in atrial and ventricular tissues. The nonselective phosphodiesterase (PDE) inhibitor 3-isobutylmethylxantine (IBMX, 10 microM) enhances the contractile effect of glucagon on ventricular myocardium. However, glucagon still failed to increase contractility in atrial myocardium in the presence of 10 microM, IBMX. Also, in left atria of rats pretreated with pertussis toxin, glucagon did not produce any positive inotropic effect, either alone or in the presence of 10 microM, IBMX. Western blotting analysis indicates that glucagon receptors expression is 5 times higher in ventricular than in atrial myocardium. Taken together, these results indicate that the lack of inotropic effect of glucagon in atrium is not due to Gi protein or PDEs activity but seems to be a consequence of a lower glucagon receptor density in this tissue.