RESUMEN
Due to the resurgence of tuberculosis and the emergence of multidrug-resistant strains, fluoroquinolones (FQ) are being used in selected tuberculosis patients, but FQ-resistant strains of Mycobacterium tuberculosis have rapidly begun to appear. The mechanisms involved in FQ resistance need to be elucidated if the effectiveness of this class of antibiotics is to be improved and prolonged. By using the rapid-growing Mycobacterium smegmatis as a model genetic system, a gene was selected that confers low-level FQ resistance when present on a multicopy plasmid. This gene, lfrA, encodes a putative membrane efflux pump of the major facilitator family, which appears to recognize the hydrophilic FQ, ethidium bromide, acridine, and some quaternary ammonium compounds. It is homologous to qacA from Staphylococcus aureus, tcmA, of Streptomyces glaucescens, and actII and mmr, both from Streptomyces coelicoler. Increased expression of lfrA augments the appearance of subsequent mutations to higher-level FQ resistance.
Asunto(s)
Antiinfecciosos/farmacología , Antiportadores/genética , Ciprofloxacina/farmacología , Farmacorresistencia Microbiana , Mycobacterium/metabolismo , Secuencia de Aminoácidos , Antiportadores/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Transporte Biológico Activo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Genes Bacterianos , Concentración de Iones de Hidrógeno , Datos de Secuencia Molecular , Mycobacterium/efectos de los fármacos , Plásmidos , Alineación de Secuencia , Homología de Secuencia de AminoácidoRESUMEN
The mechanisms of anti-hypertensive effect of diuretics remain unknown. The purpose of this study was to test the hypothesis that long-term treatment with chlorthalidone decreases the responsiveness of resistance vessels to neurohormones. The study was performed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats with and without treatment with chlorthalidone (Chlor. 8 mg/day, for 20 days). Resting mean arterial pressure in freely moving state was significantly reduced in DOCA-salt-Chlor rats when compared to DOCA-salt rats (116 +/- 3 vs 147 +/- 7 mmHg, respectively). Chlorthalidone treatment reduced the high plasma sodium content observed in DOCA-salt rats to the same levels observed in normotensive control groups. Results obtained in isolated perfused mesenteric arteries showed: a) the increase in perfusion pressure elicited by norepinephrine (NE), serotonin (SE) and vasopressin (VP) was significantly greater in DOCA-salt than in DOCA-salt + Chlor rats or control normotensive rats; b) the endothelium removal increased the pressor responses to NE, SE and VP in a similar way in all groups. These data provide evidence that long-term chlorthalidone treatment reduces vascular hyperresponsiveness to these neurohormones. In addition, these results indicate that this reduction in vascular hyperresponsiveness, associated with a decrease in extracellular sodium level, could be a possible mechanism by which the diuretics reduce the high blood pressure.
Asunto(s)
Clortalidona/farmacología , Hipertensión/tratamiento farmacológico , Resistencia Vascular/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Desoxicorticosterona , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Técnicas In Vitro , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiopatología , Norepinefrina/farmacología , Ratas , Ratas Endogámicas , Serotonina/farmacología , Sodio/sangre , Resistencia Vascular/fisiología , Vasoconstricción/efectos de los fármacos , Vasopresinas/farmacologíaRESUMEN
Hypertension caused by deoxycorticosterone-salt (DOC-salt) may involve enhanced sympathetic tone and some diuretics may exert their antihypertensive action by modulating presynaptic adrenergic sensitivity. This study analyzes the noradrenergic sensitivity of the perfused mesentery isolated from DOC-salt hypertensive rats treated or not with chlorthalidone. Chlorthalidone treatment reduced arterial hypertension in DOC-salt treated rats (from 160 +/- 7 to 127 +/- 5 mmHg). The diuretic completely prevented the increase in sympathetic tone and blunted the decreased vagal tone observed in DOC-salt rats. Norepinephrine-induced vasoconstriction was enhanced in perfused mesenteries isolated from DOC-salt rats. This alteration was attenuated in preparations from chlorthalidone-treated DOC-salt animals. Blockade of neuronal catecholamine uptake using cocaine did not change these responses. These data suggest that chlorthalidone reduces the vascular hyperresponsiveness to catecholamines observed in DOC-salt treated hypertensive rats.
Asunto(s)
Clortalidona/uso terapéutico , Hipertensión/tratamiento farmacológico , Resistencia Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Animales , Desoxicorticosterona , Hipertensión/inducido químicamente , Masculino , Norepinefrina/farmacología , Ratas , Ratas EndogámicasRESUMEN
Hypertension caused by deoxycorticosterone-salt (DOC-salt) may involve enhanced sympathetic tone and some diuretics may exert their antihypertensive action by modulating presynaptic adrenergic sensitivity. This study analyzes the noradrenergic sensitivity of the perfused mesentery isolated from DOC-salt hypertensive rats treated or not with chlorthalidone. Chlorthalidone treatment reduced arterial hypertension in DOC-salt treated rats (from 160 ñ 7 to 127 ñ 5 mmHg). The diuretic completely prevented the increase in sympathetic tone and blunted the decreased vagal tone observed in DOC-salt rats. Norepinephrine-induced vasoconstriction was wnhanced in perfused mesenteries isolated from DOC-salt rats. This alteration was attenuated in preparations from chlorthalidone-treated DOC-salt animals. Blockade of neuronal catecholamine uptake using cocaine did not change these responses. These data suggest that chlorthalidone reduces the vascular hyperresponsiveness to catecholamines observed in DOC-salt treated hypertensive rats