RESUMEN
Endothelium-derived hyperpolarising factor (EDHF) is an important regulator of vascular tone; however, its identity is still unclear. Several different molecules have been suggested, the most recent of which is the 22-amino acid peptide C-type natriuretic peptide (CNP). CNP induces hyperpolarisation and relaxation of rat mesenteric resistance artery vascular smooth muscle through activation of natriuretic peptide receptor subtype C (NPR-C) and the same potassium channels as EDHF. In addition, this peptide is released from endothelial cells of the perfused rat mesenteric bed in response to endothelium-dependent vasodilators. Thus, CNP is likely to play a vital role in regulation of vascular tone. In addition, since there is evidence that up-regulation of EDHF occurs where normal endothelium function has been compromised, modulation of this pathway represents a novel target for therapeutics in the treatment of inflammatory cardiovascular pathologies characterised by endothelial dysfunction.
Asunto(s)
Factores Biológicos/metabolismo , Endotelio Vascular/metabolismo , Péptido Natriurético Tipo-C/metabolismo , Animales , Factores Biológicos/química , Factores Biológicos/farmacología , Enfermedades Cardiovasculares/tratamiento farmacológico , Humanos , Péptido Natriurético Tipo-C/química , Péptido Natriurético Tipo-C/farmacologíaRESUMEN
Endothelial dysfunction is a characteristic of, and may be pathogenic in, inflammatory cardiovascular diseases, including sepsis. The mechanism underlying inflammation-induced endothelial dysfunction may be related to the expression and activity of inducible nitric oxide synthase (iNOS). This possibility was investigated in isolated resistance (mesenteric) and conduit (aorta) arteries taken from lipopolysaccharide (LPS)-treated (12.5 mg/kg i.v.) or saline-treated iNOS knockout (KO) and wild-type (WT) mice. LPS pretreatment (for 15 h, but not 4 h) profoundly suppressed responses to acetylcholine (ACh) and significantly reduced sensitivity to the NO donor spermine-NONOate (SPER-NO) in aorta and mesenteric arteries of WT mice. This effect was temporally associated with iNOS protein expression in both conduit and resistance arteries and with a 10-fold increase in plasma NOx levels. In contrast, no elevation of plasma NOx was observed in LPS-treated iNOS KO animals, and arteries dissected from these animals did not express iNOS or display hyporeactivity to ACh or SPER-NO. The mechanism underlying this phenomenon may be suppression of eNOS expression, as observed in arteries of WT animals, that was absent in arteries of iNOS KO animals. These results clearly demonstrate that iNOS induction plays an integral role in mediation of the endothelial dysfunction associated with sepsis in both resistance and conduit arteries.
Asunto(s)
Arterias/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Lipopolisacáridos/farmacología , Óxido Nítrico Sintasa/genética , Espermina/análogos & derivados , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Acetilcolina/farmacología , Animales , Arterias/metabolismo , Arterias/fisiopatología , Relación Dosis-Respuesta a Droga , Endotelio Vascular/fisiopatología , Genotipo , Técnicas In Vitro , Ratones , Ratones Noqueados , Nitratos/sangre , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Nitritos/sangre , Óxidos de Nitrógeno , Norepinefrina/farmacología , Espermina/farmacología , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
LY 303366, an inhibitor of 1, 3-beta-D-glucan synthase, was tested alone, or in co-culture with neutrophils or monocytes, for antifungal activity against Aspergillus fumigatus using the XTT metabolism assay. LY 303366 at 0.1 mg/L for 48 h significantly inhibited growth by conidia in a microtest plate XTT assay system. Inhibition was similar if the drug was removed after only 24 h. Microscopically this correlated with less growth and stunted malformed hyphae. LY 303366 (0.1 mg/L) also inhibited the further growth of germlings (43%) in a 24 h assay. Antifungal activity of neutrophils against 24 h control hyphal growth was limited at an effector: target ratio of 400:1. In co-cultures of neutrophils plus drug with hyphal growth from 24 h LY 303366 cultures the antifungal activity was additive. Neutrophils had a similar additive effect even if the drug were not present (i.e. when germinating conidia were pretreated with drug). Under conditions where monocytes did not have significant antifungal activity against hyphae, they collaborated with LY 303366 for significantly increased inhibition from 38% by LY 303366 alone to 67% by co-culture. Thus, LY 303366 has activity against germinating or germinated conidia of Aspergillus, human effector cells act co-operatively with LY 303366, and LY 303366 can sensitize germinating conidia for damage by host cells.