RESUMEN
BACKGROUND: We have documented profound release of nitric oxide (NO) and endothelium-derived hyperpolarization factor (EDHF) by angiotensin II (ANGII) receptor 1 (AT1) blocker (ARB) losartan and its unique metabolite EXP3179, a pleiotropic effect that may help rationalize the protective properties of ARBs. Since blood pressure (BP) lowering by ARBs likely require an ANGII-dependent switch from AT1 to ANGII receptor 2 (AT2) signaling, a receptor known to stimulate endothelial NO release, we investigated the contribution of AT1 and AT2 to losartan and EXP3179's endothelial function-activating properties. EXPERIMENTAL APPROACH: Two AT1 ligands were used in an attempt to block the AT1-dependent endothelium-enhancing effects of EXP3179. AT2-null mice were used to evaluate the acute ex vivo and chronic in vivo effects of EXP3179 (20µM) and losartan (0.6 g/l), respectively, on endothelial function, BP and aortic stiffness. KEY RESULTS: Ex vivo blockade of AT1 receptors did not attenuate EXP3179's effects on NO and EDHF-dependent endothelial function activation. We observed significant reductions in PE-induced contractility with EXP3179 in both WT and AT2 knockout (KO) aortic rings. In vivo, a 1-month chronic treatment with losartan did not affect pulse wave velocity (PWV) but decreased PE-induced contraction by 74.9 % in WT (p < 0.0001) and 47.3 % in AT2 KO (p < 0.05). Presence of AT2 was critical to losartan's BP lowering activity. CONCLUSION: In contrast to BP lowering, the endothelial function-enhancing effects of losartan and EXP3179 are mostly independent of the classic ANGII/AT1/AT2 pathway, which sheds light on ARB pleiotropism.
Asunto(s)
Presión Sanguínea , Endotelio Vascular , Losartán , Ratones Noqueados , Receptor de Angiotensina Tipo 2 , Animales , Losartán/farmacología , Presión Sanguínea/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Ratones , Receptor de Angiotensina Tipo 2/metabolismo , Receptor de Angiotensina Tipo 2/genética , Masculino , Óxido Nítrico/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 1/genética , Imidazoles/farmacología , Ratones Endogámicos C57BL , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Rigidez Vascular/efectos de los fármacos , Sulfonamidas , TiofenosRESUMEN
OBJECTIVE: Maxillomandibular advancement (MMA) surgery is considered a highly successful treatment for obstructive sleep apnea (OSA). Various modifications to the technique have been described. We aim to study the long-term results in Asian patients who underwent a modified MMA procedure intended to avoid bimaxillary protrusion and which involved four-quadrant bicuspid extractions with posterior maxillary alveolar setback. METHOD: A review of operative logs from 2000 to 2003 was conducted to identify Asian patients who underwent modified MMA during that period, for treatment of moderate and severe OSA. Sleep indices and psychometric performances were prospectively analyzed. RESULTS: Eight Asian patients were included. The mean length of follow-up was 14.4 years (range: 13.0-16.5). Mean preoperative apnea-hypopnea index (AHI) was 48.9 (range: 19.0 to 84.8). Mean post-operative AHI was 31.6 (range: 6.2 to 79.5). This reduction was statistically significant (p<0.05). Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire (FOSQ) revealed that majority of the patients (75%) did not have excessive daytime somnolence and all patients had high FOSQ totalled scores (mean 17.7, range 11.8 to 20), indicating good functional performance. CONCLUSION: This series is the longest follow-up of an Asian cohort who underwent modified MMA. With a mean follow-up of 14.4 years, improvement in AHI is still observed but not at a degree as large as prior studies with shorter lengths of follow-up. The purported efficacy of MMA for Caucasian patients may not be reproducible in Asian patients and long-term sustainability of this treatment's efficacy requires rigorous evaluation.
Asunto(s)
Avance Mandibular , Apnea Obstructiva del Sueño , Humanos , Avance Mandibular/métodos , Resultado del Tratamiento , Apnea Obstructiva del Sueño/cirugía , Maxilar/cirugía , SueñoRESUMEN
BACKGROUND AND PURPOSE: Losartan is an anti-hypertensive angiotensin II (ANGII) type 1 receptor (AT1R) blocker (ARB) with many unexpected therapeutic properties, even in non-blood pressure (BP)-related diseases. Administered as a prodrug, losartan undergoes serial metabolism into EXP3179, a metabolite alleged to lack AT1R-blocking properties, and EXP3174, the dominant AT1R antagonist. Having observed that losartan can decrease vascular tone in mice with low AT1R expression and inhibit Marfan aortic widening at very high doses, we investigated whether EXP3179 may have unique, AT1R-independent effects on vascular tone and endothelial function. EXPERIMENTAL APPROACH: We compared the AT1R blocking capabilities of EXP3179 and EXP3174 using AT1R-expressing cell lines. Their BP lowering and vasoactive properties were studied in normal, hypertensive and transgenic rodents, and ex vivo wire myography. KEY RESULTS: We observed that both EXP3179 and EXP3174 can fully block (100%) AT1R signaling in vitro and significantly decrease BP in normotensive and spontaneously hypertensive rats. Only EXP3179 prevented PE-induced contraction by up to 65% (p < 0.01) in L-NAME and endothelium removal-sensitive fashion. Use of transgenic mice revealed that these effects involve the eNOS/caveolin-1 axis and the endothelium-dependent hyperpolarization factor (EDHF). CONCLUSION AND IMPLICATIONS: We provide direct structure-activity evidence that EXP3179 is a BP-lowering AT1R blocker with unique endothelial function-enhancing properties not shared with losartan or EXP3174. The major pharmacological effects of losartan in patients are therefore likely more complex than simple blockade of AT1R by EXP3174, which helps rationalize its therapeutic and prophylactic properties, especially at very high doses. Reports relying on EXP3179 as an AT1R-independent losartan analogue may require careful re-evaluation.