RESUMEN
Aside from respiratory suppression in overdose, full opioid agonist agents are known to cause sleep-disordered breathing (SDB). The increasing rates of opioid overdose in the United States have led to increasing use of medication-assisted treatments for opioid use disorders. Dose-dependent increase in SDB has been documented with methadone. There is emerging literature in the form of case reports providing evidence of buprenorphine and buprenorphine-naloxone contributing to sleep apnea. We report an additional case of a female patient developing central sleep apnea during initiation of buprenorphine-naloxone treatment. The condition resolved with dose reduction.
Asunto(s)
Buprenorfina , Trastornos Relacionados con Opioides , Síndromes de la Apnea del Sueño , Apnea Central del Sueño , Analgésicos Opioides/efectos adversos , Buprenorfina/efectos adversos , Combinación Buprenorfina y Naloxona/uso terapéutico , Reducción Gradual de Medicamentos , Femenino , Humanos , Metadona/uso terapéutico , Naloxona/uso terapéutico , Antagonistas de Narcóticos/efectos adversos , Trastornos Relacionados con Opioides/complicaciones , Trastornos Relacionados con Opioides/diagnóstico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Síndromes de la Apnea del Sueño/inducido químicamente , Síndromes de la Apnea del Sueño/diagnóstico , Apnea Central del Sueño/inducido químicamente , Apnea Central del Sueño/complicaciones , Apnea Central del Sueño/diagnósticoRESUMEN
BACKGROUND: We have previously shown that the thromboxane (TXA2) receptor agonist, U46619, can directly induce ventricular arrhythmias that were associated with increases in intracellular calcium in cardiomyocytes. Since TXA2 is an inflammatory mediator and induces direct calcium changes in cardiomyocytes, we hypothesized that TXA2 released during ischemia or inflammation could also cause cardiac remodeling. METHODS: U46619 (0.1-10 µM) was applied to isolated adult mouse ventricular primary cardiomyocytes, mouse ventricular cardiac muscle strips, and cultured HL-1 cardiomyocytes and markers of hypertrophy and cell death were measured. RESULTS: We found that TXA2 receptors were expressed in ventricular cardiomyocytes and were functional via calcium imaging. U46619 treatment for 24 h did not increase expression of pathological hypertrophy genes (atrial natriuretic peptide, ß-myosin heavy chain, skeletal muscle α-actin) and it did not increase protein synthesis. There was also no increase in cardiomyocyte size after 48 h treatment with U46619 as measured by flow cytometry. However, U46619 (0.1-10 µM) caused a concentration-dependent increase in cardiomyocyte death (trypan blue, MTT assays, visual cell counts and TUNEL stain) after 24 h. Treatment of cells with the TXA2 receptor antagonist SQ29548 and inhibitors of the IP3 pathway, gentamicin and 2-APB, eliminated the increase in cell death induced by U46619. CONCLUSIONS: Our data suggests that TXA2 does not induce cardiac hypertrophy, but does induce cell death that is mediated in part by IP3 signaling pathways. These findings may provide important therapeutic targets for inflammatory-induced cardiac apoptosis that can lead to heart failure.
Asunto(s)
Miocitos Cardíacos/metabolismo , Receptores de Tromboxano A2 y Prostaglandina H2/metabolismo , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Animales , Compuestos de Boro/farmacología , Cardiomegalia , Muerte Celular/efectos de los fármacos , Línea Celular , Células Cultivadas , Gentamicinas/farmacología , Masculino , Ratones , Proteínas Musculares/metabolismo , Miocardio/metabolismo , ARN Mensajero/metabolismo , Receptores de Tromboxano A2 y Prostaglandina H2/genéticaRESUMEN
Fibroblast growth factor 23 (FGF23) is a hormone released primarily by osteocytes that regulates phosphate and vitamin D metabolism. Recent observational studies in humans suggest that circulating FGF23 is independently associated with cardiac hypertrophy and increased mortality, but it is unknown whether FGF23 can directly alter cardiac function. We found that FGF23 significantly increased cardiomyocyte cell size in vitro, the expression of gene markers of cardiac hypertrophy, and total protein content of cardiac muscle. In addition, FGFR1 and FGFR3 mRNA were the most abundantly expressed FGF receptors in cardiomyocytes, and the coreceptor α-klotho was expressed at very low levels. We tested an animal model of chronic kidney disease (Col4a3(-/-) mice) that has elevated serum FGF23. We found elevations in common hypertrophy gene markers in Col4a3(-/-) hearts compared with wild type but did not observe changes in wall thickness or cell size by week 10. However, the Col4a3(-/-) hearts did show reduced fractional shortening (-17%) and ejection fraction (-11%). Acute exposure of primary cardiomyocytes to FGF23 resulted in elevated intracellular Ca(2+) ([Ca(2+)](i); F/F(o) + 86%) which was blocked by verapamil pretreatment. FGF23 also increased ventricular muscle strip contractility (67%), which was inhibited by FGF receptor antagonism. We hypothesize that although FGF23 can acutely increase [Ca(2+)](i), chronically this may lead to decreases in contractile function or stimulate cardiac hypertrophy, as observed with other stress hormones. In conclusion, FGF23 is a novel bone/heart endocrine factor and may be an important mediator of cardiac Ca(2+) regulation and contractile function during chronic kidney disease.