Effects of terlipressin and naloxone compared with epinephrine in a rat model of asphyxia-induced cardiac arrest

OBJECTIVE: To evaluate the hemodynamic and metabolic effects of terlipressin and naloxone in cardiac arrest. METHODS: Cardiac arrest in rats was induced by asphyxia and maintained for 3.5 minutes. Animals were then resuscitated and randomized into one of six groups: placebo (n = 7), epinephrine (0.02 mg/kg; n = 7), naloxone (1 mg/kg; n = 7) or terlipressin, of which three different doses were tested: 50 µg/kg (TP50; n = 7), 100 µg/kg (TP100; n = 7) and 150 µg/kg (TP150; n = 7). Hemodynamic variables were measured at baseline and at 10 (T10), 20 (T20), 30 (T30), 45 (T45) and 60 (T60) minutes after cardiac arrest. Arterial blood samples were collected at T10, T30 and T60. RESULTS: The mean arterial pressure values in the TP50 group were higher than those in the epinephrine group at T10 (165 vs. 112 mmHg), T20 (160 vs. 82 mmHg), T30 (143 vs. 66 mmHg), T45 (119 vs. 67 mmHg) and T60 (96 vs. 66.8 mmHg). The blood lactate level was lower in the naloxone group than in the epinephrine group at T10 (5.15 vs. 10.5 mmol/L), T30 (2.57 vs. 5.24 mmol/L) and T60 (2.1 vs. 4.1 mmol/L). CONCLUSIONS: In this rat model of asphyxia-induced cardiac arrest, terlipressin and naloxone were effective vasopressors in cardiopulmonary resuscitation and presented better metabolic profiles than epinephrine. Terlipressin provided better hemodynamic stability than epinephrine. .

Bases moleculares da glomerulopatia diabética / Molecular bases of diabetic nephropathy

O principal determinante da nefropatia diabética é a hiperglicemia, mas hipertensão e fatores genéticos também estão envolvidos. O glomérulo é o foco de lesão, onde proliferação celular mesangial e produção excessiva de matriz extracelular decorrem do aumento da glicose intracelular, por excesso de glicose extracelular e hiperexpressão de GLUT1. Seguem-se aumento do fluxo pela via dos polióis, estresse oxidativo intracelular, produção intracelular aumentada de produtos avançados da glicação não enzimática (AGEs), ativação da via da PKC, aumento da atividade da via das hexosaminas e ativação de TGF-beta1. Altas concentrações de glicose também aumentam angiotensina II (AII) nas células mesangiais por aumento intracelular da atividade da renina (ações intrácrinas, mediando efeitos proliferativos e inflamatórios diretamente). Portanto, glicose e AII exercem efeitos proliferativos celulares e de matriz extracelular nas células mesangiais, utilizando vias de transdução de sinais semelhantes, que levam a aumento de TGF-beta1. Nesse estudo são revisadas as vias que sinalizam os efeitos da glicose e AII nas células mesangiais em causar os eventos-chaves relacionados à gênese da glomerulopatia diabética. As alterações das vias de sinalização implicadas na glomerulopatia, aqui revisadas, suportam dados de estudos observacionais/ensaios clínicos, onde controle metabólico e anti-hipertensivo, especificamente com inibidores do sistema renina-angiotensina, têm-se mostrado importantes - e aditivos - na prevenção do início e progressão da nefropatia. Novas estratégias terapêuticas dirigidas aos eventos intracelulares descritos deverão futuramente promover benefício adicional.

The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra- and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-beta1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-beta1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of diabetic nephropathy. New therapeutic strategies directed to the described intracellular events may give future additional benefits.

Uso de la vasopresina en el estado de choque / Vasopressin Use in Shock

La arginina-vasopresina (VP) también conocida como hormona antidiurética es esencial para mantener el equilibrio hídrico. Su síntesis y liberación depende de la interacción de estímulos osmóticos, hipovolémicos, hormonales y no osmóticos. Se ha demostrado que en estados de choque es fundamental para mantener la homeostasis cardiovascular a través de la regulación del tono vasomotor, el cual determina las resistencias vasculares sistémicas y la presión arterial media, a través de los receptores VI. El estado de choque con vasodilatación refractaria que se presenta en sepsis, respuesta inflamatoria sistémica, hipovolemia, paro cardiaco, politraumatismo, etc... se caracteriza por una fase inicial en la que hay liberación y aumento en los niveles séricos de VP, ésta es seguida por una segunda fase en la que se presentan niveles inapropiadamente bajos de la hormona y éstos se asocian con refractariedad al manejo con volumen, inotrópicos y vasopresores. Se ha demostrado, en estudios experimentales y clínicos, que en esta condición el tratamiento con vasopresina exógena incrementa la resistencia vascular sistémica, la presión de perfusión y el aporte de oxígeno a los tejidos periféricos lo cual hace posible la disminución y suspensión de los vasopresores e incrementa la supervivencia.

Arginine-vasopresin (VP), also known as the antidiuretic hormone, is essential for water homeostasis. Its synthesis and liberation depends on regulation of osmotic, hypovolemic, hormonal, and nonosmotic stimuli. It has been demonstrated that it is key for maintenance of cardiovascular homeostasis through vasomotor regulation, the determinant of systemic vascular resistance and mean arterial pressure, a process acting through VI receptors. Shock state with refractary vasodilation seen in sepsis, systemic inflamatory response, hypovolemia, cardiac arrest, polytrauma, etc., is characterized by an initial phase of liberation and increased levels of VP followed by a second phase caracterized by inappropirately low levels of this hormone that are associated with refractariness to management with volume, inotropics, and vasopressors. It has been demonstrated in clinical and experimental studies that exogenous VP treatment under this condition increases systemic vascular resistance, perfusion pressure, and oxygen supply to peripheral tissues, which makes it possible to decrease and to suspend vasopressors and also to increase survival.