Influences of hypertonic and hypovolemic treatments on vasopressin response in propylthiouracil (PTU) induced hypothyroid rat and effect on supplementation with L-thyroxine.

This study was performed to investigate the effects of L-thyroxine treatment on plasma vasopressin (AVP) levels in rats with hypothyroidism induced by propylthiouracil (PTU). Animals were separated into three groups each having 6 rats: control, PTU, PTU+L-thyroxine groups. Then, the groups were further divided into 3 sub-groups including 6 rats (a; basal, b; hypertonic stimulated and c; hypovolemic stimulated). At the end of the experiments all rats were decapitated in order to obtain plasma samples for analysis in terms of Hct, osmolality, TT 3 , TT 4 and vasopressin. Haematocrit (Hct) levels were the highest in hypovolemic stimulated sub-group (P < 0.001). Osmolality levels were higher in hypertonic stimulated sub-groups (P < 0.001). Total T 3 and T 4 values were the lowest in the PTU group and the highest in the L-thyroxine treated group (P < 0.001). Plasma AVP levels were reduced by hypothyroidism. However, L-thyroxine treatment after the hypothyroidism prevented this reduction (P < 0.001). Vasopressin responses to basal, hypovolemic and hypertonic stimulations were the lowest in the PTU group (P < 0.001). The results of the present study show that basal and stimulated plasma vasopressin levels are reduced in PTU-induced hypothyroidism. However, L-thyroxine treatment following hypothyroidism prevents this reduction.

Efeitos cardiovascular e metabólico da reposição volêmica com hidroxietilamido 130/0, 4 em felinos domésticos com hipovolemia induzida / Cardiovascular and metabolic effects of volemic expansion with hydroxyethyl starch 130/0, 4 in domestic cats with induced hypovolemia

O objetivo deste estudo foi comparar os efeitos da expansão volêmica produzida pelo hidroxietilamido 130/0,4 (HES 130/0,4) ou pelo sangue em gatas com hipovolemia induzida. Foram utilizadas 12 gatas adultas, sem raça definida (SRD), com peso médio de 2,85±0,28kg e hígidas. Os animais foram induzidos à anestesia geral com isofluorano a 5V por cento, intubados e conectados a um sistema sem reinalação de gases. Após a instrumentação, os animais foram mantidos sob anestesia com isoflurano em 1,3V por cento e mantidos em ventilação mecânica, ciclada a pressão. Em seguida, foi induzida a hipovolemia por meio da retirada de 30ml kg-1 de sangue da artéria femoral. Após 60 minutos da estabilização do paciente, os tratamentos foram iniciados. No grupo hidroxietilamido (GH, n=06), os animais receberam, como reposição volêmica, o hidroxietilamido 130/0,4 no mesmo volume de sangue retirado e, no grupo sangue (GS, n=06), os animais receberam o próprio sangue retirado, sendo considerado grupo controle. A pressão arterial sistólica, a diastólica e a média e a pressão venosa central aumentaram após a reposição volêmica em ambos os grupos. Observou-se, para o GH, aumento da PaCO2 no T15, no T30 e no T60. Houve redução do pH no T30 e no T45 e de íons Na+ no T90 para GH. A restauração das pressões arteriais com a administração de HES 130/0,4 foi similar ao grupo controle. A reposição volêmica com HES 130/0,4 produz aumento acentuado da PVC; e o uso do HES 130/0,4 em gatas submetidas à hipovolemia não produziu alterações clinicamente significativas no equilíbrio ácido-básico.

The aim of this study was to compare the volemic expansion effects produced by hydroxyethyl starch 130/0.4 (HES 130/0.4) or blood, in female cats with induced hypovolemia. Twelve healthy adult female cats, crossbreed and weighing an average of 2.85±0.28kg were used. They were induced into general anesthesia with isofluorane at 5V percent, intubated and connected to a non-rebreathing system. After instrumentation, the animals were maintained under anesthesia with isofluorane at 1.3V percent and maintained on pressure cycled mechanic ventilation. Afterwards, hypovolemia was induced by withdrawal of 30ml kg-1 of blood from the femoral artery. After 60 minutes of stabilization of the patient, the treatments were initiated. In the hydroxyethyl starch group (GH, n=06) the animals received hydroxyethyl starch 130/0.4 as volemic expansion at the same volume of blood withdrawed, in the blood group (GS, n=06) the animals received their own withdrawed blood, being considered the control group. The systolic, diastolic and mean arterial pressures and central venous pressure increased after volemic expansion in both groups. An increase of PaCO2 at T15, T30 and T60 in GH was observed. In addition, there was reduction of pH at T30 and T45 and Na+ ions at T90 in GH. The arterial pressure restoration with the use of HES 130/0.4 was similar to the control group; the volemic expansion with HES 130/0,4 produces accentuated increase of CVP; the use of HES 130/0,4 in female cats submitted to hypovolemia did not produce clinically significant alterations in acid-base equilibrium.

Hipokalemia, hipovolemia y repercusión electrocardiográfica secundarias a ingesta prolongada de furosemida: Caso clínico / Hypokalemia, hypovolemia and electrocardiographic changes due to furosemide abuse: Report of one case

Hypokalemia (serum K+ < 3.5 mEq/1) is a potentially serious adverse effect of diuretic ingestión. We report a 27 year-old woman admitted with muscle weakness, a serum potassium of 2.0 mEq/1, metabolic alkalosis and EKG abnormalities simulating cardiac ischemia, that reverted with potassium chloride administration. She admitted high dose furosemide self-medication for edema. Glomerular filtration rate, tubular sodium reabsortion, potassium secretion, the renin-aldosterone system, total body water distribution and capillary permeability, were studied sequentially until 90 days after her admission. There was hyperactivity of the renin-aldosterone axis, reduction in extracellular and intracellular volumes, normal capillary permeability and high sodium tubular reabsorption, probably explained by a "rebound" salt retention associated with her decreased extracellular volume.

[Hypokalemia, hypovolemia and electrocardiographic changes due to furosemide abuse. Report of one case]. / Hipokalemia, hipovolemia y repercusión electrocardiográfica secundarias a ingesta prolongada de furosemida: Caso clínico.

Hypokalemia (serum K+ < 3.5 mEq/1) is a potentially serious adverse effect of diuretic ingestion. We report a 27 year-old woman admitted with muscle weakness, a serum potassium of 2.0 mEq/1, metabolic alkalosis and EKG abnormalities simulating cardiac ischemia, that reverted with potassium chloride administration. She admitted high dose furosemide self-medication for edema. Glomerular filtration rate, tubular sodium reabsorption, potassium secretion, the renin-aldosterone system, total body water distribution and capillary permeability, were studied sequentially until 90 days after her admission. There was hyperactivity of the renin-aldosterone axis, reduction in extracellular and intracellular volumes, normal capillary permeability and high sodium tubular reabsorption, probably explained by a "rebound" salt retention associated with her decreased extracellular volume.

Involvement of anteroventral third ventricular AMPA/kainate receptors in both hyperosmotic and hypovolemic AVP secretion in conscious rats.

The area of the brain called the anteroventral third ventricular region (AV3V) includes three different subtypes of glutamate receptor, as well as neural circuits controlling fluid balance and cardiovascular and neuroendocrine functions. Although our previous data indicate the ability of AV3V N-methyl-d-aspartate (NMDA) and metabotropic receptors to provoke vasopressin (AVP)-releasing, pressor and hyperglycemic responses, the roles of non-NMDA receptors selective for alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainate have not been elucidated to date. To address this question, the effects of intracerebral infusion with FWD or NBQX (specific agonist and antagonist for non-NMDA receptors, respectively) on plasma AVP, glucose, osmolality, electrolytes and cardiovascular parameters were examined in conscious rats in the absence or presence of an osmotic or volemic stimulus. When applied topically to AV3V structures such as the median preoptic nucleus, FWD augmented plasma AVP, osmolality, glucose and arterial pressure in a dose-associated fashion. All responses of the variables were abolished by pre-administering NBQX, which exerted no conspicuous effect on any variable except arterial pressure. It was revealed that NBQX administration in AV3V structures such as the median preoptic nucleus and the periventricular nucleus inhibited the rise of plasma AVP in response to intravenous infusion with hypertonic saline or removal of systemic blood through the femoral artery. Elevation of plasma osmolality and sodium evoked by osmotic load, and elevation of plasma osmolality, glucose and angiotensin II and decrease of arterial pressure caused by bleeding, were not significantly affected by NBQX treatment. These results suggest that AV3V non-NMDA receptors, as well as NMDA receptors, may elicit AVP-releasing, pressor and hyperglycemic actions when stimulated in the basal state, and may facilitate AVP secretion under both hyperosmotic and hypovolemic conditions, without contributing to cardiovascular, blood glucose or other responses.

Activation of renal afferent pathways following furosemide treatment. I. Effects Of survival time and renal denervation.

Three experiments were performed to determine whether renal afferent pathways were activated by the diuretic drug, furosemide. It was hypothesized that activated neurons of the renal afferent pathway would express the protein product Fos of the c-fos immediate early gene and be identified by immunocytochemical staining for Fos in the cell nucleus. In the first two experiments, rats were injected with either furosemide (5 mg) or vehicle solution (sterile isotonic saline) and sacrificed either 1.75 h (short-survival experiment) or 3.5 h (long-survival experiment) after injection. In both experiments, the furosemide-treated rats had significantly more Fos-positive cell nuclei than vehicle-treated rats in the subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT), supraoptic nuclei (SON), and magnocellular region of the paraventricular nuclei (PVN) - areas previously shown to be activated by hypovolemia or peripheral angiotensin. In the short-survival experiment, the furosemide-treated rats had more Fos-positive cell nuclei in the nucleus of the solitary tract (NTS) and in the dorsal horn of the spinal cord at spinal levels T(11), T(12), and T(13). In contrast, furosemide treatment did not produce more Fos-positive cell nuclei in the NTS and dorsal horn of the spinal cord in the long-survival experiment. These results suggest that the activation of the SFO, OVLT, SON and PVN may be via a different mechanism than that of NTS or spinal cord dorsal horn. Based upon our previous work, we hypothesized that the NTS and spinal cord dorsal horn labeling was due to activation of sympathetic afferents originating in the kidney and labeling in forebrain structures was due to stimulation by angiotensin generated by renal renin release. To test this hypothesis, a third experiment was devised that was identical to the short-survival experiment, except that all rats had bilateral renal denervation surgery 1 week previously. In this experiment, furosemide administration increased the number of Fos-positive cells in the SFO, OVLT, SON and PVN, but not in the caudal thoracic spinal cord or NTS. These results together with the results of first two experiments lend support to our hypothesis that furosemide-induced neuronal activation in the thoracic spinal cord and NTS is due to activation of second- and/or third-order neurons of a renal sympathetic afferent pathway. Furosemide-induced activation in the SFO, OVLT, SON and PVN does not depend on renal innervation. It is hypothesized that activation in these forebrain regions depends on the action of angiotensin II that is generated after furosemide treatment. Our results indicate that both a hormonal pathway and a renal sympathetic afferent pathway conduct information from the kidney to the central nervous system (CNS) after furosemide treatment.

Activation of renal afferent pathways following furosemide treatment. II. Effect Of angiotensin blockade.

The goal here and in the accompanying paper was to evaluate the two pathways used by the kidney to provide information to the central nervous system (CNS); e.g., the indirect, hormonal route via activation of the renin-angiotensin system and the direct pathway via activation of sympathetic afferents in the caudal thoracic spinal cord. Here, three experiments were designed to evaluate the actions of angiotensin elicited by subcutaneous injection of furosemide on neural activation of the CNS. The number of neurons immunocytochemically staining for the protein product (Fos) of the c-fos gene was used as an index of neuronal activation. In the first experiment, furosemide injection was preceded by treatment with a dose of Captopril, CAP, (an angiotensin-converting enzyme (ACE) inhibitor) that blocks the peripheral but not the central formation of angiotensin II. In the second experiment, furosemide injection was preceded by treatment with a higher dose of CAP; this dosage blocks the peripheral and central formation of angiotensin II. In the third experiment, furosemide injection was preceded by treatment with Losartan, a competitive receptor antagonist of type I angiotensin II receptors at a dose that would block central and peripheral angiotensin receptors. Control animals in each experiment received injections of vehicle (sterile isotonic saline) instead of furosemide. In each experiment, rats were sacrificed 1.75 h following furosemide or saline injection by transcardial perfusion and tissues were immunocytochemically processed for demonstration of Fos antigen. Rats receiving furosemide plus the low CAP dose showed more Fos-positive cells than control rats in the subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT), supraoptic nucleus (SON), magnocellular region of the paraventricular nucleus, nucleus of the solitary tract (NTS), and caudal thoracic/rostral lumbar spinal cord dorsal horn. Rats receiving furosemide plus Losartan or furosemide plus the higher CAP dose did not show increased Fos immunoreactivity in any of the abovementioned structures relative to their respective control animals. We conclude that the receptor-mediated action of angiotensin II is in some way involved in the activation of the pathway that occurs in the SFO, OVLT, SON, and magnocellular region of the paraventricular nucleus (PVN) in response to furosemide treatment. It is possible that the furosemide-induced activation in the SON and PVN is not due to direct actions of angiotensin II on angiotensin receptors in those structures, but instead occurs synaptically as a result of inputs from the SFO and OVLT, which have themselves been activated directly by angiotensin II. In the accompanying paper, furosemide-induced activation in the NTS and caudal thoracic spinal cord is abolished by prior bilateral renal denervation, meaning that these neurons are likely part of a renal afferent pathway. Here, these structures did not elaborate Fos in animals injected with furosemide plus the high CAP dose or furosemide plus Losartan. Thus, the present results also suggest that the central blockade of the formation of angiotensin II or blockade of the actions of angiotensin II prevents in some way the activation of the renal afferent pathway mediated by the renal nerves (the direct pathway) in response to the actions of furosemide. Therefore, these results suggest that central angiotensin II is somehow involved in "priming" or increasing the sensitivity of the direct renal afferent pathway. Taken together with the accompanying paper, our results indicate that interruption of the direct pathway via renal denervation did not interfere with the elaboration of Fos in the lamina terminalis; in contrast, modification of the humoral renal afferent pathway can affect the sensitivity of the direct pathway. These results may have important implications for pathophysiological changes associated with fluid balance disorders including renal hypertension.