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Kinsman B, Cowles J, Lay J, Simmonds SS, Browning KN, Stocker SD. Osmoregulatory thirst in mice lacking the transient receptor potential vanilloid type 1 (TRPV1) and/or type 4 (TRPV4) receptor. Recent studies suggest the ability of the central nervous system to detect changes in osmolality is mediated by products of the genes encoding the transient receptor potential vanilloid-1 (TRPV1) or vanilloid-4 (TRPV4) channel. The purpose of the present study was to determine whether deletion of TRPV1 and/or TRPV4 channels altered thirst responses to cellular dehydration in mice. Injection of 0.5 or 1.0 M NaCl produced dose-dependent increases in cumulative water intakes of wild-type (WT), TRPV1 Ϫ/Ϫ , TRPV4 Ϫ/Ϫ , and TRPV1 Ϫ/Ϫ V4 Ϫ/Ϫ mice. However, there were no differences in cumulative water intakes between WT versus any other strain despite similar increases in plasma electrolytes and osmolality. Similar results were observed after injection of hypertonic mannitol. This was a consistent finding regardless of the injection route (intraperitoneal vs. subcutaneous) or timed access to water (delayed vs. immediate). There were also no differences in cumulative intakes across strains after injection of 0.15 M NaCl or during a time-controlled period (no injection). Chronic hypernatremia produced by sole access to 2% NaCl for 48 h also produced similar increases in water intake across strains. In a final set of experiments, subcutaneous injection of 0.5 M NaCl produced similar increases in the number of Fos-positive nuclei within the organum vasculosum of the lamina terminalis and median preoptic nucleus across strains but significantly smaller number in the subfornical organ of WT versus TRPV1 Ϫ/Ϫ V4 Ϫ/Ϫ mice. Collectively, these findings suggest that TRPV1 and/or TRPV4 channels are not the primary mechanism by which the central nervous system responds to cellular dehydration during hypernatremia or hyperosmolality to increase thirst. hypernatremia; water intake; organum vasculosum of the lamina terminalis; subfornical organ; cellular dehydration THE CENTRAL NERVOUS SYSTEM plays a pivotal role in body fluid homeostasis through its ability to sense changes in osmotic pressure and subsequently alter fluid intake, secretion of antidiuretic hormone, natriuresis, and sympathetic nerve activity (5,19,30,42,45,50). Physiologically, changes in extracellular osmotic pressure are typically the result of changes in the extracellular concentration of Na ϩ and/or Cl Ϫ to produce cellular dehydration. The most influential set of osmosensitive neurons is located within the forebrain lamina terminalis (5). This region of the brain contains several structures including two circumventricular organs: the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO). A number of laboratories have demonstrated that acute or chronic hypernatremia increases Fos immunoreactivity in the OVLT and SFO (21,36,40,46). Second, in vivo and in vitro electrophysiological studies have reported that acute hypernatremia or hyperosmolality i...

Surgery and blood transfusions have both been reported to cause decreases in various measures of cell-mediated immunity. A study of in vitro T helper lymphocyte type 2 (Th2) cytokine secretion after major joint replacement surgery was performed because these cytokines (IL4 and IL10) generally down-regulate cellular immune function. Th1 cytokines such as IL2 tend to up-regulate cellular immunity. Forty-three patients undergoing elective joint replacement surgery had pre- and multiple post-operative levels of IL2, IL4 and IL10 secretion measured and analysed with regard to demographic and clinical outcome data. Total joint replacement alone without allogeneic transfusions led to substantial increases in peak mean IL4 (2.1 times the pre-operative level) and IL10 secretion in vitro (4.3-fold) compared with much more modest increases in IL2 (1.36-fold) (P < 0.0001 for changes from baseline for each cytokine). In 14 patients who received allogeneic transfusions, these changes were greater than those in recipients of only autologous blood for IL4 (5.0-fold; P = 0.0036 vs. no allogeneic transfusion) and IL10 (15.7-fold; P = 0.079) but not for IL2 (1.38-fold; P = 0.38). The dramatic increase in Th2 cytokine secretion and minimal change in Th1 cytokine secretion after total joint replacement, with or without allogeneic transfusions, was seen regardless of type of anaesthetic, duration of surgery or whether knee or hip replacement occurred. These changes in cytokine patterns may contribute to the decreases in cellular immune function seen after surgery. Allogeneic transfusions but not autologous transfusions appear to exacerbate this immune deviation toward a T helper 2 (Th2) type response, and thus probably contribute to down-regulation of cellular immunity in the setting of joint replacement surgery.

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