TRPV4 activates autonomic and behavioural warmth-defence responses in Wistar rats.

AIM: In this study, we aimed at investigating the involvement of the warmth-sensitive channel - TRPV4 (in vitro sensitive to temperatures in the range of approx. 24-34 °C) - on the thermoregulatory mechanisms in rats. METHODS: We treated rats with a chemical selective agonist (RN-1747) and two antagonists (RN-1734 and HC-067047) of the TRPV4 channel and measured core body temperature, metabolism, heat loss index and preferred ambient temperature. RESULTS: Our data revealed that chemical activation of TRPV4 channels by topical application of RN-1747 on the skin leads to hypothermia and this effect was blocked by the pre-treatment with the selective antagonist of this channel. Intracerebroventricular treatment with RN-1747 did not cause hypothermia, indicating that the observed response was indeed due to activation of TRPV4 channels in the periphery. Intravenous blockade of this channel with HC-067047 caused an increase in core body temperature at ambient temperature of 26 and 30 °C, but not at 22 and 32 °C. At 26 °C, HC-067047-induced hyperthermia was accompanied by increase in oxygen consumption (an index of thermogenesis), while chemical stimulation of TRPV4 increased tail heat loss, indicating that these two autonomic thermoeffectors in the rat are modulated through TRPV4 channels. Furthermore, rats chemically stimulated with TRPV4 agonist choose colder ambient temperatures and cold-seeking behaviour after thermal stimulation (28-31 °C) was inhibited by TRPV4 antagonist. CONCLUSION: Our results suggest, for the first time, that TRPV4 channel is involved in the recruitment of behavioural and autonomic warmth-defence responses to regulate core body temperature.

[Effect of short-term nonsteroidal antiinflammatory therapy on mean blood pressure. A prospective, randomized clinical trial]. / Efecto del tratamiento a corto plazo con antiinflamatorios no esteroideos en la presión arterial media. Un ensayo clínico aleatorizado.

Our objective was to evaluate the effect of short-term therapy with nonsteroidal antiinflammatory drugs (NSAID) on mean blood pressure (MBP). Two hundred thirty-three consecutive patients (185 women, 54 men; 53.9±13.5 years) requiring NSAID therapy were prospectively randomized to: indomethacin (21 patients), naproxen (33 patients), diclofenac (40 patients), sulindac (42 patients), meloxicam (35 patients) and celecoxib (40 patients) for 8.5±2 days. BP was measured at the beginning and end of follow-up using a Kenz OS22 monitor. At the end of follow-up, 211 (88%) patients were still available for evaluation. A slight posttreatment decrease in MBP (-1.4±9.0 mm Hg, 95%CI: -2.7 to -0.2) was found. No significant differences in posttreatment changes in MBP were found among the distinct NSAIDs evaluated. Fifty-five patients (23%; 95% CI: 18-29) showed a posttreatment increase in MBP of>5 mm Hg. This increase was not associated with hypertension, old age, or any specific NSAID. We conclude that, overall, shortterm NSAID therapy does not seem to have a clinically significant effect on MAP. However, 23% of patients undergoing this therapy showed an increase in MBP that, if persistent, could lead to a higher risk of cardiovascular disease. Further research is needed to identify whether this outcome persists in long-term NSAID therapy.